Long-Term Outcomes of Patients Receiving a Massive Transfusion After Trauma

Abstract

Resuscitation of patients presenting with hemorrhagic shock after major trauma has evolved to incorporate multiple strategies to maintain tissue perfusion and oxygenation while managing coagulation disorders. We aimed to study changes across time in long-term outcomes in patients with major trauma. A retrospective observational study in a single major trauma center in Australia was conducted. We included all patients with major trauma and massive blood transfusion within the first 24 h during a 6-year period (from 2006 to 2011). The main outcome measures were Glasgow Outcome Score–Extended (GOSE) and work capacity at 6 and 12 months. There were 5,915 patients with major trauma of which 365 (6.2%; 95% confidence interval [95% CI], 5.6 – 6.8) received a massive transfusion. The proportion of major trauma patients receiving a massive transfusion decreased across time from 8.2% to 4.4% (P < 0.01). There were statistically significant trends toward lower volumes of red blood cell transfusion and higher ratios of fresh-frozen plasma to red blood cells (P < 0.01). Among massively transfused patients, there was no significant change in measured outcomes during the study period, with a persistent 23% mortality in hospital, 52% unfavorable GOSE at 6 months, and 44% unfavorable GOSE at 12 months. Massive transfusion was independently associated with unfavorable outcomes at 6 months after injury (adjusted odds ratio, 1.56; 95% CI, 1.05 – 2.31) but not at 12 months (adjusted odds ratio, 0.85; 95% CI, 0.72 – 1.01). A significant reduction in massive transfusion rates was observed. Unfavorable long-term outcomes among patients receiving a massive transfusion after trauma were frequent with a substantial proportion of survivors experiencing poor functional status 1 year after injury.

INTRODUCTION

The art and science of blood transfusion during trauma resuscitation have changed substantially during the last decade (^1–3). Massive transfusions, regardless of volume, are no longer considered futile, and massive transfusion protocols have improved access to blood and blood products (^4–6). On the other hand, we now understand the myriad of adverse effects associated with blood and blood product transfusion, and moderate such effects through restrictive transfusion practices or preventive measures (⁷). In ideal practice, patients in need of blood transfusion are being delivered blood and appropriate blood products quicker, whereas blood is withheld in those patients where alternate treatment is appropriate.

In addition to this change in patient selection for transfusion after trauma, adjunct management of such patients has also changed. Our understanding of the concepts of acute traumatic coagulopathy has blossomed into the practice of hemostatic resuscitation, where ongoing hemorrhage is managed not by surgery alone but also by appropriate administration of blood products and synthetic agents directed at restoring and maintaining coagulation. We actively seek to avoid less optimal practices associated with poor outcomes such as inadequate coagulation factor administration, hypothermia, and persistent shock leading to metabolic acidosis.

Effects of the above changes in massive transfusion practices have been associated with improved outcomes, but such analyses have been largely limited to survival at 28 to 30 days or hospital discharge (¹). Little is known about the functional status of patients on discharge or the outcome of patients after discharge from acute hospital. Notwithstanding the long-term effects of the severe injury itself, there are many aspects of massive blood transfusion that have been associated with long-term adverse outcomes. There seems to be an association between the administration of blood products and the incidence of multiple organ failure (^{8, 9}). The confounding effect of transfusion as a marker of worse injury continues to be debated. Misidentification of donors, recipients with acute hemolytic transfusion reactions, administration of bacterially contaminated blood products, and transfusion-related acute lung injury are further examples of adverse events that may impact mortality and morbidity beyond hospital discharge (¹⁰). Microchimerism seems to be common among massively transfused trauma patients, but its immunological sequelae, if any, remain inadequately characterized (¹¹).

We aimed to analyze the change in patient characteristics and transfusion practice among major trauma patients who received a massive transfusion. The association between a massive transfusion and unfavorable outcome at 6 and at 12 months was explored. We further aimed to quantify outcomes at hospital discharge and at 6 and at 12 months from injury.

METHODS

Setting

The state of Victoria, Australia, has one pediatric and two adult Major Trauma Services (MTS) located within metropolitan Melbourne. Major trauma triage guidelines direct 85% of major trauma patients to an MTS for definitive treatment. The Alfred Hospital is an MTS in Victoria. During the study period, the Alfred Trauma Registry (ATR) prospectively recorded prehospital and hospital data on all major trauma patients, defined as having an Injury Severity Score (ISS) greater than 15 (using AIS 1998) (¹²), requiring urgent surgery or intensive care unit admission, or dying in hospital.

Participants

Patients included in the ATR, injured between January 1, 2006, and December 31, 2011, and who received a massive transfusion after trauma were included in the study. “Massive transfusion” was defined as the transfusion of five units or more of red blood cells (RBCs) in 4 h since presentation (¹³) or 10 units or more of RBCs in 24 h since presentation to the hospital. In 2008, a massive transfusion protocol was instituted that recommended transfusion of two units of fresh-frozen plasma (FFP) and a pool of platelets with four units of RBCs, cryoprecipitate when fibrinogen count was measured to be less than 1.0 g/L, and consideration to calcium based on the treating clinician.

Data extracted

Data on patient demographics, prehospital and emergency department (ED) vital signs, initial pathology results, body regions injured, and outcomes at hospital discharge were extracted from the ATR. Data on transfused blood and blood products were extracted from The Alfred Hospital pathology database. “Acute traumatic coagulopathy” was defined as an abnormal international normalized ratio (upper limit of normal, 1.3) on arrival to the ED (¹⁴). “Shock Index (SI)” was defined as heart rate divided by systolic blood pressure, and we used an SI ≥ 1 as an indicator of shock (¹⁵).

Six- and 12-month outcome data were extracted from the Victorian State Trauma Registry (VSTR) for eligible patients. The VSTR is a population-based trauma registry capturing data about all major trauma patients in Victoria to enable monitoring and improvement of the state’s trauma system (¹⁶). The VSTR contains data on circumstances of injury, demographics of the patient, admitting hospital and length of stay, ISS, and mortality. Since July 2005, the collection of Glasgow Outcome Score–Extended (GOSE) data at 6 months, and from October 2006, GOSE scores at 12 and 24 months after injury was initiated. For this study, 12-month follow-up data for patients presenting from January to September 2006 were therefore missing and excluded from analysis of 12-month outcome measures. The GOSE is a global measure of function covering a range of domains including social and leisure activities (¹⁷). The GOSE is scored by allocating patients to one of eight categories using a standardized structured interview. These categories are “dead,” “vegetative state,” “lower severe disability,” “upper severe disability,” “lower moderate disability,” “upper moderate disability,” “lower good recovery,” and “upper good recovery” and scored from 1 to 8, respectively. Those without any injury-related disability are assigned to the “upper good recovery” (GOSE, 8) category. A GOSE score of 4 or less is considered an unfavorable outcome (¹⁸). In addition, we extracted from the VSTR preinjury demographics such as patients’ level of education, occupation, and their employment status before injury; work-related disability including whether the patient returned to work and, if so, whether it was to the same employer and role within the organization.

Analysis

All analyses were performed using Intercooled Stata version 11.2 (StataCorp, College Station, Tex). Time periods were grouped into 2-year blocks. The primary outcome measure was the GOSE at 6 and 12 months after injury. Return to work at 6 and 12 months was a secondary outcome measure. Parametric data are presented as mean (SD), and significance for trend across time was analyzed using linear regression. Nonparametric data are presented as median (interquartile range [IQR]), and trends across time are analyzed using a Wilcoxon-type test for trend (¹⁹). Two-sided values of P < 0.05 were considered significant. Missing data were handled using pairwise deletion for each statistical run. Potential variables on presentation to hospital associated with unfavorable outcomes at 6 and at 12 months were evaluated using odds ratios (ORs) and presented with 95% confidence intervals (95% CIs). Variables demonstrating significant univariate association were entered into a logistic regression model to determine if massive transfusion was associated with unfavorable outcomes at 6 and 12 months after injury. Age was categorized into eight groups, and the ISSs were categorized using the Sampalis categories of injury severity—to ISS of 16 to 24 (survivable), ISS of 25 to 49 (probably survivable), and ISS of 50 or higher (nonsurvivable) (²⁰). The study was approved by The Alfred Hospital Research and Ethics Committee.

RESULTS

There were 5,915 major trauma patients entered into ATR during the study period, of which 365 patients (6.2%; 95% CI, 5.6 – 6.8) received a massive transfusion. There was a reduction from 8.2% (95% CI, 7.0 – 9.5) to 4.4% (95% CI, 3.5 – 5.4) in the incidence of a massive transfusion during the 6-year period (P < 0.01; Fig. 1).

Fig. 1: Incidence of massive transfusion.

Demographics and vital signs on presentation to the hospital of patients receiving a massive transfusion are listed in Table 1. There were 33 (9.0%) patients with a penetrating mechanism of injury. There were 182 (49.9%) patients who arrived at the ED by air transport, 172 (47.1%) by road ambulance, and 11 (3.0%) patients presented by private transport. Prenotification was received for most patients (345; 94.5%) and were met by a trauma team on arrival to the ED. A statistically significant trend over time was observed only for systolic blood pressure on presentation (z = -2.2; P = 0.03), whereas no trend could be observed in any other baseline variables (Table 1).

Table 1: Patient demographics and vital signs at hospital admission

Transfusion practice, urgent surgery, and duration of mechanical ventilation are summarized in Table 2. There were decreasing trends during the study period in total volume of RBC units transfused at 4 h (z = -2.3, P = 0.02) and at 24 h (z = -5.5; P < 0.01). Total volumes of FFP administered were similar throughout the study period. The proportion of patients receiving FFP:RBC ratios of 1:2 or greater increased, both at 4 h (z = 4.8; P < 0.01) and at 24 h (z = 5.5; P < 0.01). Cryoprecipitate was administered to 145 (39.7%) patients, with no change in administration volumes across time (z = 1.4; P = 0.20). There was also an increase in the number of patients who underwent urgent surgical or angiographic procedures (z = 3.1; P < 0.01) and a significant decrease in the average time to such procedures (z = -2.1; P = 0.03).

Table 2: Management of patients receiving massive transfusions

Complete data on follow-up at 6 months was available on 324 (88.8%) patients and on 263 (72.1%) patients at 12 months. The association of variables on presentation with unfavorable outcome at 6 months is listed in Table 3. Massive blood transfusion was independently associated with unfavorable outcome at 6 months (P = 0.02) when adjusted for age, sex, presenting vital signs, and injury severity but not at 12 months (P = 0.40) (Table 4).

Table 3: Univariate and adjusted association of variables with unfavorable outcome at 6 months

Table 4: Univariate and adjusted association of variables with unfavorable outcome at 12 months

Follow-up rates and GOSE scores at 6 and 12 months for patients receiving a massive transfusion after trauma are listed in Tables 5 and 6. After hospital discharge, death was uncommon, with four deaths at 12 months, of which one was within 6 months of discharge from the hospital. Vegetative states were also uncommon, with two patients at 6 months and none at 12 months.

Table 5: Outcomes at 6 months among patients who received a massive transfusion after trauma

Table 6: Outcomes at 12 months among patients who received a massive transfusion after trauma

Among 324 patients successfully followed up at 6 months, 152 (46.9%) patients were working or studying before injury; at 6 months, 52 (34.2%) had returned to work, with 39 at the same organization and 37 working in the same role as their preinjury occupation. Among 263 patients successfully followed up at 12 months, 128 (48.7%) patients were working or studying before injury, and 60 (46.9%) of those patients had returned to work, with 44 at the same organization and 41 in the same role.

DISCUSSION

Routine, population-based, long-term follow-up of seriously injured patients is rare, with only a few regions achieving this to date (²¹). Among patients presenting to this adult major trauma center, the rate of unfavorable outcomes at 6 and 12 months after massive transfusion following trauma remains high at about 50%, with a small proportion being able to return to work within 12 months. These results portray a substantially greater burden than the 23% mortality observed at hospital discharge. Outcomes were also substantially worse when compared with all major trauma patients in the state of Victoria who experienced, in 2011, a hospital mortality of 13%, 12-month unfavorable GOSE rate of 25%, and a return-to-work rate at 12 months (among those working before injury) of 65% (²²).

Massive transfusion, independent of injury severity, has been previously associated with adverse outcomes in the hospital (^{23, 24}). We have shown that this association was no longer demonstrable at 12 months after injury. Long-term outcomes and variables associated with unfavorable outcomes were similar to those reported more than 20 years ago (²⁵) despite a significant change in transfusion practice. Such changes included a significant reduction in the median volume of RBCs transfused and, with volumes of FFP transfusion remaining constant, a significantly higher proportion of patients received high ratios of FFP:RBC. Massive transfusion protocols were most likely responsible for the change in practice and, perhaps through early hemostasis, the incidence of massive transfusions was lower (²⁶). A higher proportion of urgent surgery and reduced time to the operating theater were also observed and may have contributed to reduced blood transfusion volumes.

Along with the decreasing incidence of massive transfusions overall, there was a decrease in the total number of RBCs transfused. This may be partially explained by earlier access to emergency surgical or radiological procedures. However, it may also be a reflection of true effectiveness of massive transfusion protocols to induce earlier hemostasis. During the same period, there was a substantial increase in the total number of major trauma presentations across the state of Victoria with similar ISS and a reduction in the risk-adjusted hospital mortality (²²). It is therefore possible that massive transfusion was required only for a “sicker” cohort of patients, with effective adjunct management avoiding the requirement for massive transfusions among others. In support of this hypothesis, a statistically significant trend toward lower presenting systolic blood pressures and higher rates of coagulopathy on presentation was observed but, in rebuttal, no such difference was observed for presenting Shock Index, initial serum lactate levels, or ISS. If existent, such a selection bias could explain worse outcomes relative to improved resuscitation among massively transfused patients in later years.

The result of potential opposing effects of a selection bias toward sicker patients versus improved transfusion practice may explain the lack of any change in short- or longer-term outcome measures. The alternate hypothesis is that poor outcomes were a reflection of injury severity alone, with changes in resuscitative practice insufficient to improve outcomes. The exact reasons for poor outcomes cannot be ascertained from this retrospective review but present opportunities to further explore strategies to improve transfusion practice during trauma resuscitation. The guidance given in massive transfusion protocols continues to be based primarily on retrospective reviews and prospective randomized trials of fluid type and volume, ratios of blood cells and products, synthetic agents, and age of products being delivered are needed.

Although apparent improvements in transfusion practice were observed, retrospective reviews are a poor reflection of the dynamic nature of trauma resuscitation. There continues to be a sequential structure to the delivery and transfusion of blood and blood products. Pre-thawed plasma and plasma products are only available in a small number of centers and generally lag well behind transfusion of packed cells (²⁷). Fibrinogen concentrate replacements are usually performed in reaction to pathology tests that can take up to 60 min. This reactive approach in transfusion practice seems to have been validated by a consistently high proportion of patients with low ratios of blood products at 4 h, with figures improving once clinicians had “caught up” by the 24-h period. Therefore, in addition to the content of massive transfusion protocols, there seems to be room for improvement in the practice of delivery of massive transfusions.

This study is limited in being a retrospective review of data collected by clinical registries and included patients from a single center. However, the registries used have robust governance on data quality and a high rate of capture. A small proportion of patients had missing data on longer-term outcomes but, assuming all missing patients had favorable outcomes, functional status of massively transfused trauma patients would still be poor. There were 73 patients who were not followed up to 12 months in 2006 because 12-month follow-up started in October 2006 (Table 6). It is unlikely that outcomes for these missing patients would have been significantly different to those who were followed up. Generalizability of this study may be limited in trauma systems with different patient populations (e.g., larger proportion of penetrating trauma), different prehospital systems (e.g., shorter transport times, different paramedic training), or different trauma center processes (e.g., availability of blood, blood products, surgical and angiographic services).

CONCLUSIONS

Massive transfusion rates after trauma have reduced significantly. In-hospital mortality was at 23%, and a further 27% of patients had unfavorable outcomes at 6 and 12 months—with little change over time. Long-term outcomes with functional status should be measured and more commonly reported to reflect the actual sequelae of major trauma and massive blood transfusions.

ACKNOWLEDGMENTS

We would like to thank Ms. Louise Niggemeyer for extraction of data from The Alfred Trauma registry. The VSTR is a funded initiative of the Department of Health, Victoria and the TAC. BM is supported by a Early Career Fellowship and BG is supported by a Career development Fellowship from The National Health & Medical Research Council, Commonwealth of Australia.