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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 159-172

An exploratory, hypothesis-generating, meta-analytic study of damage control resuscitation in acute hemorrhagic shock: Examining the behavior of patient morbidity and mortality in the context of plasma-to-packed red blood cell ratios


1 Department of Surgery, St. Luke's University Health Network and St. Luke's Regional Level I Trauma Center, Bethlehem, PA 18015, USA
2 Department of Surgery, Division of Trauma, Critical Care and Burn, The Ohio State University, Columbus, OH 43210, USA
3 Department of Anesthesiology, The Ohio State University, Columbus, OH 43210, USA

Date of Submission02-Jan-2016
Date of Acceptance03-Feb-2016
Date of Web Publication28-Dec-2016

Correspondence Address:
Stanislaw P Stawicki
St. Luke's University Health Network, EW2 Research Administration, 801 Ostrum Street, Bethlehem, PA 18015
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2455-5568.196862

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  Abstract 


Both traumatic and nontraumatic hemorrhagic shock continues to be associated with unacceptably high mortality and morbidity. Although significant progress has been made within the transfusion science in terms of research and subsequent implementation of life-saving massive transfusion protocols, controversies persist regarding the optimal fresh frozen plasma-to-packed red blood cell (FFP-to-PRBC) ratios in the setting of hemorrhagic shock resuscitation, especially in the context of postresuscitation sequelae. To further compound the problem, there continues to be a paucity of prospective and high-quality retrospective data in this important clinical area. The goal of this hypothesis-generating, meta-analytic study was to combine data from all available high-quality literature sources in order to enhance our understanding of the relationship between FFP-to-PRBC ratios and associated morbidity/mortality across the entire reported spectrum of transfusion component combinations. Major findings of this analysis include the significant association between increasing FFP-to-PRBC ratios and decreasing mortality, as well as the concurrent increase in morbidity among survivors. More specifically, mortality odds were significantly lower with “higher” versus “lower” FFP-to-PRBC ratios (odds ratio [OR] 0.569; 95% confidence interval [CI] 0.463–0.700) in a combined cohort of 10,610 patients. At the same time, multi-organ failure was more likely to occur in the “higher” FFP-to-PRBC ratio group (OR 1.417, 95% CI 1.243–1.616). Formal studies that focus on risk-benefit aspects of higher FFP-to-PRBC ratios are needed. Research efforts should be directed at continued mortality reduction following massive transfusion while focusing on strategies designed to minimize the incidence and severity of complications among survivors of hemorrhagic shock. The current study provides a potentially useful platform for planning and implementation of future research efforts in the area of damage control resuscitation.
The following core competencies are addressed in this article: Patient care, practice-based learning and improvement, systems based practice, medical knowledge

Keywords: Blood component therapy, damage control resuscitation, hemorrhagic shock, massive transfusion, morbidity and mortality, traumatic hemorrhage


How to cite this article:
Barry N, Mubang RN, Wojda TR, Evans DC, Sharpe RP, Hoff WS, Thomas P, Cipolla J, Stahl DL, Papadimos TJ, Stawicki SP. An exploratory, hypothesis-generating, meta-analytic study of damage control resuscitation in acute hemorrhagic shock: Examining the behavior of patient morbidity and mortality in the context of plasma-to-packed red blood cell ratios. Int J Acad Med 2016;2:159-72

How to cite this URL:
Barry N, Mubang RN, Wojda TR, Evans DC, Sharpe RP, Hoff WS, Thomas P, Cipolla J, Stahl DL, Papadimos TJ, Stawicki SP. An exploratory, hypothesis-generating, meta-analytic study of damage control resuscitation in acute hemorrhagic shock: Examining the behavior of patient morbidity and mortality in the context of plasma-to-packed red blood cell ratios. Int J Acad Med [serial online] 2016 [cited 2022 Jan 19];2:159-72. Available from: https://www.ijam-web.org/text.asp?2016/2/2/159/196862




  Introduction Top


Significant progress has been made since the late 20th century in our understanding of hemorrhagic shock, its physiologic and molecular consequences, as well as the corresponding adaptive and compensatory mechanisms of the human body.[1],[2] In trauma patients, hemorrhagic shock contributes to early mortality and is a predictor of worse outcomes.[3] Moreover, early posttrauma hypotension is associated with end-organ failure and development of infectious complications.[4] In addition to primary hemostasis, current management of hemorrhagic shock involves large volume packed red blood cell (PRBC) transfusions, which can be associated with multiple organ failure (MOF), longer Intensive Care Unit (ICU) lengths of stay, and increased mortality.[5],[6] Consequently, more effective clinical approaches to acute hemorrhage have emerged during the last two decades.[7],[8] One of the most significant changes in the management of traumatic hemorrhagic shock, particularly in the setting of coagulopathy, has been the introduction of massive transfusion protocols (MTPs).[9],[10]

As massive transfusion science continued to evolve, evidence emerged that certain ratios of blood and blood components (e.g. fresh frozen plasma (FFP), platelets, cryoprecipitate) may be more beneficial to outcome optimization when treating the acutely hemorrhaging patient.[8],[10],[11] Pioneered by the military and major urban trauma centers, the concepts “damage control resuscitation (DCR),”[12] “balanced-ratio massive transfusion,”[13] or “hemostatic resuscitation”[7] have emerged as predominant trends in modern traumatology and transfusion science. For the sake of consistency and uniformity, the authors of the current report will primarily utilize the terms “DCR”[12] and “MTP”.[9],[10]

The concept of “damage control,” both in operative and nonoperative trauma,[14],[15],[16],[17] has taken a new meaning with the advent of modern DCR.[16],[17],[18],[19],[20] Surgical damage control addresses major bleeding, organ injuries, and tissue contamination, whereas the DCR/MTP approach addresses the vicious cycle of hypothermia, acidosis, and coagulopathy (e.g., “the lethal triad”) that arises as a consequence of trauma (or surgical hemorrhage) and the ensuing hemorrhagic shock.[12],[14] In the setting of severe injuries, such as those seen in the military setting, as many as 25–38% of patients experience “the lethal triad” early in their postinjury course – a finding associated with significant morbidity and mortality.[12],[21],[22]

Despite the overall progress, including improved understanding of transfusion-related coagulopathy management, the optimal ratios of blood component therapy are yet to be fully elucidated and understood.[23],[24] Quantitatively optimal administration of various blood components to trauma patients in the acute setting appears to be critically important in mitigating the effects of early postinjury coagulopathy.[22],[25] Although evidence demonstrates that higher FFP-to-PRBC ratios appear to reduce post hemorrhage mortality, the need for further optimization is highlighted as evidenced by reported increases in post-DCR sepsis, MOF, and hospital lengths of stay among survivors.[13],[26],[27] This hypothesis-generating, meta-analytic study examines the effect of transfusion component ratios on patient mortality and morbidity in the context of FFP-to-PRBC ratios utilized during DCR.


  Methods Top


Study justification

An exploratory, hypothesis-generating, meta-analytic study was undertaken by our research team. The need for such study is highlighted by the clinical impact of hemorrhagic shock on posthemorrhagic morbidity and mortality.[28],[29] Vast majority of studies published on DCR and MTP are phenomenological and descriptive in nature; however, important hypothesis-generating evidence can be glimpsed from the available large volume of published, relatively fragmented data.[7],[8],[9],[11],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[36] The current undertaking represents such an attempt. Due to lack of standardized outcome reporting among studies in this clinical area, we opted to both simplify and generalize the exploratory scientific question, as follows: “Following DCR/MTP using “higher” versus “lower” FFP-to-PRBC ratios, as defined and reported by each individual study, did the corresponding patient groups demonstrate any differences in mortality or morbidity?”

Literature search

An exhaustive literature search was performed (Google™ Scholar, PubMed, Bioline International, and Open Access Journals Search Engine), resulting in >1,700 publications on “massive transfusion,” “FFP-to-PRBC ratios,” and “clinical outcomes.” Additional search terms, used in various combinations, included “transfusion,” “MOF,” “hemorrhage,” “trauma,” “blood component,” “blood product(s),” “plasma transfusion,” “therapy,” “damage control,” and “complication(s).” The first two phases of literature screening were performed by the first author (NB) and the senior author (SPS) of this manuscript [Figure 1]. Secondary screening involving 87 studies was performed by the entire author group.
Figure 1: Schematic illustrating literature search performed for the current study

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Out of the >1,700 initial search results, we subsequently excluded reviews, case series and reports, letters to editor, and other low-quality, small-sample studies. The resulting 791 manuscripts were further critically reviewed for methodological suitability and inclusion in the subsequent, more detailed screening. From the resultant group of 87 studies, further reports were excluded for being purely descriptive (e.g. lack of comparison groups), having inadequate methodology and/or reporting, involving nonhuman or nonclinical study design/model, lack of information on FFP-to-PRBC ratios as well as lack of adequate clinical endpoint reporting. The final list included 17 manuscripts of quality sufficient for inclusion in the current meta-analytic exploration [Figure 1] and [Table 1].
Table 1: Descriptive characteristics of studies included in the current meta-analysis: Demographic and blood product ratio stratification information

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Meta-analysis

After abstracting descriptive characteristics of each included study, meta-analytic calculations were performed using OpenMetaAnalyst software by Wallace, Dahabreh, Trikalinos et al. (2014). A random effects model was utilized with mortality as the primary endpoint. Overall, input data quality was low, with significant heterogeneity between studies (I2 = 77%). The primary endpoint of this study was post-DCR mortality as examined according to “higher” versus “lower” FFP-to-PRBC ratios in a combined cohort of 10,610 patients.

Secondary analyses were performed using cumulative, pooled data to determine whether DCR with “higher” versus “lower” FFP-to-PRBC ratios correlates with the development of MOF, infection/sepsis, or respiratory complications. Additional analyses of healthcare resource consumption included the endpoints of hospital length of stay (HLOS), ICU LOS (ILOS), as well as ventilator support duration metrics (when available). The goal here was to determine if there is a link between higher FFP-to-PRBC ratios and increased healthcare resource utilization among surviving patients.

Finally, we examined the relationship between MOF, mortality, and transfusion ratios according to a step-wise stratification of FFP-to-PRBC proportions as abstracted from all source manuscripts. Data from all included studies were reviewed and sorted into predefined FFP-to-PRBC ratio categories (ranges) of ≤0.25, 0.26–0.50, 0.51–0.75, 0.76–1.00, 1.01–1.25, and ≥1.26. Third-order polynomial mortality and MOF model plots were then superimposed across the FFP-to-PRBC measurement range outlined above in order to descriptively characterize the relationship between mortality and MOF.

It is important to emphasize that due to the variability of FFP-to-PRBC ratios in the available literature, our study team decided that for any given report, FFP-to-PRBC ratio would simply be classified as a binary variable (e.g., “higher” versus “lower”), depending on the “effective” component therapy combination(s) employed in each respective comparison group. As a result, our hypothesis would aim to determine the effects of an arbitrary selection (and subsequent MTP group assignment) of “higher” versus “lower” FFP-to-PRBC ratios on our primary and secondary study endpoints. Given the limited amount of data published on the topic of DCR, the use of absolute cut-offs for fixed blood component therapy ratios would severely limit both the final sample size and the ability to perform meaningful secondary analyses. Biases inherent in the current approach are further discussed in the limitations section of this manuscript.


  Results Top


A total of 17 studies were included in this analysis, spanning a period between 2007 and 2015, and including a total of 10,610 patients [Table 1] and [Table 2].[7],[8],[9],[11],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[36] Of those, 4,939 underwent DCR utilizing “higher FFP-to-PRBC ratio” and 5,671 underwent “lower FFP-to-PRBC ratio” DCR. Detailed characteristics of all included reports are presented in [Table 1], [Table 2], [Table 3].
Table 2: Descriptive characteristics of studies included in the current meta-analysis: Key outcome and physiologic parameters

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Table 3: Descriptive characteristics of studies included in the current meta-analysis: Selected complications and secondary outcomes.

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Mortality analysis

The study's primary endpoint, mortality, was reported by all 17 studies included in this analysis.[7],[8],[9],[11],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[36] Overall, the odds of mortality were reduced by more than 43% when study-specific “higher FFP-to-PRBC ratio” was utilized [Figure 2]. Mortality in the combined “higher FFP-to-PRBC group” was 1,338/4,939 (27.1%) while in the “lower FFP-to-PRBC group,” it was 1,960/5,671 (34.6%). The directionality and magnitude of the observed effect suggest that the choice of greater FFP-to-PRBC ratio is associated with lower mortality, regardless of the ratio cut-off value (odds ratio [OR] 0.569, 95% confidence interval [CI] 0.463–0.700, P < 0.001). These results can be classified as having considerable heterogeneity (I2 = 77.29%) despite most studies demonstrating similar directionality of the effect. To further delineate whether certain FFP-to-PRBC ratios may be associated with lower or higher mortality, especially at the extremes of reported FFP-to-PRBC ratio ranges (e.g., <0.50 and >1.25), we performed additional post hoc analyses (see subsequent sections).
Figure 2: The directionality and magnitude of the observed effect suggest that the clinical choice of “greater” fresh frozen plasma-to-packed red blood cell ratio is associated with lower mortality, regardless of the ratio cut-off value (odds ratio 0.569, 95% confidence interval 0.463–0.700, P < 0.001). These results show considerable heterogeneity (I2 = 77.3%) despite most studies demonstrating similar directionality of the effect

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Morbidity analyses

Although very limited in scope, important details can be gleamed by examining pooled morbidity data available from individual source studies. General information regarding complications reported in source manuscripts can be found in [Table 3]. All morbidity categories, along with the associated basic descriptive characteristics and meta-analysis results, are presented in the subsequent sections.

Single-organ failure

Only four studies featured single-organ failure (SOF) [Figure 3] as an unambiguous, separate reporting category.[22],[26],[27],[31] SOF was more likely to occur in the “higher FFP-to-PRBC ratio” DCR group (OR 1.604, 95% CI 1.207–2.131, P < 0.001). More specifically, 1,204/1,888 (63.8%) patients in the “higher FFP-to-PRBC” group developed SOF, compared to 1,770/3,076 (57.5%) patients in the “lower FFP-to-PRBC” group. Heterogeneity of reported results was high (I2 = 71.13%); however, it is difficult to determine the meaning of heterogeneity in such a limited, four-study sample.
Figure 3: Single-organ failure was more likely to occur in the “higher fresh frozen plasma-to-packed red blood cell ratio” damage control resuscitation group (odds ratio 1.604, 95% confidence interval 1.207–2.131, P < 0.001). Heterogeneity of reported results was high (I2 = 71.1%); however, it is difficult to determine the meaning of heterogeneity in a limited four-study sample

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Multi-organ failure

Eight studies reported on the incidence of MOF [Figure 4].[9],[13],[22],[25],[26],[27],[30],[31] MOF was more likely to be reported in the “higher FFP-to-PRBC ratio” DCR group (OR 1.417, 95% CI 1.243–1.616, P < 0.001). In the “higher FFP-to-PRBC” group, 1,478/3,511 (42.1%) patients were reported to have MOF, compared to 1,586/4,095 (38.7%) patients in the “lower FFP-to-PRBC” group. Results in this category were relatively homogeneous (I2 = 18.2%).
Figure 4: Multi-organ failure was more likely to occur in the “higher fresh frozen plasma-to-packed red blood cell ratio” damage control resuscitation group (odds ratio 1.417, 95% confidence interval 1.243–1.616, P < 0.001). Results in this category were relatively homogeneous (I2 = 18.2%)

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Infection/sepsis

Seven studies reported on “sepsis/infection,” which were treated as a composite endpoint in this analysis.[9],[13],[22],[25],[26],[27],[31] In one case, due to lack of reporting on “diagnostic overlap,” we chose to include “sepsis” versus “infection” for the purposes of the current analysis.[25] In this particular category of events [Figure 5], “higher FFP-to-PRBC ratio” was significantly associated with greater odds of infection/sepsis (OR 1.376, 95% CI 1.136–1.667, P < 0.001). For the “higher FFP-to-PRBC ratio” group, 723/3,259 (22.2%) patients developed this endpoint, compared to 746/3,881 (19.2%) patients in the “lower FFP-to-PRBC ratio” group. Observed heterogeneity for this variable was moderate (I2 = 47.4%).
Figure 5: For infection/sepsis, “higher fresh frozen plasma-to-packed red blood cell ratio” was significantly associated with greater incidence of category-specific events (odds ratio 1.376, 95% confidence interval 1.136–1.667, P < 0.001). Heterogeneity for this variable group was moderate (I2 = 47.4%)

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Respiratory complications

This category of clinical events constitutes a composite endpoint that was compiled from a very limited number of reporting sources, with significant definitional differences. Only four studies provided details sufficient for inclusion in the current meta-analytic exploration.[9],[22],[25],[30] There was no significant association between FFP-to-PRBC ratio and cumulative respiratory complications (acute respiratory distress syndrome, acute lung injury, pneumonia) when examining pooled data (OR 1.121, 95% CI 0.487–2.581, P > 0.05, I2 = 81.2%, graph not shown). The “higher FFP-to-PRBC” group registered “respiratory events” in 119/854 (13.9%) cases while the “lower FFP-to-PRBC” group had 149/953 (15.6%) reported events in this category.

Lengths of stay and ventilator support duration metrics

This important set of variables constitutes an indirect reflection of overall patient acuity and the amount of healthcare resources required to address the needs of post-DCR survivors. Higher FFP-to-PRBC ratios were associated with longer hospital and intensive care lengths of stay (HLOS and ILOS, respectively), as well as significantly elevated ventilator support duration metrics.

Hospital length of stay

Seven studies reported on HLOS [Figure 6].[13],[22],[26],[27],[30],[31],[32] Higher FFP-to-PRBC ratios were significantly associated with longer hospital stays (mean difference 4.151 days, 95% CI 0.791–7.511, P = 0.015, I2 = 85.5%).
Figure 6: Higher fresh frozen plasma-to-packed red blood cell ratios were significantly associated with longer hospital stays (mean difference 4.151 days, 95% confidence interval 0.791–7.511, P = 0.015, I2 = 85.6%)

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Intensive care length of stay

For ILOS, results were provided by 8 source studies [Figure 7].[11],[13],[22],[26],[27],[30],[31],[32] Overall, “higher FFP-to-PRBC” ratios were associated with longer ICU stays (mean difference 2.413 days, 95% CI 0.625–4.201, P = 0.008, I2 = 82.4%). Given the high heterogeneity in this result category, any clinical conclusions have to be approached with caution.
Figure 7: Higher fresh frozen plasma-to-packed red blood cell ratios were associated with longer Intensive Care Unit stays (mean difference 2.413 days, 95% confidence interval 0.625–4.201, P = 0.008, I2 = 82.4%). Heterogeneity of the result makes clinically-based conclusions somewhat limited

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Ventilator support duration metrics

Finally, when examining the duration of mechanical ventilation as a reported outcome, seven studies provided data points suitable for inclusion [Figure 8].[13],[22],[26],[27],[30],[31],[32] Overall, patients in the “higher FFP-to-PRBC ratio” group had greater number of “ventilator days” (mean difference 1.943 days, 95% CI 0.533–3.009, P = 0.005, I2 = 77.0%). Again, the high heterogeneity limits the clinical applicability of these results.
Figure 8: Patients in the “higher fresh frozen plasma-to-packed red blood cell ratio” group had greater number of “ventilator days” (mean difference 1.771 days, 95% confidence interval 0.533–3.009, P = 0.005, I2 = 77.0%). Heterogeneity of findings in this category limits their clinical applicability

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Summary of key secondary outcomes

The overall summary of all key secondary outcome parameters, outlining the relationship between “higher” versus “lower” FFP-to-PRBC ratios, is presented in [Figure 9].
Figure 9: Summary of pooled data analyses, by category. Event-specific odds and mean differences are presented as “higher” versus “lower” fresh frozen plasma-to-packed red blood cell ratios (e.g., “higher” ratios were associated with 2.4 days longer ICU LOS compared to “lower” ratios). Data are shown as either odds ratios or mean differences with corresponding 95% confidence intervals. Legend: SOF = single-organ failure; MOF = multi-organ failure; I/S = infection/sepsis; RESP = Respiratory complications; ICU LOS = intensive care unit length of stay; HOSP LOS = hospital length of stay; VENT DAYS = ventilator days

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Synthesis

When pooled mortality data from all studies that reported on this outcome using specified blood product ratios/ranges [7],[8],[9],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[37],[38],[39] are plotted against predetermined FFP-to-PRBC ratio ranges (≤0.25, 0.26–0.50, 0.51–0.75, 0.76–1.00, 1.01–1.25, and ≥1.26), a distinct pattern of mortality emerges. The correlation between the two variables is very high when using the third-order polynomial equation shown in [Figure 10], r2 = 0.964]. This, in turn, corroborates fragmentary evidence from a number of isolated studies supporting the notion that “higher FFP-to-PRBC ratios” in DCR may be associated with lower mortality. Data shown in [Figure 10] also demonstrate a spike in mortality (nearly 54%) at FFP-to-PRBC ratios of ≤0.25, followed by a relatively “stable” intermediate mortality levels (27–35%) for FFP-to-PRBC ratios between 0.25 and 1.00, suggesting no significant added benefit until the ratio of ≥1.26 is reached (mortality of approximately 23%).
Figure 10: Pooled mortality data stratified by fresh frozen plasma-to-packed red blood cell ratios. Mortality exceeds 50% for the lowest fresh frozen plasma-to-packed red blood cell ratios. Conversely, fresh frozen plasma-to-packed red blood cell ratios ≥1.26 are associated with mortality <25%

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When the third-order polynomial model of “FFP-to-PRBC ratio versus mortality” is superimposed on the third-order polynomial representation of “FFP-to-PRBC ratio versus MOF,” an interesting trend/pattern emerges [Figure 11]. More specifically, the two curves display a degree of inverse symmetry. It can be seen in [Figure 11] that at FFP-to-PRBC ratios ≤0.25, the proportion of patients who died far outweighs the proportion of patients who developed MOF. The two trendlines cross at approximately the 0.25 FFP-to-PRBC ratio level and continue towards their respective end-points of minimal mortality and maximum MOF at the FFP-to-PRBC level of ≥1.26. Once could speculate that the graph demonstrates a “trade-off” between “hemorrhage-related mortality” versus “postresuscitation survival with high complication rates.” In fact, many of the differences in secondary outcomes noted between FFP-to-PRBC ratio groups in this study may be explained by the greater proportion of survivors in the “higher FFP-to-PRBC ratio” group. Due to low granularity of our source data, the above observation certainly faces a number of important limitations. Nevertheless, the pattern seems very compelling from the current study's hypothesis-generating perspective.
Figure 11: Relationship between mortality and multi-organ failure, stratified by fresh frozen plasma-to-packed red blood cell ratios. When using increasing fresh frozen plasma-to-packed red blood cell ratios as reference point, the percentage of patients who experience multi-organ failure increases as mortality decreases

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  Discussion Top


Despite significant progress in the understanding and management of hemorrhagic shock, more remains to be learned.[1],[2] From the continued development of increasingly effective clinical management strategies for hemorrhage and hemorrhagic shock emerged the recent paradigm shift toward the use of MTPs, DCR, and blood component therapy strategies.[7],[8],[9],[10],[25] As massive transfusion science evolved over the last 20 years, it became apparent that certain ratios of blood and blood components (e.g., FFP, platelets, cryoprecipitate) during DCR may be more beneficial to outcome optimization in the patient experiencing acute hemorrhage.[8],[10],[11],[25]

While surgical damage control addresses the surgical bleeding, organ injuries and tissue contamination, DCR/MTP helps address the vicious cycle of hypothermia, acidosis, and coagulopathy (e.g., “the lethal triad”) that arises as a consequence of trauma-associated hemorrhagic shock.[12],[14],[15],[16],[17],[18],[19],[20] As previously stated, the primary aim of this hypothesis-generating, meta-analytic study was to revisit the notion that “higher FFP-to-PRBC ratios” are associated with reduced mortality in trauma patients undergoing DCR. Secondary aims of this study included superimposition and better characterization of the survival advantage associated with “higher FFP-to-PRBC ratios” on the concomitant (and largely expected) increases in morbidity and healthcare resource utilization.

Controversy continues around the optimal approach to blood component therapy during DCR in the setting of acute hemorrhage.[34],[40],[41],[42] Although a substantial number of studies show mortality benefit associated with “higher FFP-to-PRBC ratios” (e.g., >0.5:1) approach, methodological deficiencies limit the generalizability of each individual study beyond narrowly defined institutional or study characteristics.[7],[8],[9],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[37],[38],[39] For example, a recently published study randomized patients to either 1:1 or 0.5:1 effective FFP-to-PRBC ratios.[25] The selected ratios, in turn, may have contributed to the lack of statistically significant differences in key outcome metrics (e.g., the current analysis suggests that both 1:1 and 0.5:1 FFP-to-PRBC ratios are on the relatively “flat” portion of the mortality curve – [Figure 10] and [Figure 11]). Furthermore, the survival bias in patients with significant levels of injury severity who underwent protocolized transfusions using high FFP-to-PRBC ratios may be more pronounced than previously appreciated.

If the use of “higher FFP-to-PRBC ratios” indeed reduces mortality, it could be argued that the survivors (and thus beneficiaries) of such a reduction of mortality would be at inherently greater risk of complications related to MTP/DCR, hemorrhagic shock, and other postinjury sequelae, thereby explaining the association of “higher FPP-to-PRBC ratio” with significant morbidity among survivors in the current analysis.[7],[8],[9],[12],[13],[22],[25],[26],[27],[30],[31],[32],[33],[34],[35],[37],[38],[39],[43]

Our meta-analysis supports Borgman et al.'s use of the Trauma Associated Severe Hemorrhage score (>15) in its relation to an FFP-to-PRBC ratio of >1:2 (or > 0.5:1, transfused <5 h from admission), corroborating the higher ratio's association with better survival.[26] Furthermore, a higher FFP-to-PRBC ratio may also result in less supplemental concentrated clotting factor use, which not only provides potential economic savings but also could decrease the incidence of iatrogenic-induced thrombotic events.[26],[44],[45] Moreover, early establishment of the >0.5:1 FFP-to-PRBC ratio seems to reduce the extent of coagulopathy.[40] Most importantly, those involved in trauma care must be cognizant that the amount of coagulation factors replaced, as well as the time delay in replacing such coagulation factors, may affect outcomes.[43] The early use of FFP in the optimal ratio to PRBC is also supported by research on cryoprecipitate and fibrinogen (of which FFP contains nontrivial amounts, especially when multiple units are simultaneously infused).[36],[46],[47]

Our current hypothesis-generating, meta-analytic exploration clearly supports the need for prospective, randomized studies that offer further insight into the relationships between blood product component therapy ratios (FFP, PRBC, platelets, and fibrinogen/cryoprecipitate) in severe hemorrhage and associated clinical outcomes.[25],[48],[49],[50] This is especially important in view of the fact that MTPs are widely used and well accepted by the American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP).[51] When ACS-TQIP analyzed responses to their 2013 cross-sectional survey (62% were Level I and 38% were Level II trauma centers), nearly 70% of sites indicated that they had plasma available immediately for MTP use and that their protocols called for plasma to be given before blood, with “FFP-to-PRBC ratio” targets of >1:2.[51] The trend reported by ACS-TQIP is well supported by recent work that correlated PRBC transfusion volume and mortality during massive transfusion, use of higher FFP-to-PRBC ratios in combat, FFP-to-PRBC coagulation efficacy with the administration of whole blood in a 1:1 ratio, and a large multi-center experience demonstrating that early and balanced FFP-to-PRBC administration improves outcomes.[12],[41],[52],[53]

While we have presented important new findings regarding the concept of “FFP-to-PRBC ratio” in this hypothesis-generating study, we must be cognizant of the fact that other resuscitative blood product components are being administered at varying times during any particular trauma/hemorrhagic shock resuscitation. For instance, what was the platelet-to-FFP ratio in these studies, and what was the start time of FFP or platelets in relation to PRBC administration?[25],[30],[48] The inclusion of such additional information in the current analysis would not be feasible given the inherent limitations of individual source studies. However, this important question needs to be answered with adequate granularity in subsequent studies so that our understanding of the effects of DCR/MTP on hemorrhagic shock outcomes becomes more complete and information thus gained can lead to further reductions in both mortality and morbidity. We hope that the current analysis will provide important insight into the relationship between “FFP-to-PRBC ratios” and clinical outcomes to help guide more optimal study designs in the area of DCR in hemorrhagic shock.

Additionally, what also needs to be accounted for in future studies is the amount of crystalloid or colloid given during the prehospital resuscitation phase;[54] in other words, future research must be able to differentiate if a particular intervention is resuscitative, hemostatic, or both resuscitative and hemostatic. Furthermore, while there may not yet be an optimally effective and agreed upon ratio for FFP-to-PRBC resuscitative protocol, the question arises as to why some institutions do not actually follow their own recommended protocols and deviate from such guidelines.[55] This is especially important since noncompliance with MTPs may impact patientoutcomes. Additional measure that might help facilitate early MTP administration and potentially improve trauma (and hemorrhaging nontrauma) patient survival is the use of simple prehospital criteria that are available to all involved providers so that an “early warning” system is triggered, allowing blood and blood products to be readily available on patient arrival to the emergency department.[56]

There are important limitations to this study and analyses. First, there are undoubtedly biases and heterogeneity within the overall body of the source literature cited. Consequently, the reader should be cautioned not to use the data presented as conclusive, but rather as a hypothesis-generating foundation for further research. Second, the paucity of information regarding specific complications and other secondary endpoints severely limits the authors' ability to quantify the relationship between “FFP-to-PRBC ratios” and such secondary endpoints. Third, some of the smaller sample reports included in this analysis may show an exacerbated treatment effect, thus introducing corresponding biases into our final results. For example, morbidity data reported for surviving study patients may be biased by the baseline mortality characteristics for each corresponding “FFP-to-PRBC ratio.” In other words, morbidity data uncorrected for patient survival or various physiologic/injury confounders may be heavily skewed, depending on the magnitude of inter-variable interactions. Fourth, the relative lack of prospective data in this important area of transfusion medicine has prompted us to utilize high-quality retrospective evidence, which can lead to the transmission of systematic and/or recall biases from individual source reports and ultimately into our results. Fifth, some of the reporting institutions may follow different trauma resuscitation standards and regulatory frameworks, accounting for some of the observed heterogeneity. This is especially relevant in terms of institutional variability regarding time between patient arrival and MTP initiation, which was neither standardized nor universally reported across our source studies. Finally, the current analysis did not examine the effects or parameters associated with important adjuncts used to help guide transfusion therapy during DCR. One such diagnostic modality is the thromboelastography – a tool that can help differentiate and better characterize the nature of exsanguination and massive transfusion-related coagulopathy.[57] In terms of strengths, the current report analyzes cumulative evidence from over 10,600 patients who received massive transfusion. Consequently, it is unlikely that for such a large sample, any of the abovementioned limitations would become prohibitive. Nonetheless, we elected to present our results as purely exploratory and hypothesis-generating in nature, thus setting stage for future multi-center validation efforts that will hopefully confirm observations reported herein.


  Conclusions Top


This hypothesis-generating study supports the general consensus that, in the setting of massive transfusion, the use of “higher FFP-to-PRBC ratios” may result in lower mortality. In addition, the survival benefit of “higher FFP-to-PRBC ratios” may be accompanied by a proportionate increase in complications, ventilator support duration measures, as well as intensive care unit and hospital lengths of stay. Further research is needed in this important area to better define key clinical relationships described herein. The current study provides a potentially useful platform for planning and implementation of future DCR/MTP research efforts.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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