Delayed Embolization Associated With Increased Mortality in Patients With Hemodynamically Stable Pelvic Fracture

Makoto Aoki (  aokimakoto@gunma-u.ac.jp ) Department of Emergency and Critical Care Center, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan https://orcid.org/0000-0001-8239-8822 Toshikazu Abe Tsukuba Memorial Hospital Shokei Matsumoto Saiseikai Yokohamashi Tobu Hospital: Saiseikai Yokohama-shi Tobu Byoin Shuichi Hagiwara Kiryu Kosei General Hospital Daizoh Saitoh National Defense Medical College Kiyohiro Oshima Gunma University Hospital


Background
Pelvic fracture is a type of severe trauma, with 5% to 20% of patients showing hemodynamic instability due to hemorrhage. The mortality among hemodynamically unstable patients with pelvic fracture was reported to be as high as 30% to 40% 1,2 . Several surgical and nonsurgical interventions for pelvic fracture-related hemorrhage exist 1,3,4 Of these, embolization has been widely accepted as a standard nonsurgical intervention 1 ; however, this practice still has challenges. The latest version of the Resources for Optimal Care of the Injured Patient issued by the American College of Surgeons Committee on Trauma stipulates that interventional radiologists should be available within 30 min to perform an emergency embolization 5 . However, the time to embolization was reported to be prolonged even in trauma centers 6

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A reduced time to intervention is well known to be associated with decreased mortality, such as in acute coronary syndrome 7 and trauma 8 . The effect of reduced time to embolization among hemodynamically unstable patients with pelvic fracture has been described [9][10][11][12] . Earlier intervention for hemodynamically unstable patients is clinically desirable. However, the effect of earlier intervention for hemodynamically stable patients with pelvic fracture is unknown 11 . Because all hemodynamically stable patients do not require embolization, a delay in embolization may sometimes occur that leads to a deterioration in patients' outcomes. Therefore, we aimed to evaluated whether a delay in embolization was associated with increased mortality among hemodynamically stable patients with pelvic fracture.

Study Design
This study was a multicenter, retrospective cohort study conducted using Japan Trauma Data Bank (JTDB) data from 2004 to 2018. JTDB is a nationwide trauma registry established in 2003 by the Japanese Association for Surgery of Trauma and the Japanese Association for Acute Medicine to improve and ensure the quality of trauma care in Japan. During the study period, 291 hospitals, including 95% of all tertiary emergency medical centers in Japan, participated in the JTDB. JTDB collects 92 data elements related to patient and hospital information, such as patient demographics, physiology, abbreviated injury scale (AIS) score, injury severity score (ISS), in-hospital procedures, and survival.

Patient Selection
Patients who were directly transferred to hospital and diagnosed with pelvic fracture (existence of pelvic fracture AIS 2005 codes) were included. In addition, we targeted patients who were aged ≧16 years and who were initially treated with embolization. The following exclusion criteria for patients were de ned: 1.
AIS grade=6 for any region. 2. Underwent any surgery for hemorrhage control for associated injuries except for external xation. 3. Lacked information on vital signs of systolic blood pressure (sBP) and heart rate (HR) on hospital arrival. 4. Hemodynamically unstable patients whose sBP <90 mmHg or HR >120 bpm. 5. Lacked information on the time from hospital arrival to embolization. 6. Time from hospital arrival to embolization was over 3 h. 7. Lacked information on outcome. Regarding the time to embolization, we excluded patients who underwent pelvic embolization 3 or more hours after admission as these cases were likely non-emergency cases 1 .

Study Endpoints
The primary outcome of this study was 30-day mortality, and the secondary outcome was 24-hour mortality.

Statistical Analysis
Study patients were divided into six groups according to 30-min blocks of time to pelvic embolization (0-30, 30-60, 60-90, 90-12, 120-150, and 150-180 min). Univariate analysis was performed comparing patients' characteristics and trauma severities between the six groups. A Chi-square or Fisher exact test was used for categorical variables, and a Mann-Whitney U test was used for continuous variables. A Cochran-Armitage test for trend was also performed to evaluate outcomes between the six groups. In addition, we adjusted the backgrounds of patients and the trauma severity with regard to clustering by institutions using generalized estimating equation (GEE) models with an independent working correlation matrix. Models were adjusted for age, sex, vital signs at hospital arrival, and ISS, which were selected a priori based on reported ndings 9,10 . We then used marginal standardization based on probability determined from the GEE model to estimate the adjusted 30-day mortality by the six groups. Because the 30-day mortality of the 0-30 min group was zero, we omitted these patients from the GEE model. We showed crude mortality and risk-adjusted 30-day mortality according to groups. As for sensitivity analysis, we estimated a linear relationship between the time to embolization and the 30-day mortality using a GEE model. The model was adjusted for patient demographics, such as age and sex, vital signs and ISS, with regard to clustering by institutions. Statistical signi cance was de ned as a two-sided pvalue < 0.05 in all statistical analyses. All analyses were performed using R software (version 3.5.

Results
A total of 361,706 patients were registered in JTDB from 2004 to 2018 (Fig. 1). Of the 29,653 adult patients with a pelvic fracture, 2,178 were treated with embolization. Of these, 1,160 hemodynamically stable patients with pelvic fracture were treated with embolization only. In turn, of these, 660 patients received embolization within three h. After excluding patients for whom information on outcome was lacking, 620 patients met the study criteria. Patients' characteristics are summarized in Table 1. The median age was 68 (48-79) years and 55% were male. The median time to embolization was 101 (74-131) min and 14.5% of patients underwent embolization within one hour. A signi cant difference was not observed regarding vital signs at hospital arrival and the trauma severities of pelvis AIS and ISS between the six groups. The median ISS was 26 (18-38), with ISS greater than 15 in 88.9% of patients.
The 30-day mortality was 8.9% (55/620) and 24-h mortality was 4.2% (26/619). Table 2 is a summary of the results of Cochran-Armitage tests for trend to evaluate outcomes. An observed trend was that a delayed time to embolization was associated with signi cantly increased 30-day (p = 0.0186) and 24-h (p = 0.033) mortality rates. Figure 2 shows crude mortality and the risk-adjusted 30-day mortality rate. Mortality during 0-30 min to embolization was 0%. The mortality rate increased with delayed time to embolization by up to 17.0% (10.2-23.9) for the 150-180 min group. A linear relationship was noted between time to embolization (min) and 30-day mortality in the GEE model (βcoe cient 0.0095; p = 0.049).

Brief summary
This study demonstrated that delayed time to embolization was associated with increased mortality among hemodynamically stable patients with pelvic fracture. Every thirty-minute delay to embolization increased mortality.

Comparison with previous studies and possible explanations for this study
This study was different in some respects from previous reports 9-11 on the assessment of the relationship between time to embolization and mortality among patients with pelvic fractures. First, we divided patients into six groups based on 30-min blocks of time although previous studies divided time to embolization by an hour 10,11 . The availability of emergency interventional radiology was required within 30 min 5 . Second, we focused only on patients who were hemodynamically stable. Previous studies included approximately 30-40% hemodynamically unstable patients with pelvic fracture 10,12 . Our results suggested that patients with pelvic fractures, regardless of hemodynamics, should be treated urgently if an intervention is considered.
One possible reason for why hemodynamically stable patients needed early intervention was that we included only embolized patients. Embolization is thought to be conducted in response to some sort of sign of bleeding, such as subsequent hemodynamic instability, a contrast blush on computed tomography or pelvic hematoma 12 . Another explanation may be the older age of this study's population (median 68 years [48-79]). Kimbrell et al. reported that older patients had a high likelihood of active retroperitoneal bleeding and recommended embolization among this age group regardless of presumed hemodynamic stability 14 .

Clinical implication of this study
As we have previously stated, early identi cation and intervention is desirable among pelvic fracture patients with ongoing hemorrhage 15 . However, delayed identi cation due to a delay in a radiological examination and intervention might occur among patients who are initially hemodynamically stable.
However, some patients may have active arterial extravasation 3 and need prompt intervention. This study revealed that early identi cation and embolization were also needed for initially hemodynamically stable patients with a pelvic fracture. In such patients, as little as a 30-min delay to embolization was associated with an increased 30-day mortality. However, this study implied that we had to permit overindicated embolization, to some extent, for hemodynamically stable patients. Early embolization may be unnecessary and a discussion about which patients really need embolization is required.
We acknowledge several limitations of this study. First, data was lacking on the indication for embolization. Second, the details of embolization for pelvic fracture were not registered in JTDB. For instance, the embolic agent and/or the embolized artery were not described. Third, no measure of errors in coding and data entry could be obtained. Therefore biases introduced in this manner could not be controlled although they were likely mitigated by the multicenter design and large patient sample used.

Conclusion
Delayed embolization was associated with increased mortality among hemodynamically stable patients with pelvic fracture. Early identi cation and embolization might reduce mortality in this patient cohort.

Declarations Ethics Approval and Consent to Participate
This study was approved by the medical ethics committee of the Saiseikai Yokohamashi Tobu Hospital. Because of the anonymous and retrospective nature of the study, the need for informed consent was waived.

Consent for publication: Not applicable
Availability of data and materials: Not applicable Competing interests: All authors declare that they have no competing interests.