Resuscitative endovascular balloon occlusion of the aorta associated with improved survival in hemorrhagic shock.

BACKGROUND: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is controversial as a hemorrhage control adjunct due to lack of data with a suitable control group. We aimed to determine outcomes of trauma patients in shock undergoing REBOA versus no-REBOA.
METHODS: This single-center, retrospective, matched cohort study analyzed patients ≥16 years in hemorrhagic shock without cardiac arrest (2000-2019). REBOA (R; 2015-2019) patients were propensity matched 2:1 to historic (H; 2000-2012) and contemporary (C; 2013-2019) groups. In-hospital mortality and 30-day survival were analyzed using chi-squared and log rank testing, respectively.
RESULTS: A total of 102,481 patients were included (R = 57, C = 88,545, H = 13,879). Propensity scores were assigned using age, race, mechanism, lowest systolic blood pressure, lowest Glasgow Coma Score (GCS), and body region Abbreviated Injury Scale scores to generate matched groups (R = 57, C = 114, H = 114). In-hospital mortality was significantly lower in the REBOA group (19.3%) compared to the contemporary (35.1%; p = 0.024) and historic (44.7%; p = 0.001) groups. 30-day survival was significantly higher in the REBOA versus no-REBOA groups.
CONCLUSION: In a high-volume center where its use is part of a coordinated hemorrhage control strategy, REBOA is associated with improved survival in patients with noncompressible torso hemorrhage.

Background

Resuscitative Endovascular Balloon Occlusion of Aorta (REBOA) has been gaining popularity over the past decade as an endoluminal adjunct to resuscitation in non- compressible subdiaphragmatic torso hemorrhage (NCTH). Despite promising evidence that it can provide circulatory support in patients with hemorrhagic shock [1, 2], the use of REBOA has proven to be controversial as there is a lack of high quality evidence of clear survival benefit.

The current evidence base consists of large population studies using national trauma registries which demonstrate conflicting outcomes in terms of mortality of trauma patients treated by REBOA. A study by Norii and colleagues, using the Japanese trauma bank, utilized propensity score matching to compare trauma patients who received REBOA to those who did not and demonstrated that REBOA treatment results in mortality three times higher than controls [3]. In contrast, another group which used the same database but with a different propensity model demonstrated that severely injured patients treated with REBOA had a higher survival rate than those who did not receive REBOA [4]. Another study by a group that used the national American College of Surgeons Trauma Quality Improvement Program data set (ACS-TQIP) found that mortality was doubled in REBOA patients compared to no REBOA [5].

There is ongoing clinical uncertainty with regards to the use of REBOA in management of trauma patients. The evidence base is currently lacking data with a suitable control group from an experienced Level 1 Trauma Center. The aim of this study was to use the local trauma registry of one high-volume Level 1 Trauma Center to compare outcomes between trauma patients who were managed with REBOA and those who received standard treatment without REBOA.

Methods

Study population and data extraction

A retrospective review of the trauma registry at our institution was performed after obtaining University of Maryland Institutional Review Board approval. Request for waiver of documentation of informed consent was approved prior to study initiation. The trauma registry was developed for purposes of quality improvement and data monitoring and is a requirement for Level 1 trauma verification of our institution by the state of Maryland. It is a prospectively collected database that captures hundreds of variables ranging from demographic information to clinical presentation and outcomes. The findings are merged with databases from other trauma centers and used for national trauma outcomes reporting.

Patients were stratified into two groups: the REBOA group and the no-REBOA group. Within the no-REBOA group, historic (H = 2000–2012) and contemporary (C = 2013–2019) subgroups were created. The contemporary group was treated at a time when REBOA was available at our institution, whereas during the historic period it was not available. The use of historical controls was intended to mitigate selection bias, as unknown factors may have influenced the use of REBOA during the contemporary period. The rationale for a contemporary no-REBOA group was to control for bias associated with improvements in resuscitation and critical care management that would not have been available to the patients in the historic group. Although REBOA was being used in our institution as early as 2013, patients were included in the study starting in year 2015 to reduce poor outcomes being partially due to a learning curve after the device was initially introduced. In addition, more complete information regarding REBOA was available from 2015 onwards through the American Association for the Surgery of Trauma Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA). Demographic characteristics as well as injury, physiology and outcome data were collected from the registry. Variables not available in the trauma registry were identified through chart review, when available. Cause of death and laboratory values could not be obtained from the electronic medical record for the historic group. Specific information regarding indications, complications, and outcomes of REBOA was obtained from the local AORTA registry. Patients <16 years, as well as those in cardiac arrest upon arrival to the hospital were excluded. In addition, individuals missing data for any of the variables used to calculate the propensity score were excluded.

Institutional setting

The R Adams Cowley Shock Trauma Center serves as a quaternary care center for the state of Maryland, functioning as an enhanced level 1 trauma center. The institution admits between 6000 and 7000 trauma patients annually. An endovascular trauma service staffed by trauma surgeons with vascular surgery training is available 24/7 to assist and support hemorrhage control endeavors [6]. REBOA use is governed by an institutional guideline and is a part of a well-coordinated hemorrhage control strategy. It is used primarily to bridge patients with NCTH or junctional hemorrhage to definitive hemorrhage control. The technique is performed only by highly trained operators who have been appropriately trained and certified in its use [7]. The device is deployed on average 3–5 times per month, or 30–60 times per year. There have been no changes to indications for REBOA placement during the study period.

Data management and statistical analysis

Univariate analyses comparing demographic and clinical factors between the REBOA and no-REBOA groups (historic and contemporary) was performed using chi-square testing for categorical variables and the student’s T-test for continuous variables. A logistic regression model was then used to assign a propensity score for each patient based on pre-treatment variables that were found to be significant on univariate comparison of REBOA to no-REBOA patients. These variables were: age, sex, race, mechanism of injury, injury severity score (ISS), lowest systolic blood pressure (SBP) and Glasgow Coma Score (GCS) within the first hour after arrival, and body region Abbreviated Injury Scale (AIS) score (brain, thorax, abdomen/pelvis and upper and lower extremities). Patients in the historic and contemporary groups were propensity matched 2:1 to the REBOA group (R = 2015–2019) using the nearest neighbor method to give the closest possible match in pre-specified criteria. A match tolerance of 0.001 was used. The Kaplan-Meier estimate was used to assess survival to 30 days in each group. Post-match univariate analyses were performed between the REBOA and no-REBOA groups for primary and secondary outcomes. The primary outcome of interest was in-hospital mortality. Secondary outcomes were 24-hour mortality, 30-day survival, length of stay, total blood products transfusion, acute kidney injury and lower limb complications. R statistical package version 3.0.1 was used for analysis and the Matchit package version 3.0.2 was used for the propensity scoring. P value of <0.05 was considered statistically significant.

Results

A total of 130,651 patients were identified from the registry within the study period (H = 105,134, C = 25,410, R = 107). Patients were excluded due to age <16 (n = 2,518), arrival in cardiac arrest (n = 6,985) and incomplete data (n = 18,667). Incomplete data was missing at random, pertaining mostly to the Injury Severity Score and lowest SBP variables, and removal of these patients did not affect the overall averages of the variables used to calculate the propensity score in either no-REBOA group. Forty-eight patients were removed from the REBOA group due to arrival in cardiac arrest, and 2 had missing variables.

A total of 102,481 patients were included in the study (H = 88,545, C = 13,879, R = 57). Comparison of the REBOA group to the no-REBOA contemporary and historic groups by demographic, injury and physiology data is presented both pre- and post-match in Tables 1 and 2, respectively. Prior to matching, the REBOA group was significantly more likely to be male (R = 90% v C = 67% and H = 70%), have a higher body-region AIS and overall ISS (R = 34 v C = 10 and H = 11), lower systolic blood pressure (R = 67mmHg v C = 113 and H = 127) and lower GCS (R = 5 v C = 14 and H = 14) than the no-REBOA groups. When compared to the no-REBOA patients, the REBOA patients tended to be of younger age (R = 37y v C = 47y, H = 40y, p<0.001), and were more likely to have a penetrating mechanism (R = 23% v C = 13%, H = 13% p<0.001).

Table 1

REBOA to No-REBOA contemporary group before and after propensity-matching*.

	Before Matching			After Matching
	No-REBOA (n = 13,879)	REBOA (n = 57)	p	No-REBOA (n = 114)	REBOA (n = 57)	p
Age, y	47 ± 21	37 ± 14	<0.001	42 ± 20	37 ± 14	0.194
Sex n (%)			<0.001			0.050
Male	9326 (66.9%)	51 (89.5%)		83 (72.8%)	51 (89.5%)
Female	4607 (33.1%)	6 (10.5%)		31 (27.2%)	6 (10.5%)
Race n (%)			<0.001			0.050
White	4814 (34.5%)	24 (42.1%)		36 (31.6%)	24 (42.1%)
African-American	7917 (56.8%)	23 (40.4%)		72 (63.2%)	23 (40.4%)
Other	1205 (8.6%)	10 (17.5%)		6 (5.3%)	10 (17.5%)
Mechanism n (%)			<0.001			0.764
Blunt	11509 (80.8%)	38 (66.7%)		81 (73%)	38 (66.7%)
Penetrating	1806 (12.8%)	13 (22.8%)		18 (16.2%)	13 (22.8%)
Other	564 (6.4%)	6 (10.6%)		12 (10.8%)	6 (10.6%)
Injury Severity Score	10 ± 10	34 ± 15	<0.001	38 ± 14	34 ± 15	0.420
Lowest SBP, mmHg	113 ± 22	67 ± 18	<0.001	67 ± 21	67 ± 18	0.382
Lowest GCS, mmHg	14 ± 1	5 ± 3	<0.001	4 ± 2	5 ± 3	0.399
Body Region AIS
Brain	1 ± 1	2 ± 2	0.003	2 ± 2	2 ± 2	0.100
Thorax	1 ± 1	2 ± 1	<0.001	2 ± 1	2 ± 1	0.222
Abdominal	0 ± 1	3 ± 2	<0.001	3 ± 2	3 ± 2	0.600
Upper Extremity	1 ± 1	1 ± 1	<0.001	1 ± 1	1 ± 1	0.709
Lower Extremity	1 ± 1	2 ± 1	<0.001	2 ± 1	2 ± 1	0.587

*All values reported as median + interquartile range unless otherwise stated.

Table 2

REBOA to No-REBOA historic group before and after propensity-matching*.

	Before Matching			After Matching
	No-REBOA (n = 88,545)	REBOA (n = 57)	p	No-REBOA (n = 114)	REBOA (n = 57)	p
Age, y	40 ± 19	37 ± 14	<0.001	38 ± 17	37 ± 14	0.969
Sex n (%)			<0.001			0.050
Male	62,161 (70.2%)	51 (89.5%)		80 (70.2%)	51 (89.5%)
Female	26,367 (29.8%)	6 (10.5%)		33 (28.9%)	6 (10.5%)
Unknown	17 (0%)	0 (0%)		1 (0.9%)	0 (0%)
Race n (%)			<0.001			0.313
White	52,352 (59.1%)	24 (42.1%)		31 (27.2%)	24 (42.1%)
African-American	29,746 (33.6%)	23 (40.4%)		72 (63.2%)	23 (40.4%)
Other	6,447 (7.3%)	10 (17.5%)		11 (9.6%)	10 (17.5%)
Mechanism n (%)			<0.001			0.236
Blunt	71,166 (80.4%)	38 (66.7%)		80 (70.2%)	38 (66.7%)
Penetrating	11,380 (12.9%)	13 (22.8%)		18 (15.8%)	13 (22.8%)
Unknown	5,999 (6.6%)	6 (10.6%)		16 (14.1%)	6 (10.6%)
Injury Severity Score	11 ± 10	34 ± 15	<0.001	33 ± 16	34 ± 15	0.553
Lowest SBP, mmHg	127 ± 18	67 ± 18	<0.001	69 ± 21	67 ± 18	0.636
Lowest GCS, mmHg	14 ± 3	5 ± 3	<0.001	4 ± 2	5 ± 3	0.479
Body Region AIS
Brain	0 ± 0	2 ± 2	<0.001	2 ± 2	2 ± 2	0.589
Thorax	0 ± 0	2 ± 1	<0.001	2 ± 2	2 ± 1	0.178
Abdominal	0 ± 0	3 ± 2	<0.001	3 ± 2	3 ± 2	0.498
Upper Extremity	0 ± 0	1 ± 1	<0.001	1 ± 1	1 ± 1	0.992
Lower Extremity	0 ± 0	2 ± 1	<0.001	2 ± 1	2 ± 1	0.773

*All values reported as median ± interquartile range unless otherwise stated.

114 patients each in the contemporary and historic groups were matched to 57 REBOA patients. To determine if patients had been appropriately matched, baseline characteristics were compared. As demonstrated in Tables 1 and 2, patients in both the contemporary and historic groups did not differ in pre-treatment variables when compared to patients in the REBOA group after matching was complete. There were no differences in median levels of lactate (R = 6.1 vs C = 4.8, p = 0.073) or base deficit (R = 6.8 vs C = 7.6, p = 0.33) upon arrival between the REBOA and contemporary groups after matching.

In-hospital mortality was significantly lower in the REBOA group (19.3%) when compared to the contemporary (35.1%, p = 0.024) and historic (44.7%, p = 0.001) groups. Kaplan-Meier estimates of survival over time to 30 days demonstrated higher survival in the REBOA group compared to the historic (p = 0.035) and contemporary (p = 0.020) groups (Fig 1). Chi-square comparison of mortality at 24 hours between the REBOA and no-REBOA historic group demonstrated lower mortality in the REBOA group (12% vs 28%, p = 0.014). There were no differences in 24-hour mortality when compared to the contemporary group (Table 3). Primary cause of death was mainly due hemorrhage in both the contemporary (n = 19, 48.7%) and REBOA (n = 7, 70%) groups, followed by traumatic brain injury (R = 1 [10%], C = 17 [43.6%]), and multifactorial (R = 2 [20%], C = 3 [7.7%]). Total length of stay was longer in the REBOA group by 20 days when compared to the historic group (p<0.001) and by 9 days when compared to the contemporary group (p = 0.03). There were no differences in acute kidney injury and total transfusions of packed red blood cells (pRBCs) between groups.

Fig 1

Kaplan-Meier estimates of survival over time to 30 days by group (REBOA, contemporary and historic).

Table 3

Primary and secondary outcomes in REBOA and no-REBOA groups (contemporary and historic)*.

	REBOA	Contemporary	p	Historic	p
24-hour mortality, n(%)	7 (12.3%)	22 (19.3%)	0.175	32 (28.1%)	0.014
In-hospital mortality, n(%)	11 (19.3)	40 (35.1)	0.024	51 (44.7)	0.001
30-day mortality, n(%)	4 (7%)	18 (15.8%)	0.081	19 (16.7%)	0.062
Total length of stay, da	29 ± 29	20 ± 20	0.030	9 ± 9	< 0.001
Total pRBC transfusions	18 ± 18	19 ± 18	0.533	17 ± 14	0.498
Acute Kidney Injury, n(%)	13 (22.8%)	28 (25%)	0.455	27 (23.7%)	0.530

*All values reported as median ± interquartile range unless otherwise stated, aIncludes in-hospital deaths.

The overall incidence of lower extremity complications was low. A review of lower extremity complications in patients who underwent REBOA placement did not show any difference in rates of lower extremity amputation, exploration, fasciotomy or thrombectomy when compared to no-REBOA patients (Table 4).

Table 4

Lower extremity complications in REBOA patients by lower extremity AIS score vs No-REBOA patients.

	REBOA	Contemporary	p	Historic	p
Lower Extremity Amputation	3 (5.3%)	1 (0.9%)	0.075	2 (1.8%)	0.203
Lower Extremity Exploration	8 (14.0%)	8 (7.1%)	0.143	8 (7.0%)	0.143
Fasciotomy	4 (7.0%)	3 (2.6%)	0.181	8 (7.1%)	0.976
Thrombectomy	2 (3.5%)	2 (1.8%)	0.445	5 (4.4%)	0.571

When evaluating additional hemorrhage control procedures performed in each group, individuals in the REBOA group were more likely to undergo laparotomy than the contemporary or historic groups (79% vs 46.5% & 57%, respectively, p = 0.0003). Individuals in the contemporary group were more likely to undergo thoracotomy (C = 14.9% vs R = 7% & H = 2.6%, p = 0.004), and individuals in the historic group were more likely to undergo angiography (H = 29.8% vs C = 14% & R = 22.8%, p = 0.016). Amongst 53 patients for which data was available, zone of REBOA deployment was zone 1 for most individuals (N = 41, 77.4%) and zone 3 for the remainder (N = 12, 22.6%).

Discussion

This is the first study from a high-volume trauma center in the U.S with considerable experience with REBOA that compares REBOA outcomes to a similar control group undergoing standard measures for hemorrhage control. Our findings demonstrate lower in-hospital mortality and improved 30-day survival in patients for which REBOA was used as compared to both a historical and contemporary cohort matched on injury severity, injury pattern and physiology. REBOA patients did not have increased acute kidney injury or lower extremity complications when compared to the no-REBOA groups. These findings underscore that REBOA is a valuable hemorrhage control tool that can reduce mortality when used in severe states of hemorrhagic shock.

REBOA patients also experienced lower 24-hour mortality when compared to the historic group and demonstrated a trend towards reduced 24-hour mortality when compared to the contemporary patients which did not reach statistical significance. Concepts such as balanced blood product resuscitation, permissive hypotension and damage control surgery were newly entering practice during the historic period, which may have contributed to increased survival in both the REBOA and contemporary groups when compared to the historic group. Low overall numbers may have also influenced the non-significance of the comparison of 24-hour mortality between the REBOA and contemporary group. Greater blood transfusion requirements in the REBOA group are likely due to longer survival in these patients.

REBOA was originally described by Lieutenant Carl Hughes in 1954 as a method for controlling intra-abdominal hemorrhage during the Korean war [8]. However, due to limited availability of this device, it was not readily adopted at the time [9]. Since 2011, when it was re-introduced into clinical practice [10], its use has grown across trauma centers nationwide and its role in the management of NCTH has been met with both appraise [11, 12] and criticism [3, 5]. Despite the growth in utilization of the technique, there is a paucity of evidence evaluating REBOA from high-volume centers within the United States with an adequate control group. Much of the literature that exists to date are from international sites [4], national databases that include both low and high-volume centers [5] and national registries that do not provide a suitable control group, if any [13, 14].

The importance of evaluating REBOA outcomes in experienced centers cannot be overstated. A recent review of the American Association for the Surgery of Trauma (AAST) Aortic Occlusion for the Resuscitation in Trauma (AORTA) registry found that low-volume centers had a longer time to initiation of REBOA placement, longer time to aortic occlusion and lower odds of successful placement when compared to high-volume centers [15]. Critical to successful deployment of REBOA is early and expedient common femoral artery access [16], which can be challenging in a hypovolemic patient and is a technique that must be practiced regularly. Although REBOA volume by center has yet to be directly liked to clinical outcomes, the relationship between experience and performance has been demonstrated in several other procedural techniques. Given the introduction of the technique into the trauma landscape only 10 years prior, worldwide experience with REBOA is still building, and most centers are low-volume and still on the learning curve.

Recent reviews of REBOA have been conducted using large database analyses and/or in other countries, which has yielded results that are not highly applicable to high-volume centers in the United States. The study by Joseph et. al that demonstrated worse outcomes using REBOA used the Trauma Quality Improvement Program (TQIP) database from 2015–2016, which draws information from hundreds of Level I -III trauma centers across the US, many of which only recently started using REBOA [5]. Reports from the Japan Trauma Data Bank have been mixed regarding outcomes using REBOA, but their database includes a large rural population with trained ED providers deploying REBOA [3, 17]. Our institution is a Level I trauma center located in an urban setting with a high volume of penetrating trauma and high acuity blunt trauma, which is vastly different than the settings for REBOA use in Japan and other trauma centers in the US.

It is crucial that REBOA be a part of a coordinated hemorrhage-control strategy, whether that utilizes endovascular or open hemorrhage control techniques. At our institution, we provide 24/7 endovascular coverage by trauma-trained, vascular surgeons as part of an Endovascular Trauma Service which has resulted in faster times to hemorrhage control [6]. Similarly, we have a dedicated hybrid operating room for trauma which allows for rapid performance of concomitant endovascular and open procedures on patients who have undergone REBOA placement, if needed [18]. These resources ensure that REBOA is used in quick succession with other hemorrhage control techniques.

This study has some limitations that must be noted. Despite the superior ability of propensity matching to minimize bias and compare similar groups amongst highly heterogenous populations when compared to multivariable linear regression, it is still a retrospective, non-randomized analysis and can only determine associations rather than direct causation. It cannot control for unknown covariates that may influence the primary outcome, such as additional factors that affected the decision to place or not place a REBOA catheter, which may have resulted in selection bias. Another caveat of propensity matching is that all fields used for creating the propensity score must be filled. In this study, a high proportion of patients were removed due to missing data. This can unduly influence the results, as the characteristics of the study population are biased towards individuals that have all data available. By excluding patients who differ in their pre-treatment characteristics from the REBOA population, the findings demonstrate the average effect on the treated, which is a severely injured group in hemorrhagic shock, and not the entire study population. Hence, the results are only applicable to individuals with similar injury characteristics. Due to data limitations and the single center design, this is a small study that only includes 57 patients in the treatment group which should be taken into consideration when interpreting the results.

This study cannot determine the institution-specific factors that may have contributed to improved outcomes with REBOA, as these were not captured in the retrospective data. We can only speculate that high-volume REBOA users at our institution may have played a role in improving survival in the REBOA group. These same experienced surgeons also treated the patients who did not receive REBOA. The study results are applicable to centers that have a similar patient population, level of experience with REBOA, and resource availability to expediently manage subdiaphragmatic torso hemorrhage.

Conclusion

This single-institution, propensity-matched, retrospective study comparing REBOA use to no-REBOA use in contemporary and historic cohorts demonstrated lower in-hospital mortality and improved 30-day survival for REBOA when compared to both contemporary and historic no-REBOA groups, and lower 24-hour mortality when compared to the historic group. Lower extremity complications were similar across groups. In a high-volume center where its use is part of a coordinated hemorrhage control strategy, REBOA is associated with improved survival in patients with noncompressible torso hemorrhage.

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Reviewer #1: 1. The authors state that REBOA improves survival in the title of the manuscript and throughout its body. This is a retrospective study, therefore the authors cannot state cause and effect, they can only report associations.

2. It appears the REBOA group consisted of patients treated during the period from 2015-2019 to allow a learning period after REBOA was started in 2011. The contemporary period was chosen between 2013 and 2019 and is not truly contemporary with relationhip to when REBOA was started or when the study of REBOA was started. Please explain the rationale for this choice. It seems the contemporary period should be the same as the period of study of REBOA.

3. The authors state that 60 REBOA catheters are placed in their institution per year but their study group only includes 57 patients who received REBOA over a 4 year period. Please explain.

4. The authors state in the limitations section that a large number of patients were removed from the study due to missing data needed for the propensity scoring. The data used for propensity scoring in this study are straight forward and should be available. Why are these data missing in so many patients? Does the removal of patients due to missing data bias the study? What types of patients were removed for missing data?

5. The authors state patient who received REBOA catheters were treated by highly experienced surgeons. Could the experience of the surgeon play a role in the improved outcome.

6. There are many factors that go into the decision of whether or not to place a REBOA catheter that are not captured in the propensity analysis. Patients may not have received a REBOA catheter because they were either too sick or not sick enough. These unknown factors not included in the propensity study could also bias the study. This should be discussed in the limitations.

7. After excluding all ineligible patients, only 57 patients who received a REBOA remain in this 4 year study. This is a small study. This should be discussed in the limitation section.

Reviewer #2: the authors are very experienced in the REBOA procedure and are leaders in this field. This work is an important contribution. Their stated aim, " The aim of this study was to use the local trauma registry of one high-volume Level 1 Trauma Center to compare outcomes between trauma patients who were managed with REBOA and those who received standard treatment without REBOA," is right on target.

However I find the inclusion of patients from the prereboa historical era distracting and not helpful at all. As they state many things have changed since that early time period. so much so that this groups should be dropped from the paper. Its simply distracting and not helpful. Additionally its not consistent with their stated aim.

The authors state that REBOA improves outcomes. However given that their data are retrospective, all they should say is that its associated with improved outcomes.

There is a trend towards decreased death in the reboa group vs contemporary. Please add a table on the causes of death in these patients.

Since reboa is supposed to decrease bleeding and hemorrhagic death, why wasn't there a decrease in transfusion and 24 hr deaths? Please address in the discussion.

Reviewer #3: Thank you for the opportunity to review this manuscript examining outcomes associated with the use of REBOA in a high-volume trauma centre.

The key limitation is the methodology. Although the authors have attempted to mitigate bias associated with a retrospective comparative study (and also discussed this in their limitations), the most significant issue is the likelihood of selection bias. This should be addressed further in the limitations discussion.

Also it would be helpful to understand what were the institutional indications for REBOA. Did these indications change over time?

Why were other markers of bleeding/shock not utilized in the propensity matching? ie heart rate, base deficit, lactate, MTP activation/number of PRBC transfused in the first 4 hours

Adding further variables would provide a more comparable control group

Why were the specific time periods selected for the dichotomy of “historic” vs “contemporary?” What changes in resuscitation/procedures/approaches occurred?

Although no direct comparison between the baseline characteristics of the historic vs contemporary cohorts was made, it appears that the contemporary group are older, less injured (by ISS, although I don’t understand why the AIS are higher in the contemporary group), and different in ethnicity. The outcomes appear to be improved in the contemporary cohort. Explaining the potential differences in the cohorts will assist the reader in understanding the findings of the study.

Reviewer #4: Nicely written work of relevance.

Main concern is around missing data which despite being discussed as limitation remains somewhat obscure. I suggest the authors provide more information in the methods and results section on what the missing important clinical data is rather than just generically stating this and only providing the total number in the results.

For completeness, the methods should also state that acute kidney injury is accounted for as a measured outcome given that it is.

Lastly, this : "60 times per year" and "but were available to the patients in the contemporary and REBOA groups" is redundant, the authors could remove it if they like.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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3 Feb 2022

February 3, 2022

Dear Dr. Balogh,

Thank you to you and the reviewers for their thoughtful comments regarding our manuscript. Please find below a point-by-point response to each comment. A tracked version of the manuscript has been attached. We have uploaded the minimal anonymized data set necessary to replicate our findings as Supporting Information files. In addition, we have added a sentence describing study approval by the IRB.

We hope you and the reviewers find the changes acceptable and the manuscript worthy of publication in PLOS ONE.

Sincerely,

Melike Harfouche, MD

Corresponding Author

mharfouche@som.umaryland.edu

22 S Greene St,

Baltimore, MD 21201

609-610-3165

Reviewer #1:

1. The authors state that REBOA improves survival in the title of the manuscript and throughout its body. This is a retrospective study; therefore the authors cannot state cause and effect, they can only report associations.

Thank you for this comment. We have revised the title and body of the manuscript so that it states an association with survival rather than a cause and effect.

2. It appears the REBOA group consisted of patients treated during the period from 2015-2019 to allow a learning period after REBOA was started in 2011. The contemporary period was chosen between 2013 and 2019 and is not truly contemporary with relationship to when REBOA was started or when the study of REBOA was started. Please explain the rationale for this choice. It seems the contemporary period should be the same as the period of study of REBOA.

Thank you for this question. We have clarified further our reasoning for this split in time periods. We wanted to select a contemporary time period during which REBOA was available to clinicians at our institution, where they could choose between using it/not using it and then select a time period when REBOA was not available, hence the patients were not “at risk” of being exposed to REBOA. That was the rationale for including historical controls, and for starting our contemporary period at the time REBOA was available to be used in 2013. We had incomplete data regarding patients who received REBOA between 2013-2015 as we were only newly entering these patients into the AORTA registry. The two-year delay in inclusion of REBOA patients allowed for minimization of bias from the learning curve associated with introducing a new technique. We have explained this further in the methods portion of the manuscript.

3. The authors state that 60 REBOA catheters are placed in their institution per year but their study group only includes 57 patients who received REBOA over a 4 year period. Please explain.

Patients who received REBOA and were in cardiac arrest were excluded. Similarly, those with incomplete data were excluded as well. We originally identified 107 patients who were eligible for inclusion over the four years but had to exclude some for the aforementioned reasons. The range per year also varies from approximately 30-60 per year. We have adjusted this statement in the methods section so it is clearer. Thank you for pointing out this discrepancy.

4. The authors state in the limitations section that a large number of patients were removed from the study due to missing data needed for the propensity scoring. The data used for propensity scoring in this study are straight forward and should be available. Why are these data missing in so many patients? Does the removal of patients due to missing data bias the study? What types of patients were removed for missing data?

Our trauma registry has undergone several changes over the years, which has led to the missingness of certain data points such as injury severity score, race and vital signs. These were the variables that were missing in most of the patients that were removed. However, removal of these patients did not shift the means of the variables included in the propensity score for either no-REBOA group. We have also added more detail regarding removal of the REBOA patients in the results paragraph. As these variables were missing at random, they did not bias the results of the study.

5. The authors state patient who received REBOA catheters were treated by highly experienced surgeons. Could the experience of the surgeon play a role in the improved outcome.

Thank you for this comment. We indeed believe that surgeon experience may have played a role in the improved outcome in the REBOA group, but we cannot demonstrate this with the data. The same experienced surgeons treated the no REBOA patients. Please see the sentence in the last paragraph of the discussion which I have added onto the sentence starting with “We can only speculate…”.

6. There are many factors that go into the decision of whether or not to place a REBOA catheter that are not captured in the propensity analysis. Patients may not have received a REBOA catheter because they were either too sick or not sick enough. These unknown factors not included in the propensity study could also bias the study. This should be discussed in the limitations.

Thank you. I have added to the sentence in the limitations section to make it clear that additional factors may have affected the decision to place or not place a REBOA catheter, which may have influenced the primary outcome of mortality.

7. After excluding all ineligible patients, only 57 patients who received a REBOA remain in this 4 year study. This is a small study. This should be discussed in the limitation section.

I have added a sentence to the limitations section that emphasizes that this is a small study and should be interpreted as such.

Reviewer #2:

1. I find the inclusion of patients from the pre-REBOA historical era distracting and not helpful at all. As they state many things have changed since that early time period. so much so that this groups should be dropped from the paper. Its simply distracting and not helpful. Additionally its not consistent with their stated aim.

Thank you for these comments, and I hope we can address your concerns regarding including of a historical period. Our reasoning for including patients from 2000-2012 was to provide historic controls that were treated during a period when REBOA was not available. This would eliminate any bias associated with unknown factors that influenced whether REBOA was used during the contemporary period. However, due to changes in resuscitation techniques and advancements in trauma care, we also included a contemporary no-REBOA group. We have clarified this is in more detail in the methods section.

2. The authors state that REBOA improves outcomes. However given that their data are retrospective, all they should say is that its associated with improved outcomes.

Thank you for pointing this out. We have adjusted the title and edited the discussion so it is clearer that this is an association and we cannot conclude a direct causation.

3. There is a trend towards decreased death in the REBOA group vs contemporary. Please add a table on the causes of death in these patients.

Thank you for this point. We have done additional retrospective chart review to determine cause of death in both contemporary and REBOA groups. Hemorrhage was the primary cause of death in both groups, with a slightly higher proportion of deaths primarily attributable to TBI in the contemporary group which did not reach statistical significance. We have updated the results section with these findings.

4. Since REBOA is supposed to decrease bleeding and hemorrhagic death, why wasn't there a decrease in transfusion and 24 hr deaths? Please address in the discussion.

Thank you for these comments. We have added a paragraph to the discussion regarding the lack of significance in the 24-hour survival of the REBOA vs contemporary group. We have also added a sentence explaining our thoughts regarding the lower transfusion requirements in the no-REBOA groups.

Reviewer #3: Thank you for the opportunity to review this manuscript examining outcomes associated with the use of REBOA in a high-volume trauma centre.

1. The key limitation is the methodology. Although the authors have attempted to mitigate bias associated with a retrospective comparative study (and also discussed this in their limitations), the most significant issue is the likelihood of selection bias. This should be addressed further in the limitations discussion.

Thank you. We have addressed this issue of selection bias in more detail in the limitations section.

2. Also it would be helpful to understand what were the institutional indications for REBOA. Did these indications change over time?

Thank you for this comment. There were no changes to indications for REBOA placement during the study period. We have added two sentences to the Methods section under “Institutional Setting” to explain our approach to REBOA placement.

3. Why were other markers of bleeding/shock not utilized in the propensity matching? ie heart rate, base deficit, lactate, MTP activation/number of PRBC transfused in the first 4 hours. Adding further variables would provide a more comparable control group.

Thank you for these comments. Unfortunately, base deficit, lactate, and MTP activation/blood transfusion in 4 hours are not variables that are available in the trauma registry which is why they could not be included in calculation of the propensity score. We strongly agree that they add additional information regarding the comparability of the groups. We have gone back and done an additional chart review to collect variables that are available in the electronic medical record and have added information regarding lactate and base deficit levels in the REBOA and contemporary groups post-match, confirming that they are in fact comparable. Please see changes in the results and methods section. We could not obtain this data for the historic group in the EMR. MTP activation and blood transfusion data cannot be reliably collected from the EMR retrospectively and hence we did not include them. We believe lowest systolic blood pressure within the first hour after arrival is more closely associated with mortality than initial heart rate, which is why we did not include it in calculation of our propensity score.

4. Why were the specific time periods selected for the dichotomy of “historic” vs “contemporary?” What changes in resuscitation/procedures/approaches occurred?\\

Although no direct comparison between the baseline characteristics of the historic vs contemporary cohorts was made, it appears that the contemporary group are older, less injured (by ISS, although I don’t understand why the AIS are higher in the contemporary group), and different in ethnicity. The outcomes appear to be improved in the contemporary cohort. Explaining the potential differences in the cohorts will assist the reader in understanding the findings of the study.

Thank you for this question. We have added a more detailed explanation in the methods section regarding our reasoning for selecting historic (2000-2012) and contemporary (2013-2019) groups. The historic group is meant to represent a period when REBOA was not available, and hence reduce selection bias. However, changes in resuscitation and management techniques (primarily balanced resuscitation, damage control surgery and permissive hypotension) likely influenced outcome in the historic group, which is why a contemporary group was also included to compare to REBOA. This contemporary group was selected to start at the time REBOA was being used at our institution. We have added more to the discussion section to emphasize how changes in resuscitation techniques may have led to better outcomes in the REBOA and contemporary groups when compared to the historic group.

Reviewer #4: Nicely written work of relevance.

1. Main concern is around missing data which despite being discussed as limitation remains somewhat obscure. I suggest the authors provide more information in the methods and results section on what the missing important clinical data is rather than just generically stating this and only providing the total number in the results.

Thank you for this question. The missing clinical data pertained to the variables used to calculate the propensity score (mainly injury severity score and vital signs). This was missing at random, and as such did not bias the study. The overall averages in the variables used to calculate the PS did not change after these patients were removed. We have added clarifying information to the methods and results section.

2. For completeness, the methods should also state that acute kidney injury is accounted for as a measured outcome given that it is.

Thank you, this has been added.

3. Lastly, this : "60 times per year" and "but were available to the patients in the contemporary and REBOA groups" is redundant, the authors could remove it if they like.

Thank you. We have removed the “were available…” portion of that sentence to make it less redundant. We have left the 60 times per year statement as it indicates that our center is considered high volume and may have influenced better outcomes.

Submitted filename: Response to Reviewers.pdf

Click here for additional data file.

8 Mar 2022

RESUSCITATIVE ENDOVASCULAR BALLOON OCCLUSION OF THE AORTA ASSOCIATED WITH IMPROVED SURVIVAL IN HEMORRHAGIC SHOCK

PONE-D-21-37832R1

Dear Dr. Harfouche,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Zsolt J. Balogh, MD, PhD, FRACS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

thank you

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have not substantially changed the manuscript in response to the reviewers comments. The inclusion of historical controls remains problematic due to the many changes that have occurred over time. It remains unclear why so many patients were excluded due to missing data when the data necessary for propensity matching should be present in any version of a trauma registry. The population studies is very small due to all of the exclusions but the conclusions are very bold in the face of the limitations.

Reviewer #2: The authors state the historical control groups is to mitigate selection bias. Since REBOA wasn't available during that time, selection isn't possible. I'm not sure why they use this group at all; selection bias is not a reason.

Reviewer #3: (No Response)

Reviewer #4: All comments adequately addressed except reviewer 2 comment 1, for which a supportive explanation was given. I think the review could be considered reasonably acceptable

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

14 Mar 2022

PONE-D-21-37832R1

Resuscitative Endovascular Balloon Occlusion of the Aorta ASSOCIATED WITH IMPROVED Survival in Hemorrhagic Shock

Dear Dr. Harfouche:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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PLOS ONE