a b s t r a c t

Background: The mortality rate of patients with hemodynamic instability due to severe pelvic fracture remains substantial and massive transfusion happens frequently. Angio-embolization, external fixation and preperitoneal pelvic packing of the pelvis are the main managements used to control bleeding in these patients. In this paper, we aimed at characterizing the rationale of these surgical managements, and placed them in optimal manage- ment algorithm to compose a new guideline.

Methods: We selected controlled trials, assessing safety of management for the intervention of hemorrhagic shock from mortality data, and assessing efficacy from volume of first 24 h blood transfusion following hospital- ization. Six single and combined managements were extracted as comparison. A pairwise meta-analysis was con- ducted using a random effect model, and then the analysis was extended to a Network meta-analysis. Pooled effect sizes were ranked and demonstrated the probability of being the best treatments for safety and efficacy. Results: 13 clinical trials and 24,396 participants were identified for this analysis. The assessment of rank proba- bility indicated that pelvic packing presented the greatest likelihood of improving safety, while external fixation was indicated most efficient among the interventions for controlling hemorrhage.

Conclusions: Clinical protocols for guidelines of hemodynamically unstable pelvic fracture patients have been multidirectionally developed. We strongly support the initial application of an external fixator. Provided that pa- tients remain hemodynamically unstable after application of an external fixation, pelvic packing is the next proce- dure to consider. Angio-embolization is the complementary but not alternative method of choice subsequently.

(C) 2018

Introduction

pelvic fractures account for approximately 3% of skeletal injuries, and the associated mortality rates range between 8% and 16% [1]. In patients with pelvic fracture, uncontrollable bleeding is the most common cause of death within the first 24 h after injury [2]. Therefore, early Hemorrhage control is vital for successful treatment. Treatment for bleeding pelvic fractures involves pelvic stabilization (i.e., pelvic binders, a bed sheet, and medical antishock trousers) and invasive procedures, such as angio- embolization (AE), external fixation/fixator (EXFIX), or preperitoneal/ret- roperitoneal pelvic packing (PPP) [3]. Despite these available options, high mortality and massive transfusions continue to occur in cases of he- modynamically unstable pelvic fractures and lead to a need for advanced protocols, including various treatment sequences [3].

The appropriate processes for emergency management of patients with multiple injuries as well as pelvic ring disruption and severe

* Corresponding author.

E-mail address: [email protected] (J. Zhao).

¹ These authors contributed equally to this work and should be considered as co-first authors.

hemorrhage are still being debated, and stabilization of the pelvic ring is mostly considered the best procedure choice and sequence for initial management [4]. Immediate skeletal external fixation, including a non- invasive pelvic binder is available in routine early emergency aid. The application of external pelvic fixators or C-clamps is a quick and mini- mally invasive procedure that produces a ‘tamponade effect’ of the pel- vis and is often exclusively used for control of hemorrhage. This may partially explain the good hemostatic efficiency of mechanical stabiliza- tion that is unanimously recommended in the modern literature [5]. However, experience shows that in stressful circumstances involving severe hemodynamic instability, clinicians did not always agree about which procedure should have priority, despite a growing amount of lit- erature supporting the application of skeletal fixation prior to any lapa- rotomy or peritoneal lavage or angiographic procedure [4].

Angio-embolization, on the other hand, has high effectiveness for Bleeding control but requires an angiography suite and technical staff [5]. When hemoperitoneum are hard to control with packing receiving emergency laparotomy, 11% of these patients are arterial bleedings, and subsequent angio-embolization is required [6]. The technique to directly address primary pelvic venous and bone hemorrhage through direct packing of the pelvis using a preperitoneal approach has been

https://doi.org/10.1016/j.ajem.2018.06.027

0735-6757/(C) 2018

advocated by several European groups [6]. Thus, pre-peritoneal and later refined retroperitoneal pelvic packing reduces the need for angiography, decreases Blood transfusion requirements, and lowers mortality [7].

Despite using a multidisciplinary treatment approach to determine how frequently the three most commonly used techniques, including AE, EXFIX, and PPP, are selected, the clinical importance among them for hemodynamically unstable pelvic fractures remains unclear. Even though many authors see a single procedure as beneficial, an optimized sequence is crucial in a multitrauma setting and severely injured hem- orrhagic shock patients do not tolerate multiple interventions well [8]. Until now, good predictors for treatment choice have been unavailable, and management of hemodynamically unstable pelvic fractures re- mains a matter of debate.

The system review/meta-analysis of direct comparison has been car- ried out strictly and recognized as the highest Level of evidence to eval- uate the efficacy of interventions.

When there is a lack of direct research evidence, a comparison of

common control measures can be made. Thus direct evidence is com- bined with indirect evidence to increase the credibility of evidence. Pro- vided that the best treatment is chosen from many interventions, the advanced meta-analysis is needed to compare various interventions, namely reticulation network meta-analysis (NMA). NMA is an exten- sion of traditional meta-analysis and can compare the efficacy of three or more interventions from quantitative comparison of similar disease at the same time, and then choose the Optimal treatment plan.

In this study, we report on a NMA in which three or more surgical procedures for hemorrhagic shock control in pelvic fractures were com- pared in terms of mortality and early blood transfusion in adult patients. The aim of this study was to identify a preferable treatment sequence and determine the safety and efficacy of this approach for hemodynam- ically unstable pelvic fractures.

Methods

Identification of trials

In preparation for this network meta-analysis, we drafted a study protocol and published it on the PROSPERO website (CRD42018084484). Clinical trials comparing at least two different treatments were searched in MEDLINE (1950 to January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 8, 2017), and EMBASE (1974 to January 2017) with the following search terms: “pelvic fracture” or “pelvic trauma“; and “hemodynamic instability” or “hemodynamic unstable” or “hemorrhage” or “bleeding”; and “pelvic packing” or “angiography” or “angiography embolisation” or “angio-embolisation” or “external fixation” or “C-clamp”. The search results were restricted to articles reporting studies involving adults. Two investigators within the reviewing team independently screened the titles and abstracts re- trieved from the searches. Additionally, the reference lists of all included publications and relevant reviews were screened, and ClinicalTrials.gov was searched for trials in progress. Criteria in PICOS were described as follows: Population (P) with adult pelvic fracture patients diagnosed with hemodynamic instability; Interventions (I) and Comparisons

(C) with AE, EXFIX, PPP and combinations of those techniques; Out- comes (O) with in-hospital mortality and first 24 h blood transfusion; and Study design (S) with Clinical trials.

Selection criteria

Clinical trials in which adults suffering from pelvic fractures with hemodynamic instability were the subjects and comprehensive comparisons of any of the following surgical procedures were included: AE, EXFIX, PPP and combinations of those techniques. Hemodynamic in- stability was defined as acute hemorrhagic shock (i.e., systolic blood pres- sure <=90 mmHg or heart rate N120 beats per minute or estimated blood

loss N1500 mL (>=30%)). Trials specifically involving paediatric and geriat- ric patients were excluded. Trials for which only abstracts were published (with no additional data available from other sources) and articles pub- lished in a language other than English were also excluded.

Data extraction

The primary safety outcome was the in-hospital mortality. The pri- mary efficacy outcome was the amount of blood transfusion (Units) during the first 24 h after admission, whether the transfusion occurred in the emergency room or hospital. Records of other elements of fluid resuscitation, except for red blood cells were ignored. Two investigators reviewed all of the abstracts and references, evaluated the integrity of the data abstraction, and rated the quality of included studies indepen- dently. Any disagreement was settled by discussion and a consensus was reached for all data. methodological quality and risk of bias were assessed with the Cochrane handbook (version 5.1).

Data synthesis and statistical analysis

All data analyses were conducted in Stata, version 14.0 software (Stata Corp, USA). First, the number of deaths and corresponding total number of participants in each treatment arm were extracted from the in- cluded studies and used to calculate the outcome measure of treatment safety as odds ratio (OR) and corresponding 95% confidence intervals (CIs), while effect size of efficacy was measured as mean difference (MD) accordantly. Second, we conducted a network meta-analysis for safety analysis within a frequentist framework using the Stata network suite. A safety analysis on mortality (dichotomous data) was conducted with a standard contrast-based model, whereas an adjusted indirect treatment comparison model was adopted for efficacy analysis. A multi- variate random-effects meta-analysis (mvmeta and network command) was performed with the assumption that heterogeneity variance was consistent across all treatment contrasts. P b 0.05 was considered statisti- cally significant. We looked at a plausible range for population difference magnitude. The contribution plot was conducted with the ‘netweight’ command to display the proportion of direct comparisons in the whole network. Within the networks, we assessed consistency between direct and indirect evidence using the design-by treatment interaction model. A loop-specific approach was applied to detect local inconsistencies within closed-loop network meta-analysis models if the information was sufficiently similar across sources to be combined. The difference (inconsistency factor, IF) between direct and indirect estimations for a specific comparison was calculated with 95% CIs as a measure of within- loop inconsistency. However, open loop efficacy treatments multiple- analysis failed to calculate the inconsistency factor. Publication bias was estimated by comparison-adjusted funnel plots [9]. The I² statistic was ob- tained as an index of heterogeneity. Forest plots were conducted with the ‘network forest’ command to demonstrate single and pooled effect sizes and reflect the heterogeneity. Surface under the cumulative ranking (SUCRA) probabilities were used to rank the treatments for an outcome, and large SUCRA scores should indicate more effective or safer interven- tions. Then, we used the ‘network cluster rank’ option to evaluate the probability that each treatment could be the most (or second most, third most, etc.) efficacious treatment. The treatment safety was ranked with the same method.

Results

Study selections

A total of 450 potentially relevant studies were retrieved, which in- cluded 210 non-repetitive potentially eligible literatures. Then 99 liter- atures was excluded for irrelevant areas of discipline, non-experimental trials. Based on our eligibility criteria (i.e., clinical control trials whose subjects were adult pelvic fracture patients with hemodynamic

Fig. 1. Flow diagram of the study Selection process according to criteria of preferred reporting items for systematic reviews and meta-analyses.

instability and that received anti-shock surgical procedures), 62 litera- tures were excluded during the title/abstract Review process, and 36 lit- eratures were subsequently excluded after a full-text review (20 without controlled managements, 12 no mention data of mortality or blood transfusion and 4 reviews). Ultimately, 13 articles published from 2000 to 2016 were included in our network meta-analysis. The trial selection process is summarized in Fig. 1.

Study characteristics

The characteristics of the 13 included trials are summarized and pre- sented in Table 1. Briefly, trial durations for follow-up ranged from 2 years to 15 years, and a majority (63%) of the participants were male. Nine studies included data extracted for mortality analysis [1-3, 10-15], and seven studies included blood transfusion data for efficacy analysis [2, 4, 10, 14-17]. Data from 24,396 individuals were included in the effi- cacy and safety analyses. Most (11/13; 85%) of the studies had two arms, and two studies had three arms. Regarding methodological quality, only one study was a quasi-randomized study, but there was no mention of the exact manner of randomization, whereas others were retrospective cohort studies derived from registration databases (Table 1).

Evidence network

Our safety analyses on mortality included 1806 pelvic fracture pa- tients with hemorrhage in nine trials that examined a total of six treat- ments (Fig. 2A), and the network plot displayed close loops. Our efficacy analyses based on the early 24 h red cell transfusion (continuous data)

Table 1

Characteristics of selected studies of multiple treatments in hemodynamically unstable pelvic fractures

Study	Location	follow-up (y)	Age	No. of cohorts	Treatments (no. of cases)	Study design	Sex (male/f)	Adjustments
Wonga,b 2000	China	3	24.6 (16-47)	17	AE(11) AE +	Retrospective	7/10	Age, ISS, sex, transfusion, mortality,
Millera 2003	USA	7	46 +- 21	35	EXFIX (6) AE (19) EXFIX	cohort Retrospective	28/7	Contrast medium extravasation. Age, ISS, sex, Base deficit, heart rate,
					(6) AE + EXFIX	cohort		systolic blood pressure, transfusion,
Kataokaa 2005	Japan	5	46.9 +- 19.9	64	(10) AE (61) AE +	Retrospective	28/44	mortality. Age, ISS, sex, fracture type, systolic
Sadrib 2005	Switzerland	8	38.5 +- 14.2	13	PPP (3) EXFIX (9) AE +	cohort Retrospective	Not reported	blood pressure, transfusion, mortality. Age, ISS, fracture type, transfusion,
Verbeekb 2008	Australia	3	41 +- 19	217	EXFIX (4) AE (34) PPP (58)	cohort Multicenter	153/58	mortality. Age, sex, ISS, Glasgow coma scale,
						retrospective		systolic blood pressure, transfusion,
Osborna 2009	USA	6	39.5 +- 17.4	40	AE (20) PPP (20)	cohort Retrospective	Not reported	temperature, fracture type, mortality. Age, ISS, systolic blood pressure,
Taia,b 2011	China	2	37.9 +- 18.9 45 (18-84)	24	AE (13) PPP (11)	cohort Retrospective	15/9	transfusion, hospital days. Age, sex, ISS, Glasgow coma scale,
						cohort		systolic blood pressure, hemoglobin,
								transfusion, mortality, INR.
Hauschild	German	5	52.3 +- 15.4	152	AE (17) NON-AE	Retrospective	104/48	Age, sex, ISS, AIS, mortality,
2012 Abrassarta	Switzerland	10	45.8 +- 19.9 43 (20-74) 39	70	(135) EXFIX (29) AE +	cohort Retrospective	Not reported	hemoglobin, fracture type. Age, ISS, mortality.
2013			(17-76) 36		EXFIX (11)	cohort
			(22-58)		EXFIX + PPP
Chengb 2015	Switzerland	15	46.8 +- 21.4	199	(11) AE (76) PPP (49)	Retrospective	Not reported	Age, ISS, GCS, systolic blood pressure,
Chua 2016	USA	3	45.3 +- 21 Not reported	22,568	AE (746) EXFIX	cohort retrospective	872/537	hemoglobin, transfusion, mortality. Age, sex, ISS, race, region, GCS, systolic
Lia,b 2016	China	10	40 +- 9 43 +- 13	973	(663) AE (27) PPP (29)	cohort Quasi-randomized	32/24	blood pressure, heart rate, mortality. Age, sex, ISS, fracture type, transfusion,
						study (no mention		mortality, operation time, complication.
Minga,b 2016	Australia	3	54 +- 20	24	AE (10) PPP (14)	on randomization) Retrospective	20/4	Age, sex, ISS, fracture type, systolic
						cohort		blood pressure, transfusion, mortality.

AE: angio-embolization, PPP: preperitoneal pelvic packing, EXFIX: external fixation.

^a Including data of mortality in treatment of hemodynamically unstable pelvic fractures patients.

^b Including data of blood transfusion within early 24 h. Age (measured as mean +- sd, mean and range) was grouped according treatments.

Fig. 2. Network geometry of the procedures used in controlling hemorrhage for safety (A) and efficacy (B). The width of the lines is proportional to the number of studies comparing each pair of treatments, and the size of each node is proportional to the number of participants (sample size). AE: angio-embolisation, PPP: preperitoneal pelvic packing, EXFIX: external fixation.

included 348 patients in seven trials that examined a total of four treatments (Fig. 2B), and the graph displayed open loop. Ultimately, the following six treatments were analysed relative to pelvic fracture hemodynamic control in the present meta-analysis: angiography embo- lization (AE) (9 trials), preperitoneal pelvic packing (PPP) (6 trials), ex- ternal fixation (EXFIX) (3 trials), AE + PPP (1 trial), AE + EXFIX (4 trials), and EXFIX + PPP (1 trial). The combinED treatments are con- nected with ‘+’ and were designated conducting the procedures one by one successively and did not proceed simultaneously.

Network meta-analysis of individual treatments

Fig. 3 shows the contribution of each direct comparison in the network estimates. The comparison of angio-embolisation versus AE + EXFIX (A vs E) had the largest contribution to the entire network (27.0%).

The efficacy (Fig. 4A) and safety (Fig. 4B) analysis results obtained for acute hemorrhagic shock surgical managements, as determined by direct pairwise meta-analyses, and the distribution of each direct

Fig. 3. Contribution plot for the mortality of procedures in hemodynamic control. AE (A): angio-embolisation, PPP (B): preperitoneal pelvic packing, EXFIX (C): external fixation, AE + PPP (D), AE + EXFIX (E), EXFIX + PPP (F).

Fig. 4. Forest plot showing the safety (A) and efficacy (B) of surgical procedures for management of hemorrhage in a pairwise meta-analysis, and original studies and distribution of each comparisons. AE (a): angio-embolisation, PPP(b): preperitoneal pelvic packing, EXFIX(c): external fixation, AE + PPP(d), AE + EXFIX(e), EXFIX + PPP(f).

pairwise comparisons are shown in forest plots. A direct comparison using a pairwise meta-analysis showed that there were comparable pro- cedures for treatments of hemorrhage based on the mortality outcomes. A Pooled analysis showed two remarkable significances in terms of mortal- ity outcomes between PPP and angio-embolisation (OR: 0.27, 95% CI: 0.10-0.78, p = 0.013), so PPP was found to have significantly better safety. Additionally, the mortality outcome displayed statistical signifi- cance between EXFIX and angio-embolisation (OR: 0.61, 95% CI: 0.46-0.80, p = 0.001) (Fig. 5), and EXFIX was indicated to be safer than AE. The consistency of overall mortality outcome (p = 0.067 >= 0.05) reflected no significant disagreement between direct and indirect esti- mate comparisons. Concurrently, the loop inconsistency test suggested

similar results for including less heterogeneity between direct and indi- rect estimate comparisons (range of 95% CI >= 0) (loop AE- EXFIX- AE

+ EXFIX, IF: 3.19, 95% CI: 0-6.44; loop EXFIX- AE + EXFIX- EXFIX

+ PPP, IF: 2.93, 95% CI: 0-7.1). Overall, heterogeneity was moderate. Fig. 5 shows no differences in blood transfusion outcomes among the treatments of interest, and the absence of a closed loop in the network of treatments led to an inefficient test of inconsistency.

Comparison-adjusted funnel plots for efficacy and safety (Fig. 6) re-

vealed reporting bias in all 9 studies. Both plots were drawn close to the ‘zero’ line and were considered symmetrical. PPP N EXFIX N AE became the best ranking order in the SUCRA rank for safety, whereas EXFIX N PPP N AE became the best rank order in the SUCRA rank for efficacy

Fig. 5. Efficacy and safety of the six treatments. Data of “OR with 95%CI” on lower left come from mortality of two treatments comparison, and “MD with 95%CI” on top right corner come from the volume of blood transfusion meanwhile. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column- defining treatment and the row-defining treatment. For efficacy, MDs lower than 0 favour the column-defining treatment. For safety, ORs higher than 1 favour the column-defining treatment. Significant results are in bold and underlined. NA: not available. AE: angio-embolisation, PPP: preperitoneal pelvic packing, EXFIX: external fixation.

(Fig. 7). In other words, PPP appeared to be safer but less effective after removal of the early two surgical procedures. Consequently, all treat- ments for hemorrhage control were cluster-ranked according to their own probability of being the best ones for efficacy and safety, and the final scatter plot showed that PPP and EXFIX occupied the conspicuous zone that suggested they were more efficacious and potentially safer (Fig. 7C).

Discussion

There is enormous evidence indicating that uncontrolled hemor- rhage in unstable pelvic fractures remains a frequent Life-threatening complication and is a common denominator of non-central nervous system death. The uncontrolled hemorrhage of unstable pelvic fractures is usually the result of blood loss from broad cancellous surfaces at frac- ture sites and lacerated veins and Soft tissues, or even from arterial bleeding sites, which account for 10% to 15% of the hemorrhage [18]. An open surgical exploration to gain access to the retroperitoneum with an attempt to pack the venous plexus or ligate the injured arteries is not always effective. The use of diagnostic angiography and specific arterial embolization seems to work by stopping the arterial bleeding and promoting tamponade effect of the haematoma to control venous

bleeding. There is still debate over the issue of whether or not pelvic ex- ternal fixation is necessary before angio-embolisation [11]. Several studies have confirmed that application of an external fixator can re- duce pelvic volume and along with the Blood clots, it can place direct pressure on bleeding vessels to promote an effective tamponade [19]. Stabilizing the pelvis with an external fixator may also prevent repeated insults to the already clotted vessels. Therefore, the optimal sequence of surgical procedures is extremely critical for the management of patients with hemodynamic instability and the interactions of multiple variables were analysed.

Our study indicates that pelvic packing is the method that should be the first choice to control bleeding in hemodynamically unstable pa- tients with pelvic fracture, given that acute mortality will be decreased. In general, bleeding is more frequently venous than arterial bleeding be- cause pelvic veins are arranged in large plexuses and larger veins have a closer relationship to bony structures than arteries [20]. Immediate ve- nography through the femoral vein might demonstrate an extravasa- tion of contrast medium at the site of venous injury and provide more objective evidence for an early approach. It is unlikely that spontaneous cessation of bleeding would occur with a venous injury as severe as the injuries are in many cases. Therefore, positive approaches for stabiliza- tion these major pelvic vein injuries were prioritized. Surgical repair

Fig. 6. Comparison-adjusted funnel plot for safety (A) and efficacy (B). AE (a): angio-embolisation, PPP (b): preperitoneal pelvic packing, EXFIX (c): external fixation, AE + PPP (d), AE

+ EXFIX (e), EXFIX + PPP (f).

Fig. 7. Plots of the surface under the cumulative ranking curves for all treatments in hemorrhage. (A) Ranking for safety. (B) Ranking for efficacy. (C) Clustered ranking plot for efficacy and safety. AE: angio-embolisation, PPP: preperitoneal pelvic packing, EXFIX: external fixation.

for venous bleeding is often difficult and sometimes impossible in the face of massive retroperitoneal haematoma, but a retroperitoneal gauze pack with an effective tamponade mostly provides a quick and effective solution for controlling hemorrhage [15]. The prevesicular and presacral spaces are tightly packed, or direct packing of the retroperitoneum without opening the peritoneal cavity in improved versions, can lead to tamponade of bleeding, which plays a crucial role

in patient survival. Direct retroperitoneal pelvic packing is an effective and safe ‘Damage control‘ procedure that permits more comprehensive and Rapid treatment of severe pelvic trauma than angio-embolisation [13], and our cohort-based data refine and clarify the full impact of this management approach.

Our data concerning the role of external fixation in hemorrhage con- trol recommend the initial use of external fixation in amenable frac- tures, if there is evidence of ongoing bleeding, which ultimately reduces the hyperperfusion syndrome of massive transfusion and en- hances efficiency of early fluid resuscitation. External fixation remains one of the mainstays in pelvic fracture management. Skeletal stabiliza- tion is allocated to aid hemorrhage control, the mechanism of which is proposed that closure of the pelvis reduces pelvic volume, which pro- vides a tamponade effect [21]. Other proposed mechanisms include re- duction of bleeding by re-apposition of bony fragments, or promotion of hemostasis by avoiding clot disruption with bony movement [22]. Rapid methods of fixation, such as a C-clamp, which is preferable for mechan- ical superiority over an anterior frame, are placed in the emergency department steps due to the dilemma of delaying therapy that is poten- tially more efficient. Alternatives to EXFIX have been proposed, includ- ing medical antishock trouser suits, bean bags, or wrapping of the pelvis with a bedsheet or a specialized binder, which would appear to accom- plish some of the goals of EXFIX until more definitive means can be employed. However, it is unlikely that such techniques can generate sufficient pressure to stop arterial bleeding [4].

Angio-embolisation is currently established as an effective means of dealing with Arterial hemorrhage. If there is continued evidence of bleed- ing after an initial external fixation placement, angio-embolisation is rec- ommended according to the results of this study. Some authors reported a mortality of approximately 50%, despite successful embolization to control arterial bleeding. In addition, angiography and embolization can be time consuming, and the overall time for performance of emboli- zation has been reported to range from 50 min to 5.5 h [14, 18]. While waiting for the angiographic team to set up, other quick, effective tools to reduce venous bleeding should be considered to reduce the need for blood transfusion. A decrease in blood transfusion requirement was found in patients undergoing preperitoneal packing but not for patients undergoing angiography [13].

The impact of the abovementioned single surgical management ap- proaches and the optimal algorithm based on our data are rational and clearly structured. First, the external fixation (C-clamp) and adjunctive embolization appear to be as efficient for controlling hemorrhage be- cause the C-clamp approach is compared with laparotomy and pelvic packing [4] while avoiding second-look procedures that are needed for removal of preperitoneal packing. Therefore, C-clamp is confirmed to be the initial management approach for all efficient protocols. Sec- ond, in hospitals where angiography facilities are available, it seems rea- sonable to recommend that patients who remain hemodynamically unstable after rapid application of the C-clamp be treated with arterial embolization. When the median time to angiography was greater, deaths were attributed to acute exsanguination before operative inter- vention [13]. Pelvic packing may help control pelvic arterial hemorrhage and to select individuals who might benefit most from pelvic angiogra- phy; pelvic packing also appears to increase the effectiveness of external fixation of the pelvis [23]. Undoubtedly, early pelvic packing ranks as the second-most efficient and complementary management. As the in- cidence of active pelvic arterial bleeding is reduced after pelvic packing, implementation of angiography is subsequently applied only for those persons who remain hemodynamically unstable and acidotic and who require further transfusions. However, the combined management comparisons from our data are still indistinct and have high heteroge- neity due to the absence of abundant controlled trials or illogical com- parison (Fig. 5). Thus, part of the 95% confidence intervals of these combined management approaches were missing (data of blood trans- fusion from AE + PPP, EXFIX + PPP comparison to other treatments), and should be re-estimated prudently. Further clinical controlled data

are in need consequently for integrating unbiased multiple factor net- work analysis.

Clinical practice guidelines for the management of hemodynami- cally unstable pelvic fracture patients have been developed. A variety of guidelines have contributed to the introduction of an aggressive treatment protocol, and promoted timely orthopaedic pelvic stabiliza- tion (pelvic C-clamp) followed by surgical hemorrhage control (packing). Ongoing hemorrhage has been addressed by pelvic angiogra- phy embolization as a secondary procedure [16, 24]. The Liverpool Evidence-based guidelines on this issue recommend the use of early an- giography in cases of persistent pelvic bleeding after (non-invasive) sta- bilization of the pelvic ring [25]. The German system has developed an approach for pelvic fractures in which fractures tend to be fixed earlier and large expanding retroperitoneal haematomas are managed with packing against the restored pelvic ring. Nevertheless, in Anglo- American systems, arterial bleeding in hemodynamically unstable pa- tients is embolized or excluded in the angiography suite before defini- tive pelvic fixation is performed by the consulting orthopaedic trauma specialists. Emergency pelvic stabilization is performed with different timeframes recommended by different systems [26]. The efficacy for the listed interventions in reducing mortality has not been proven in level I investigations. Both guidelines could be highly efficient in appro- priate settings, but our data were used to conduct a network analysis and surgical procedures are compared in a multi-institutional fashion, which is essential to determine the impact of the individual interven- tions used during the management of severe pelvic fracture patients for effective hemorrhage control and outcome.

The major limitation of our study is that the sample size may be to

too small to reveal a genuine difference and compel us to abandon addition of previously reported confounding intervention groups (AE + EXFIX, AE + PPP, EXFIX + PPP) to our protocol. Hence our concise procedures for management of hemorrhage in acute pelvic fracture victims may be commendatory. Furthermore, the vast majority of non-randomized controlled trial data were retrospective, so they were less reliable. We hope to refine our results as we assemble an abundance of samples.

Conclusions

In conclusion, the presence of exsanguinating hemorrhage in patients with pelvic ring disruption represents a complex and difficult challenge for a trauma team. We strongly support the initial application of an external fixator, especially prior to laparotomy or packing. If patients remain hemodynamically unstable after quick and efficient implementation of an external fixation, we believe that pelvic packing is the next procedure to consider. Angio-embolization is a complemen- tary but not alternative method of choice whenever hemodynamic insta- bility coexists with an unstable pelvic ring disruption.

Author contributions

JT: developed the study concept, participated in its design, carried out the statistical analysis and wrote the first draft and revised the man- uscript. ZS: developed the study concept as well as participated in its design, analysis, writing and revising the manuscript. JZ: participated in data extraction, interpretation and revisions. All authors read and ap- proved the final manuscript, and declared no conflict of interests.

Funding

This study was funded simultaneously by grant 2017BH20308 from Liuzhou City Science and Technology Bureau and grant GuiKeAB17129001 Guangxi Science and Technology Agency. The content is solely the respon- sibility of the authors and does not necessarily represent the official views of the funding agencies.

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