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Clinical Science Aspects

Effect of Prehospital Red Blood Cell Transfusion on Mortality and Time of Death in Civilian Trauma Patients

Rehn, Marius∗,†,‡; Weaver, Anne∗,§; Brohi, Karim§,||; Eshelby, Sarah; Green, Laura§,||,¶; Røislien, Jo†,‡; Lockey, David J.∗,‡,§,||

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doi: 10.1097/SHK.0000000000001166
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Abstract

BACKGROUND

Hemorrhagic shock is the major preventable cause of death after trauma and carries a considerable mortality even in specialist centers (1). Major bleeding after injury remains a major public health problem with an incidence of 83 per million in the United Kingdom (2). Current management principles include damage control resuscitation strategies that minimize the use of crystalloids and emphasize earlier transfusion therapy to correct acute traumatic coagulopathy and prevent further dilution and consumption coagulopathy (3, 4). The move from crystalloid resuscitation to early blood transfusion resuscitation in recent years in the prehospital setting in civilian practice has mirrored military experience in recent conflicts. However, the current body of evidence supporting such practice is limited, and mostly describes the practicality rather than the effectiveness of the intervention (5, 6). Nevertheless, the concept is clinically logical where the risk of transfusion-related adverse events is minimal (5).

A recent study described an association between prehospital red blood cell (RBC) transfusion (phRTx) and increased 24-h survival (7). Powell et al. found that shorter times to RBC transfusion were associated with decreased risk of death in traumatically injured patients (8). The UK National Institute for Health and Care Excellence guidelines on the management of active bleeding in major trauma recommend using crystalloids only when blood products are not available on scene (9). In 2012, London's Air Ambulance (LAA) became the first UK civilian prehospital service to routinely offer phRTx. The aim of this study was to investigate the effect of phRTx on mortality.

METHODS

Setting

LAA is a prehospital service responding to major trauma victims within the Greater London area consisting of approximately of 5,000 km2 with a population of approximately 8.5 million people. A helicopter emergency medical service (HEMS) paramedic working in the London Ambulance Service emergency operating center targets patients with major trauma and dispatches a doctor–paramedic team by helicopter during daytime and by rapid response cars at night (10, 11). The doctor–paramedic team undertake approximately 2,000 missions per year and operate 24 h a day. The receiving hospitals are four designated major trauma centers in the London trauma network.

Practice

LAA team use basic prehospital criteria to identify patients with major trauma that require early administration of blood products. A standard operating procedure instructs that patients are declared a “Code Red” when there is suspected or confirmed hemorrhage, and systolic blood pressure less than 90 mmHg (at any time). In cases without documented noninvasive blood pressure, patients with central pulse only were assumed to have a systolic blood pressure of 90 mmHg or less (12, 13). Pediatric patients with central pulse only were considered to fulfill the “Code Red” criterion for hypotension.

Before 2012, the “Code Red” declaration involved permissive hypotensive resuscitation using only crystalloids in the prehospital phase. It also triggered a predefined inhospital major hemorrhage protocol, that is, for blood products to be available on arrival in hospital (14, 15). In 2012, blood was supplied for prehospital administration in “Code Red” patients (16). The LAA carries a Golden Hour Box (Pelican BioThermal, Minn) that contains 4 units of O negative RBCs. The boxes can maintain a steady-state temperature of 2°C to 4°C for 48 to 72 h. LAA utilizes a Belmont Buddy lite (Belmont Instrument Corporation, Mass) warming system to prewarm administered blood.

Study design

A retrospective before and after trauma database cohort study was conducted to identify all patients declared “Code Red” by the prehospital team and transported to a major trauma center for resuscitation or pronounced life extinct on-scene due to exsanguination. Patient records were examined by two prehospital clinicians to identify patients who were in prehospital cardiac arrest before the implementation of the phRTx procedure and met the “Code Red” criteria without other nonhemorrhagic lethal injury (e.g., massive head injury). Patients subject to interhospital transfer or with missing outcome data (i.e., survival status) were excluded. We included patients in the 38-month period from January 2009 through February 2012 before and the 35-month period from April 2012 to February 2015 after the introduction of the phRTx procedure. March 2012 was excluded due to possible implementation phase variability of practice.

Data were collected on demographics, incident characteristics, and survival to hospital discharge. Injury Severity Score was not calculated as prehospital deaths are usually not transferred to hospital and will have little or no prehospital or inhospital data (17). Strengthening the reporting of observational studies in epidemiology guidelines was applied (18).

Statistical analysis

Data are presented as numbers (percentages) for dichotomous data and median (quartiles) for continuous data. The unadjusted association between phRTx and mortality for both prehospital and inhospital deaths to investigate effect on time of death was assessed using univariate logistic regression. For further analyses, adjusting for potential confounders multiple logistic regression models was fitted, including age, sex, time from emergency call to emergency services to arrival in emergency department (ED), and dominating mechanism of injury (penetrating versus blunt) as potential confounders. Missing data were 24 (4.5%) for age and 195 (36.2%) times to ED. The latter is considered high, and complete-case analysis is generally not recommended (19, 20). We thus performed multiple imputations using the function mice in the R package mice (21). Regression models were fitted to each of 10 imputed datasets, and results pooled. Comparisons of covariates between prehospital deaths and patients brought to a major trauma center were performed using chi-square tests and Mann–Whitney tests for binary and continuous data, respectively. Statistical significance was assumed at P < 0.05. Data were analyzed using STATA/SE version 11.2 (StataCorp LP) and R 3.2 (22).

RESULTS

During the study period, the prehospital service attended 11,915 patients of which 623 (5.2%) met the criteria for suspected major hemorrhage. We excluded 84 (13.5%) subjects due to missing data on survival status. Descriptors of patients included before and after the implementation of phRTx are recorded in Table 1. LAA transfused a median of 2 (quartiles 1 and 3) units of prehospital RBCs during the study period. LAA provided phRTx to 21 patients below the age of 18. First 24 h, the MTCs transfused a median (quartiles) of 7 (4–12) and 0 (0–5) units of RBC before and after phRTx, respectively. Overall 187 (62.3%) patients died in the before phRTx period and 143 (59.8%) died in the after phRTx group (Fig. 1).

T1
Table 1:
Patients included before and after implementation of phRTx
F1
Fig. 1:
Flow chart of patients before and after implementation of prehospital red blood cell transfusion.

In the unadjusted analysis, there was no significant improvement in overall survival after the introduction of phRTx (P = 0.554). Results were unchanged when adjusting for confounders (Table 2). Examination of prehospital mortality demonstrated 126 (42.2%) deaths in the preblood group and 66 (27.6%) deaths in the blood administered group. There was a significant reduction in prehospital mortality in the group who received blood (P < 0.001) (Fig. 1). The result remained significant when adjusting for confounders in a multiple regression analysis (Table 3).

T2
Table 2:
Logistic regression models with overall death as dependent variable
T3
Table 3:
Logistic regression models with prehospital death as dependent variable

DISCUSSION

This study demonstrates that the introduction of prehospital RBCs for transfusion in trauma patients was associated with decreased prehospital mortality in patients with suspected major hemorrhage. There was, however, no decrease in overall mortality. A recent systematic review on the use of prehospital blood product resuscitation in trauma showed no overall survival benefit, but there was some evidence for improved survival at 24 h (5). The quality of evidence in this review was poor, with only 27 observational studies identified; however, its findings are consistent with our results. It is plausible that early transfusion with RBC may mitigate early hemorrhage/coagulopathy in patients with hemorrhagic shock and avoid the hemodilution seen with aggressive crystalloid resuscitation (23–25), leading thus to improved short-term survival. However, randomized control trials are needed to validate these findings, and one such trial, that is comparing blood transfusion with intravenous fluid in the prehospital setting, is currently recruiting in the United Kingdom (REPHILL) (26).

The present study includes 21 patients under the age of 18 years subject to phRTx, although only 4 were below the age of 10, emphasizing the feasibility of this intervention also for pediatric trauma patients (27). Early fibrinogen substitution is associated with a clinically relevant reduction in volume of RTx in children, indicating a need for studies looking into more balanced transfusion protocols, also in the prehospital phase of care (28).

Furthermore, the availability and administration of blood and blood products may improve survival where other hemostatic prehospital interventions are used, for example, tourniquet application or aortic occlusion with a resuscitative endovascular balloon occlusion of the aorta technique (29). In this study, 4 units of blood were available for transfusion, but only a median of 2 units were administered. This may be related to the short transport times in our trauma system. It is unclear whether mortality might have been influenced more by administration of greater quantities of blood in those patients with high rates of bleeding. Conversely, concerns with potential harm associated with blood transfusion must not be ignored. In addition to transfusion reactions, some studies have shown that increased use of blood components for management of bleeding is independently associated with acute respiratory distress syndrome, multiorgan failure, and immunomodulation which could potentially increase the risk for infections (30–33). However, all these studies have been observational, and one systematic review and meta-analysis concluded that a restrictive RTx strategy compared with a liberal transfusion strategy was not associated with reduced risk for infection (34).

Comparison of future studies is likely to be further complicated by the administration of different types and quantities of blood products in combination with RBCs (e.g., freeze-dried plasma, fresh-frozen plasma, fibrinogen) (35, 36). The use of prehospital transfusion has been developed to improve the mortality of bleeding trauma patients. A secondary benefit of improved survival to hospital, which has recently been raised, is the possibility of increased rates of organ donation which might mitigate the financial burden of prehospital transfusion and improve outcomes in organ recipients (37).

Strengths and limitations

The retrospective observational “before” and “after” design of the present study carries several limitations. The study involved a review of trauma registry data restricted to variables already defined in the trauma registries. Prehospital deaths are usually not transferred to hospital and will have little or no prehospital or inhospital data, thereby limiting matching of cohorts. The patients were managed in four major trauma centers in London, limiting our ability to capture data on injury patterns and hospital interventions. Management of major trauma has evolved in multiple areas over the last decade. Uncontrolled “before” and “after” study design fails to adjust for changes of practice occurring in the study period. Patients that died in the prehospital phase before implementation of phRTx were identified through manual investigation of cases with documented evidence of hypovolemic etiology without catastrophic head injuries and cardiac arrest, to prevent potentially introducing selection bias. The prehospital deaths that occurred after implementation of phRTx were identified through the administration of RBC. This means that any exsanguinating cases that died in the prehospital phase after the introduction of phRTx without transfusion are excluded.

We describe a mixed cohort of patients subject to penetrating and blunt mechanism of injuries. These mechanisms are historically managed differently, with more complex interventions instigated on-scene for patients subject to blunt trauma. Conversely, victims of penetrating injuries are generally more subject to short on-scene times with load-and-go approach which minimize the time available for phRTx. In a prospective observational study, Holcomb et al. were limited in their propensity matching by an imbalance in characteristics between the cohorts with and without blood products on helicopters. They argued that a large, multicenter, randomized study will be required to detect survival differences after phBTx (38). Prospective well-powered studies should also stratify analyses according to mechanism of injury to investigate effect of phRTx on these trauma subpopulations.

CONCLUSIONS

LAA was the first UK civilian prehospital service to routinely carry RBCs for fluid resuscitation of exsanguinating trauma patients. We found that phRTx was associated with increased survival to hospital, but not overall survival. The “delay death” effect of phRTx carries an impetus to further develop inhospital strategies to improve survival in severely bleeding patients. phRTx seems logical and randomized multicenter studies investigating the causal relationship between phRTx and outcome are warranted.

Acknowledgments

The authors thank Mrs. Elizabeth Foster for valuable assistance in managing the HEMS trauma registry.

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Keywords:

Emergency medical service; erythrocyte transfusions; injuries and wounds; mortality; ED; emergency department; HEMS; helicopter emergency medical service; LAA; London's Air Ambulance; MTC; major trauma center; PH; prehospital; phRTx; red blood cell transfusion; RBC; red blood cell

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