No blinded or randomized studies were identified—other than one prospective case series, all were retrospective observational studies. Only two studies provided more than “very low” quality evidence (see Table, Supplementary Digital Content 5, Risk of bias assessments, at http://links.lww.com/SHK/A367). Most comparative studies were limited by differences between groups (injury burden, additional in-transit interventions, or in-hospital treatment) without control by case matching or statistical methods. Common limitations of case series included lack of a clear research question, pooling of trauma and non-trauma patients, small numbers, and lack of robust clinical outcome measures.
An absolute mortality reduction of 11% was reported among battlefield casualties matched by injuries to historical controls from the same facility (40). Acknowledged confounders included limited in-hospital plasma and PRBC transfusions received by both cohorts—75% of non-recipients received no blood products after hospital arrival. Transfusion practice at this facility became more liberal over time (47); reflected in larger in-hospital transfusion volumes received by the later PHBP cohort. Other differences included shorter transport times, more frequent prehospital airway support, more tranexamic acid, and higher in-hospital transfusion ratios (FFP:PRBC 1:1 vs. 0.46:1) among PHBP recipients. Recent data from this facility show a stepwise annual survival improvement at all levels of injury (2), suggesting that comparison with this historical cohort will have introduced significant confounding.
A contemporaneous cohort study of battlefield casualties with major trauma (New Injury Severity Score≥16) treated at the above facility (46) found an independent association between PHBP receipt and mortality in multivariate analysis. However, marked differences in injury mechanisms, wounding patterns, and especially injury burden probably defied statistical correction. These military studies were limited by frequent nonavailability of prehospital vital signs; hence pretransfusion physiological status could not be assessed.
Significant baseline differences are found in two smaller civilian cohort studies (37, 48). The former compared 50 injured prehospital PRBC recipients with nine patients who also received plasma. Indications for plasma transfusion included known pharmaceutical anticoagulation. Plasma recipients had a pretransfusion INR of 2.6 (vs. 1.5 among non-recipients) and this remained higher at hospital arrival. In-hospital treatment also differed; plasma recipients received transfusion ratios closer to 1:1 and less crystalloid. Plasma recipients had a higher Trauma and Injury Severity Score (TRISS)-predicted mortality and over 50% died, despite more aggressive blood product resuscitation. The latter study (in subjects well matched by injury burden) found no survival difference, although PHBP recipients had longer prehospital times (mean 30 min) than non-recipients (mean 12 min) (48). Neither study was adequately powered to detect a mortality difference.
The earliest matched cohort study identified that PHBP recipients received almost four times more prehospital crystalloid, were intubated more frequently, and received 50% more PRBC during in-hospital resuscitation than non-recipients (49). No survival benefit was found. The authors speculated that PHBP “may have compensated for…longer transport times and possibly more gravely injured patients.”
In a matched subgroup analysis prehospital hypotension was more common in PHBP recipients but was less common at hospital arrival (35). However, in a larger study, although prehospital SBP were similar, PHBP recipients were more frequently shocked on arrival (36). The final civilian cohort study identified no difference in haemodynamic changes between PHBP recipients and non-recipients (48). In a case-control study, patients hypothermic at ED arrival were more likely to have received PHBP (57). However, the significance of this is unclear, as crystalloids were warmed before administration whereas PRBC were not (F. M. von Recklinghausen (2015) pers. comm. June 23). Collectively, the published data provide no evidence that PHBP improves physiology compared to crystalloids.
Two overlapping studies report correction of predominantly warfarin-related anticoagulation with prehospital plasma. In a case series of mixed trauma and non-trauma patients, INR reduced from 4 to 2 (38). In a cohort study—whose pooled subjects formed part of that series—greater absolute correction (INR 2.6 to 1.6) was seen in plasma recipients than non-recipients (INR 1.5 to 1.3) (37). However, pharmaceutical anticoagulation is not analogous to trauma-induced coagulopathy (TIC); thus these papers demonstrate only that plasma-mediated reversal of pharmaceutical anticoagulation can be delivered prehospital and should not be extrapolated to suggest a benefit in the treatment of TIC. In blunt trauma patients, PHBP were associated with reduced odds of TIC; however, the PHBP group also received greater volumes of crystalloid (35). The association was not found in the same group's larger study in which both cohorts received comparable crystalloid volumes (36). It is possible that greater crystalloid loading reduced TIC-inducing hypoperfusion. In military data, PHBP receipt was independently associated with TIC (46) but this probably reflects vastly greater tissue disruption in PHBP recipients.
PHBP receipt has been associated with greater acidosis at hospital arrival compared with non-recipients with comparable injury burdens (48). PHBP recipients had mean flight times of 34 min versus 12 min for non-recipients. This provided greater opportunity for PHBP administration, but potentially longer uncontrolled bleeding. In contrast, PHBP receipt was associated with a non-significant trend to lower serum lactate concentration when prehospital times were less than 150 min (58). However, no details of study size or blood products administered were available.
Among 759 PHBP recipients in studies that specifically reported presence or absence of transfusion reactions (12, 14, 25, 36, 38, 55, 59), only three possible reactions were noted. One patient suffered transient shortness of breath after infusion of 5L crystalloid and 900 mL PRBC (12), although this was probably secondary to volume overload, one patient developed a “fine [truncal] rash” following one unit of PRBC (14) and one patient had a reaction during a subsequent in-hospital transfusion (36). These studies suggest that PHBP receipt is associated with a minimal risk of transfusion-related adverse events.
PHBP resuscitation is increasingly employed to try to reduce the 23% mortality among hypotensive trauma patients (44, 45). However, provision of universal PHBP components to all trauma networks involves substantial clinical, logistical, and fiscal costs. In this first systematic review of the topic, we evaluated the clinical evidence around PHBP for trauma. We identified 27 observational studies that reported relevant clinical outcomes. Twenty-six of 27 were retrospective. Twenty-five of 27 provided very poor quality evidence. Common limitations were the lack of a control group or a control group that differed significantly from PHBP recipients. Most comparative studies were too small to permit adjustment for confounders. Studies frequently pooled primary retrievals with secondary transfers, despite these being distinct populations. While PHBP resuscitation is achievable with minimal wastage of universal donor components, and with short-term safety, no more than low-quality evidence supports this as a “standard of care.” This review did not identify an overall survival benefit. Evidence for improved survival at 24 h is derived from only two observational studies and, even if a true effect, may not translate to improved long-term outcomes.
Differences between patients and/or treatment pathways further limited the studies considered in this review. Even when subjects were matched, PHBP recipients received more in-hospital transfusions. Consequently, even where associations between PHBP and improved survival are found after statistical correction, this improvement cannot be confidently attributed to PHBP receipt.
The available clinical data show no evidence that PHBP reduces in-hospital transfusion. This is consistent with recent animal modelling of prehospital resuscitation (60). Although TIC was reduced by blood products in various ratios compared with saline, transfusion requirements over the subsequent 150 min of “hospital” resuscitation were similar in all groups. Similarly, a previous animal model of uncontrolled splenic haemorrhage showed that while Hextend increased blood loss compared with blood products—potentially reflecting the previously reported exacerbation of TIC produced by hetastarches (61)—there was no difference in post-resuscitation blood loss between blood product resuscitation and Hartmann's solution (62). The combination of lyophilized plasma and PRBC in a 1:1 ratio has been shown to reduce total blood loss in a swine polytrauma model compared with both plasma alone and with 1:1 FFP:PRBC resuscitation (63). Short-term survival was not improved by resuscitation with blood products compared with crystalloid. Long-term animal survival studies would be ethically challenging and have not been performed.
As with our findings from the clinical literature, a swine model of PHBP resuscitation did not improve acid–base status. A non-significant trend to less extreme maxima for serum lactate and pH among “haemostatically resuscitated” animals was found; however, there were fewer than 10 animals per group (60). In other animal studies, neither plasma lactate concentration (63) nor acid–base status (62) has been influenced by different blood product ratios. Any metabolic benefit from PHBP remains uncertain.
The searches for this review were not restricted by language nor by date and included all major citation databases, specialist resources, and reference lists from included studies. It is unlikely that material that would significantly change the findings has been overlooked.
The most significant weakness of the study is the low quality of evidence on which the review could draw. Consequently, no conclusions about the efficacy of PHBP resuscitation can be drawn. The extent to which this review makes use of “gray literature” reflects the poor state of evidence in this area. This material has not been subjected to the same degree of peer review as that in published papers, but is nonetheless recognized as being an essential component of a systematic review (64).
These considerations limited the possible statistical syntheses to unadjusted mortality alone, with no indication identified of improved long-term survival after PHBP receipt. However, the marked differences between the populations in included studies render this finding tenuous. These difficulties are consistent with previous reviews of blood product resuscitation for trauma (65, 66). Meta-analysis produces not only an estimate of overall effect size, but a measure of heterogeneity from which the consistency of the literature can be assessed. In meta-analysis of both unmatched and matched studies, heterogeneity was present and significant, demonstrating the degree of uncertainty that exists about a measurable benefit of PHBP resuscitation.
This review considered both military and civilian studies. The validity of extrapolating from studies of predominantly younger, massively traumatized males to the civilian population is questionable. However, the inclusion of military case series illustrates the marked change in resuscitation practice over the last decade and thus further factors that must be considered when interpreting the existing literature. Transfusion criteria used by the Israeli military initially required 2L crystalloid administration prior to administration of PRBC, with casualties receiving an average of 4.4L of prehospital crystalloid (14). Lyophilized plasma has now replaced crystalloid in Israeli retrieval missions (67), such that “crystalloid infusion was minimized” (15). Similar practices have been adopted by the UK military, with casualties retrieved by MERT(E) in Afghanistan receiving up to 4u PRBC and 4u plasma (41) with crystalloid minimized (3). This is borne out in data examined in this review (46). In contrast, civilian studies continue to include failure to respond to 2L intravenous crystalloid as an indication for PHBP. This is despite good quality evidence that aggressive clear fluid administration increases mortality and morbidity after penetrating trauma (68). Prehospital cannulation (as a surrogate for fluid administration) was associated with greater mortality in every patient subgroup examined in a registry study, other than those with Injury Severity Scores <9 (69), while more than 1L of prehospital fluid has been shown to be an independent risk factor for death in patients without severe traumatic brain injury (70). High ratios of crystalloid to PRBC given in-hospital increase morbidity (71). Whether PHBP are associated with similar volume effects is unknown. It is possible that the negative impact of crystalloid loading prior to PHBP administration has masked benefit from PHBP in many studies to date.
Very few PHBP-related adverse events were identified, implying transfusion safety. However, blood transfusions suppress the immune system and are associated with a stepwise increase in infectious complications for each unit of PRBC transfused, starting with single-unit transfusions (72). Similarly, a dose–response relationship exists between transfusion and development of multi-organ failure (73). This is a concern given the frequency with which patients in this review received PHBP but little or no in-hospital transfusion, calling into question their need for PHBP transfusion. No study in this review associated PHBP with reduced in-hospital transfusion. However, if administered inappropriately liberally, PHBP may lead to excess morbidity.
To address these various questions, four randomized clinical trials and one cohort study comparing various combinations of blood products and crystalloid are underway (see Table, Supplementary Digital Content 6, ongoing studies, at http://links.lww.com/SHK/A368). If PHBP trauma resuscitation is beneficial, universal provision should be advocated. However, robust evidence is required to justify the clinical, logistical, and financial costs of making PHBP “standard care.” This review demonstrates the lack of such evidence and makes ongoing support for these studies imperative.
Military and expedition settings require the consideration of factors specific to austere environments. Although evacuation times in recent operations have typically been short, future conflicts may require prolonged pre-evacuation field and en-route care. These timelines may necessitate PHBP support. Data collection on future operations will be essential to establish the place of PHBP in “Remote Damage Control Resuscitation.”
The literature reporting PHBP for trauma resuscitation is contradictory and provides only poor-quality evidence. Evidence-based conclusions to guide practice cannot be drawn. While PHBP resuscitation appears logical the potential harms of this practice must be recognized. More rigorous evidence of benefit is required to justify universal adoption. Whether PHBPs improve survival despite these competing risks is unknown. The only satisfactory way to answer this outstanding question of benefit from PHBP-based resuscitation for major traumatic haemorrhage is by randomized controlled trials.
The authors thank the following for assistance with retrieval and translation of non-English language literature: Lt Cdr Timothy Castrinoyannakis Royal Navy, Capt Viktor Reva, Army of the Russian Federation, Dr Robert Helling, University of Munich, and Mrs Alison Smith. Dr Jon Bishop, University of Birmingham, is thanked for statistical advice.
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