Hemostatic Interventions and All-Cause Mortality in Hemodynamically Unstable Pelvic Fractures: A Systematic Review and Meta-Analysis

Objective To conduct a systematic review and meta-analysis of the all-cause mortality associated with the most commonly used hemostatic treatments in patients with hemodynamically unstable pelvic fractures. Methods Up to April 30, 2023, we searched PubMed, Embase, Web of Science, and Cochrane, including the references to qualified papers. A meta-analysis was performed on studies that reported odds ratios (ORs) or the number of events needed to calculate them. The PROSPERO registration number was CRD42023421137. Results Of the 3452 titles identified in our original search, 29 met our criteria. Extraperitoneal packing (EPP) (OR = 0.626 and 95% CI = 0.413–0.949), external fixation (EF) (OR = 0.649 and 95% CI = 0.518–0.814), and arterial embolism (AE) (OR = 0.459 and 95% CI = 0.291–0.724) were associated with decreased mortality. Resuscitative endovascular balloon occlusion of the aorta (REBOA) (OR = 2.824 and 95% CI = 1.594–5.005) was associated with increased mortality. A random effect model meta-analysis of eight articles showed no difference in mortality between patients with AE and patients with EPP for the initial treatments for controlling blood loss (OR = 0.910 and 95% CI = 0.623–1.328). Conclusion This meta-analysis collectively suggested EF, AE, or EPP as life-saving procedures for patients with hemodynamically unstable pelvic fractures.


Introduction
Pelvic fractures represent 3% of all skeletal injuries and are predominantly observed in young adults [1,2].Tese fractures are highly lethal due to the rapid loss of blood and the severity of associated injuries [3].Patients with these injuries often experience major complications, such as cardiac arrest, infectious diseases, respiratory distress, and venous thromboembolism, which signifcantly contribute to their high mortality rates [4].Various studies have explored the efcacy of hemostatic treatments such as arterial embolism (AE), resuscitative endovascular balloon occlusion of the aorta (REBOA), extraperitoneal packing (EPP), and external fxation (EF) in reducing mortality in patients with hemodynamically unstable pelvic fractures [5][6][7].However, these studies have yielded mixed results, with some reporting signifcant reductions in mortality and others showing limited or no benefts [8][9][10].
Tis inconsistency in the research fndings underscores the need for a systematic review and meta-analysis to assess and synthesize the available evidence.By focusing exclusively on hemodynamically unstable fractures, this study aims to clarify the efectiveness of the mentioned interventions.It systematically searches the literature without language restrictions to include a comprehensive range of studies and uses rigorous meta-analytical techniques to evaluate the impact of these treatments on mortality rates.Tis analysis is crucial for improving clinical decision-making and outcomes in trauma care, particularly in emergency settings where rapid and efective intervention is critical.Te fndings of this meta-analysis are expected to provide valuable insights that could guide the development of treatment protocols and infuence clinical practices worldwide, ultimately improving survival rates and quality of care for victims of severe pelvic trauma.

Materials and Methods
Tis protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023421137.Tis study did not require ethical approval because it used data that were already in the public domain.Te PRISMA checklist is shown in Supplementary 1.
2.1.Search Strategy.Electronic searches were conducted in PubMed, Embase, Web of Science, and Cochrane, utilizing a full list of MeSH headings and text words from prior reviews and search tools in Ovid, PubMed, and Embase.We searched for published articles up to April 30, 2023, with no language restrictions.Supplementary 2 describes the search strategy we utilized.

Study Selection.
All studies that met the following criteria were included: (1) were adult patients; (2) had pelvic fractures caused by blunt pelvic injury; (3) were hemodynamically unstable or in hypovolemic shock when arriving at the emergency department; (4) examined the relationship between hemostatic interventions (AE, REBOA, EF, and EPP) and mortality in hemodynamically unstable pelvic fractures; and (5) provided odds ratios (ORs) and 95% confdence intervals (CIs) or the number of events that can calculate them.Studies that met the abovementioned inclusion criteria were excluded if they also met the following criteria: (1) were duplicate articles or data, (2) were nonhuman studies, (3) were review articles or letters, (4) had insufcient data or information to calculate ORs, or (5) the sample size was less than 20.Based on the predetermined selection criteria, all studies retrieved from the database were assessed independently by two researchers.Additionally, a third investigator resolved disagreements through discussion or consultation.

Data Extraction.
For each eligible study, two reviewers retrieved the following data independently: frst author's name, country, sample size, study design, publication year, demographic factors (e.g., sex and age), outcome (mortality), exposure (e.g., AE, REBOA, PP, and EF), and adjusted odds ratios.Any conficts were settled through consensus.

Methodological Quality Assessment.
Te Newcastle-Ottawa scale (NOS), which is commonly used for assessing the quality of nonrandomized studies in a meta-analysis [11], was used for quality assessment.Te NOS included eight items, which were grouped into the following three categories: (1) study group selection, (2) group comparability, and (3) outcome of interest.A score of 1 was given for each item in each study.High-scoring studies were considered good reports.Two authors evaluated the scores, and any inconsistencies were resolved through discussion between the two evaluating authors.A score greater than 7 suggested that there was a low risk of bias.

Statistical Analysis.
STATA version 17 was used to examine the combined associations by computing pooled odds ratios (ORs) and 95% confdence interval (CI).Te Q test was employed to examine efect size heterogeneity.Te I 2 statistic was used to calculate the fraction of total variance that may be attributed to study heterogeneity [12].Te statistical results ranged from 0% to 100% (I 2 � 0-25% for no heterogeneity, I 2 � 25-50% for mild heterogeneity, I 2 � 50-75% for moderate heterogeneity, and I 2 � 75-100% for large heterogeneity).If there was mild or moderate heterogeneity, the random efects model was utilized, and if there was moderate heterogeneity, a metaregression was performed to investigate the sources of heterogeneity.If there was high heterogeneity, a meta-analysis was not performed.Otherwise, if I 2 was less than 25%, the fxed efects model was utilized.Random efects models are widely used to account for heterogeneity among study results in meta-analyses, while fxed efects models assume that the efect size is constant across all studies.Tese models incorporate a between-study variance component, allowing for more realistic estimates of overall treatment efects [13,14].We also examined for possible publication bias by looking at the funnel plots of the main outcome and using the Egger weighted linear regression test to determine whether the funnel plots were symmetrical [15].Tis test examines the association between the observed efect sizes and their standard errors using a linear regression approach.A signifcant intercept suggests the presence of publication bias [15].If the funnel was asymmetric, a trim-and-fll method was used to assess and compensate for publication bias [16].

Search Results and Study Inclusion Criteria.
Following the initial search, 3440 documents were obtained from four databases, and another 12 records were identifed by reviewing reference citations.We eliminated 1406 studies due to duplication.Ten, 209 papers were omitted because they were reviews or animal trials.After reviewing the titles and abstracts, 1777 articles were eliminated.Sixty studies were downloaded and evaluated for eligibility after reviewing the complete text, and 29 articles were included in this meta-analysis.Te detailed selection process is depicted in Figure 1.[4,18,21,[32][33][34][35][36].Te eight studies showed moderate heterogeneity (50% < I 2 � 63.9% < 75%, p � 0.007).For the eight studies, a random efect was chosen, and AE was found to be a protective factor against death in patients with hemodynamically unstable pelvic fractures (OR � 0.459, 95% CI � 0.291-0.724,p � 0.01) (Figure 2).A symmetric funnel plot was constructed for publication bias (Supplementary 3).Egger's test was also used (p � 0.184), which demonstrated that there was no publication bias in this study.Te heterogeneity may have been produced by the varied criteria for hemodynamic instability; consequently, a meta-regression was chosen to determine the source of heterogeneity.Te regression coefcient of the hemodynamic variables was p � 0.01.Tis revealed that the criterion of hemodynamic instability had a major efect on the efect size and was the source of heterogeneity.Te eight studies were subsequently separated into two subgroups based on diferent hemodynamic instability criteria, namely, the shock group (shock index >1.5)and the BP group (initial BP <90 mmHg).Tere was no intragroup heterogeneity in the shock group (I 2 � 0, p � 0.714) or the BP group (I 2 � 0, p � 0.619), but there was intergroup heterogeneity between the two subgroups (p < 0.01).A subgroup meta-analysis was performed based on the diferent hemodynamic instability criteria.Te pooled data for the shock group revealed that AE was a protective factor against death in patients with hemodynamically unstable pelvic fractures (OR � 0.117, 95% CI � 0.051-0.267,and p < 0.01).Te pooled results for the BP group also revealed that AE was a protective factor against death in patients with hemodynamically unstable pelvic fractures (OR � 0.661, 95% CI � 0.547-0.798,and p < 0.01) (Figure 2).A symmetric funnel plot (Supplementary 3) was constructed from the publication bias test results for the two subgroups.Egger tests were also carried out.Tere was no publication bias in the shock or BP groups (p � 0.339 and p � 0.463, respectively).

REBOA.
Te data were pooled from 6 studies of 5165 patients [4,9,22,24,30,31].Moderate heterogeneity was found among the six studies (50% < I 2 � 67.7% < 75%, p � 0.009).A random efect was selected for the six studies.Te combined results showed that REBOA was a risk factor for mortality in patients with hemodynamically unstable pelvic fractures (OR � 2.824, 95% CI � 1.594-5.005,p < 0.01) (Figure 3).Te publication bias test yielded a symmetric funnel plot (Supplementary 3).Egger's test was also performed (p � 0.911), indicating that there was no publication   bias in this study.We found that three of the six studies reported ORs as efect sizes, and the other three reported dichotomous variable as efect sizes.Te inconsistency of the efect sizes may have caused heterogeneity; thus, a metaregression was selected to determine the source of heterogeneity.Te regression coefcient was p � 0.045, which indicated that the diferent efect sizes were the cause of heterogeneity.Subsequently, the six studies were divided into two subgroups, namely, the OR (reported ORs) group and the dichotomous group (reported dichotomous variable).Te results showed mild intragroup heterogeneity in the OR group (I 2 � 26.8% and p � 0.255) and no intragroup heterogeneity in the dichotomous group (I 2 �13.5% and p � 0.315), but intergroup heterogeneity was found between the two subgroups (p < 0.01).Subgroup meta-analysis was conducted based on the diferent types of efect sizes.For the OR group, the combined results showed that REBOA was a risk factor for mortality in patients with hemodynamically unstable pelvic fractures (OR � 4.009, 95% CI � 2.013-7.987,p < 0.01).For the Dichotomous group, the combined results also showed that REBOA was a risk factor for mortality in patients with hemodynamically unstable pelvic fractures (OR � 1.905, 95% CI � 1.184-3.063,and p < 0.01) (Figure 3).Te publication bias test of the two subgroups showed a symmetric funnel plot (Supplementary 3).Egger's tests were also performed.No publication bias was found for the OR or dichotomous groups (p � 0.96 and p � 0.692, respectively).

EF.
Te data were pooled from 8 studies of 3844 patients [9,[16][17][18][19][20][21][22].No heterogeneity was found among the eight studies (I 2 � 0 and p � 0.577).A fxed efect was selected for the eight studies.Te combined results showed that EF was a protective factor against mortality in patients with hemodynamically unstable pelvic fractures (OR � 0.649, 95% CI � 0.518-0.814,and p < 0.01) (Figure 4).Te publication bias test yielded an asymmetric funnel plot (Supplementary 3).Egger's test was also performed (p � 0.007), indicating publication bias in this study, and a trim-and-fll analysis was needed for bias correction.However, after two iterations, there was no indication of publication with the trim-and-fll method (no new studies were added) (Supplementary 3).

Discussion
A thorough search strategy was implemented to acquire all relevant data.Despite the exclusion of numerous ostensibly pertinent articles from our meta-analysis due to unextractable data or inconsistent study objects, the quantitative fndings of the included articles were generally consistent with the aggregated results.A comprehensive analysis of mortality resulting from hemodynamically unstable pelvic fractures was conducted by examining the AE, EPP, EF, and REBOA.Te direct and dichotomous ORs were included in the derived efect sizes.
External pelvic fxation was recommended as an adjuvant for early bleeding control in hemodynamically unstable pelvic ring ruptures according to the WSES classifcation and guidelines [1].Hu et al. showed that using an external fxator could lower the pelvic volume and blood clots while also putting direct pressure on bleeding arteries to help tamponade work [43].Because the EPP does not work without enough counterpressure from the back of the pelvis, which means that unstable pelvic ring disruptions need to be fxed from the outside, the stable counterpressure that the EF provides is very important for the next step of extraperitoneal packing [44].Furthermore, proper EF can minimize secondary damage during handling.For example, using an external fxator to stabilize the pelvis may prevent recurrent shocks to preexisting occluded arteries [45].
REBOA can be used as a "bridge" procedure in patients with abdominal pelvic or lower limb bleeding before a defnitive operation.Zone 3 (infrarenal) REBOA can be optimal, especially for pelvic bleeding, because it involves a longer occlusion time, increased blood pressure, and reduced arterial bleeding associated with pelvic injury while preventing ischemic insult to visceral organs [46].Several recent investigations, however, have shown that REBOA is related to a signifcant mortality rate in patients with hemodynamically unstable pelvic fractures.Jang et al. demonstrated that REBOA was not a risk factor for bleedingrelated death while also confrming that it was a substantial risk factor for mortality [23].Although REBOA can efectively control bleeding, one of the reasons for the increased mortality may be its consequences.Patients who received REBOA experienced problems such as limb ischemia, iatrogenic aortic dissection, acute renal injury, and rhabdomyolysis [47].Emergency Medicine International Our fndings supported previous research showing that both AE and EPP could reduce mortality in patients with hemodynamically unstable pelvic fractures.According to the WSES guidelines, angioembolization is the best way to stop bleeding in patients whose retroperitoneal pelvic bleeding originates from an artery.Patients who experience hemodynamic instability due to pelvic fractures should be evaluated consistently for preperitoneal pelvic packing, particularly in medical facilities lacking angiography capabilities [1].However, it is uncertain which comes frst.
McDonogh's meta-analysis of data from three studies involving 104 patients with EPP or AE as a primary bleeding control measure revealed no signifcant diference in mortality [11].Despite the addition of fve new trials, the data from eight studies, including 1867 participants in our study, revealed no signifcant diference in mortality.Te need for rapid hemorrhage management in patients with continuous pelvic bleeding is currently undisputed although there is no agreement on a standard approach for treating patients with hemodynamically unstable pelvic fractures.Te three primary sources of hemorrhaging in pelvic fractures are arterial damage, the surface of the fractured bones, and the pelvic venous plexus.Hemorrhaging following pelvic fractures is observed in approximately 90% of the cases involving veins and 10% of the cases involving arteries [48].AE was utilized to control arterial bleeding.Te main drawback of this procedure is its inability to control venous bleeding; hence, if the retroperitoneum perforates the abdominal cavity, delayed severe exsanguination may result.According to Li et al., patients with AE take longer to receive treatment after admission.Delaying embolization can be efective, but it increases the risk of death [37].Tis could be attributed to either pelvic hemorrhaging or an erroneous selection made at the pivotal decision point between abdominal and pelvic hemorrhaging.External pelvic pressure is used to stop venous bleeding by directly pressing on the veins and arteries  Emergency Medicine International in the sacrum.Te retroperitoneum is not breached, and hemostasis is achieved through direct pressure on the sacral plexus of veins and iliac vessels.Te period from diagnosis to surgical intervention was greatly reduced.Identifying the predominant source of pelvic bleeding during the frst resuscitation is difcult.In addition, arterial bleeding accounts for 10-15% of hemorrhages, while the primary causes of bleeding are the posterior pelvic venous plexus or fractured bone surfaces.Terefore, in patients with pelvic fractures who experience unstable hemodynamics, pelvic packing should be prioritized as the initial treatment option.If the patient continues to experience hemodynamic instability even after pelvic packing, it is important to examine the possibility of arterial bleeding, and angiographic embolization may be necessary.
Our fndings suggested external fxation as a frst step in patients with hemodynamically unstable pelvic fractures, with a pelvic bind or sheet as an alternative if no external fxation device is available.If pelvic hemorrhage is suspected, angiography can be used to determine the source of bleeding [49].If the bleeding is of arterial origin, AE should be performed frst; if it is of venous origin, EPP should be performed; if the source of bleeding is undetermined or if the hemorrhage comes from both arteries and veins, EPP should be utilized prior to AE.Although there is no signifcant diference in mortality between which approach comes frst, EPP patients experience shorter preparation times and operation times, which could signifcantly reduce mortality and transfusion requirements in pelvic fracture patients [50].If the patient continues to experience hemodynamic instability even after EPP, an AE should be performed promptly.REBOA was not considered unless extensive abdominal or lower extremity injuries occurred.Nevertheless, the particular hemostatic treatments can difer based on the characteristics and expertise of individual trauma centers.In facilities without access to interventional procedures, EPP emerges as the primary hemostatic intervention for patients experiencing hemodynamically unstable pelvic fractures subsequent to external fxation.
A key strength of this study is its comprehensive and systematic approach, as demonstrated by the extensive database search which included multiple databases like PubMed, Embase, Web of Science, and Cochrane up to April 2023.Te meta-analysis incorporated studies that provided odds ratios or the number of events needed to calculate them, enhancing the reliability of the results.Tis systematic review and meta-analysis efectively synthesized diverse fndings from 29 qualifying studies, applying rigorous metaanalytical techniques to ensure robust conclusions.Tis detailed analysis not only ofers critical insights into the survival benefts of specifc interventions but also supports improved clinical decision-making in trauma care, potentially infuencing treatment protocols worldwide and contributing to better patient outcomes in emergency settings.Tis study, while comprehensive, has several limitations that warrant consideration.First, the included studies exhibit inherent biases due to their predominantly retrospective nature, which could afect the robustness of the fndings.Notably, the heterogeneity observed across studies, as indicated by variable I 2 values, suggests diferences in study populations, intervention techniques, and outcome measures, which might infuence the generalizability of the results.In addition, assumptions made during the metaanalysis, such as the choice of statistical models and the handling of missing data, might also impact the conclusions drawn.Such factors underscore the need for cautious interpretation of the pooled estimates and highlight the necessity for prospective, standardized trials to validate these fndings and potentially guide clinical practice more reliably.Second, changes in follow-up time, which were not consistently reported, may limit the interpretability of the results.However, our fndings were consistent across studies, relevant factors, follow-up durations, and continents, supporting the primary conclusions.Tird, the complications of each measure, including the incidence and severity of complications, were not compared; these complications may have a signifcant impact on mortality in patients with hemodynamically unstable pelvic fractures.Our investigation ultimately identifed publication bias in the analyses of EF and EPP.However, there was no evidence of additional data being included in the trim-and-fll method.Tese two analyses revealed either no heterogeneity or only mild heterogeneity, indicating the reliability of the pooled data.

Conclusion
Tis meta-analysis showed that EF, AE, or EPP, as life-saving procedures, could decrease mortality in patients with hemodynamically unstable pelvic fractures.In light of the fndings, future research should focus on conducting prospective randomized controlled trials to address the limitations observed in retrospective studies and to validate the efectiveness of hemostatic interventions in hemodynamically unstable pelvic fractures.Specifcally, research should aim to standardize intervention protocols and outcome measures, thereby reducing heterogeneity and improving the applicability of results.Emergency and trauma care protocols should integrate these fndings to enhance decision-making processes, potentially improving survival outcomes.By advancing research and refning clinical practices based on solid evidence, healthcare providers can better address the complexities and challenges associated with managing severe pelvic injuries.

Table 1 :
Main characteristics of the included studies.