Purpose and Objectives
The spleen is the most commonly injured intra-abdominal solid organ following blunt injury in adults (1-3). Current guidelines for blunt splenic injury (BSI) treatment in adults favor non-operative management due to avoided operative morbidity and mortality as well as to averting the immunologic consequences of splenectomy (4). These guidelines are based primarily on retrospectively collected data and opinion. In the vacuum left by the lack of even a single randomized prospective multi-institutional trial examining this injury, several competing treatment protocols have emerged (5 – 10).
Much of the controversy surrounding BSI management in adults has to do with management of vascular abnormalities observed on computed tomography of the abdomen near to the time of injury. These abnormalities can take the form of intraparenchymal contrast accumulation (which will be defined for the purposes of this protocol as splenic pseudoaneurysm), or extravasation of contrast from the spleen not confined to the parenchyma (which will be defined for the purposes of this protocol as a contrast blush). The management of both abnormalities is controversial (5-10).
Immediate splenectomy, splenic angiography with embolization, and observation only are some of the treatment strategies used to manage these injuries. However, what is not known is the natural history and splenic salvage rates using these contrasting management techniques. Thus, there is an urgent need for a series of multi-institutional trials (including observational and randomized trials) to help determine the most advantageous BSI management strategy. Until these trials are completed, adoption of guidelines for BSI management will continue to be variable and injured patients will continue to receive, potentially, sub-optimal treatment.
To fill the significant knowledge gap we propose collecting data from adult patients with
BSI from multiple institutions across the United States and pursuing the following specific aims:
1. Ascertain the in-hospital risk of splenectomy for adult patients with BSI who present with or develop a splenic pseudoaneurysm, contrast blush or both while in-hospital.
2. Determine factors related to failure of non-operatively managed blunt splenic injuries with splenic pseudoaneurysm or contrast blush or both.
Accomplishing Specific Aim 1 will provide a description of the natural history of splenic pseudoaneurysm and contrast blush using retrospectively collected data. This information is critical so that adequately powered clinical trials for diagnosis, treatment, and follow-up care involving patients with BSI can be designed. By utilizing detailed information about each subject we will be able to address Specific Aim 2 . We will determine the physiologic, injury and management factors associated with failure of
Page 1 of 10

non-operative management of BSI in an effort to define patients that may benefit from early splenectomy.
Background and significance
Of the millions of adults in the United States who are injured every year, nearly 39,000 will be admitted with a BSI (1-3). Over the last two decades there has been a shift in management of adults with BSI from primarily operative to primarily non-operative.
While attempted non-operative management is thought to be the best strategy for adults who are hemodynamically stable with BSI, there are still big questions regarding the optimal management of these patients due to a lack of prospectively collected data.
Even the most recently published guidelines for the management of adults with BSI are based on retrospective reviews and expert opinion (4). Basic information such as the rate of splenectomy after attempted non-operative management has not been prospectively collected. The retrospective data that do exist indicate that a little over
10% of patients with non-operatively managed BSI suffer early failure resulting in splenectomy within 5 days of injury (11-13).
Factors associated with failed non-operative management of BSI are also controversial in the extant literature. It may be that early failures of nonoperative management represent a group of patients who were inappropriately observed. Age greater than 55, increasing grade of spleen injury, presence of moderate to large hemoperitoneum on imaging studies, periods of hypotension and tachycardia, as well as the presence of splenic pseudoaneurysm or contrast blush have been suggested as potential risk factors associated with splenectomy after attempted non-operative management
(12,16).
One controversial question in the management of BSI has to do with the management of patients with splenic pseudoaneurysm or contrast blush. Some advocate early splenic angiography and embolization (5,6). Using this protocol successful splenic salvage rates have been reported as 92% (6). Another strategy utilized in an attempt to maximize splenic salvage is to screen for splenic pseudoaneurysms within the first 24
–
48 hours of non-operative management of BSI. Using a splenic pseudoaneurysm screening protocol, Davis and colleagues reported an improvement in non-operative success in the setting of BSI to 94% (7). On the other hand, some groups advocate for early splenectomy in the setting of splenic pseudoaneurysm or contrast blush (9,17).
The long-term goal of this line of research is to advance the care of injured patients with
BSI so that splenic salvage is maximized while morbidity and mortality are minimized.
Achieving the specific aims of this proposal will be a significant contribution because it will be a step in a continuum of research that is expected to lead to the development of management strategies that will result in subjecting adults with BSI to the least risk while preserving the most spleens.
Research Plan / Methods
Page 2 of 10

Study Design
This study will be a retrospective data collection study. Patients will be screened for eligibility based on inclusion/exclusion criteria when they are admitted. Data collection from a review of the patient chart will include patient demographics, past medical history
(including calculation of the Charlson Comorbidity Index) injury related details, physiologic details, radiographic studies and any spleen related interventions that took place prior to study enrollment. Overall, we expect that each patient will be managed according to the local standard of care at each participating institution. The study protocol will be only to collect data obtained during standard of care treatment given to each subject as well as the outcome from the treatment. Thus, there is minimal overall study related risk to participating subjects.
Study Population
The study sample will be derived from patients admitted to the participating centers.
The inclusion criteria consist of adult (age ≥ 18) persons who suffer a BSI and who have either a splenic pseudoaneurysm or contrast blush on computed tomography of the abdomen with contrast within 24 hours of admission. Persons will be excluded from the study if they: 1) are more than twenty-four hours from the time of injury when they are admitted to the hospital; 2) have a history of a previous splenic injury; 3) have a history of surgery involving the spleen; 4) have a history of a significant bleeding disorder (eg.
Factor VII deficiency, Factor VIII deficiency); 5) are pregnant women (assessed by a urine pregnancy test); 6) or who have a history of any of the following: a. Hereditary elliptocytosis b. Hereditary spherocytosis c. sickle cell disease d. Thallassemia e. Hodgkins or Non-Hodgkins lymphoma f. Other lymphomas g. Leukemia h. Polycythemia vera i. Myeolofibrosis j. Metabolic storage diseases k. Amyloidosis l. Splenic vein thrombosis m. Cirrhosis n. Splenic cysts o. Sarcoidosis p. Systemic lupus erythematosous
We plan to make recruitment of women and minorities a priority for this project and we will include persons of any race who are eligible for the study. Persons under the age of
18 will not be included because the management of children with BSI is much less
Page 3 of 10

controversial and because children are much less likely to suffer delayed splenectomy after BSI due to the anatomy of the spleen in a child.
Recruitment and Consent Procedures
The institutional PI or his or her designee will carry out screening for this study. At each study site, similar screening procedures will be followed. If the patient meets inclusion criteria and does not meet the exclusion criteria, the patient chart will be reviewed for required data points.
Study data collected for this study is extracted from the patient chart and therefore no data will be obtained outside of data collected during standard of care procedures.
Randomization Procedures
Subjects will not be randomized in this study.
List procedures specific to the subjects being studied
Participating subjects will not undergo any procedures associated with this study except to obtain data regarding treatment. Each institution is expected to maintain treatment of subjects in accordance with the local standard of care. Below is a list of study related data that will be obtained at various time-points.
A. At study enrollment
1. Demographic data and past medical history including Charlson Comorbidity Index and use of anti-platelet drugs and/or warfarin as an outpatient will be recorded.
Smoking history and past surgical history will also be obtained.
2. Admission physiologic characteristics including admission vital signs and pertinent laboratory data.
3. Injury characteristics including Abbreviated Injury Scale for each system, the Injury
Severity Score, Glasgow Coma Score, spinal cord injury level (if the patient has a spinal cord injury) and any associated intra-abdominal injuries.
4. Spleen injury characteristics including AAST injury grade. Admission computed tomography scans will be uploaded to the data management system.
B. At the time of any spleen related intervention (in-patient)
1. Splenic angiography and/or embolization
2. Splenorrahphy
3. Splenectomy
For each of these interventions, details regarding vital signs and reason for the intervention will be obtained. If angioembolization was performed, details regarding the type of embolization material used and the location of embolization (main splenic artery
Page 4 of 10

vs selective embolization) will be obtained. Pertinent imaging will also be uploaded to the data management system.
C. At Hospital Discharge
1. Discharge related information including length of stay, length of intensive care unit stay and discharge disposition.
Details about the Charlson Comorbidity Index:
Charlson Comorbidity Index (CCI): Since injured persons may present to the trauma center with pre-existing medical conditions that could impact quality of life and functional capacity as well as survival, we will adjust for pre-existing medical disease using the
CCI. The CCI contains 19 categories of comorbidity, which are primarily defined using
ICD-9 diagnoses codes. Each category has an associated weight, taken from the original Charlson paper (18), which is based on the adjusted risk of one-year mortality.
The overall comorbidity score reflects the cumulative increased likelihood of one-year mortality. The CCI has been utilized to adjust for comorbidities in studies of injured persons and can be given in a self report form (19,20). The CCI will be calculated at the time of study enrollment.
Benefits to subjects
This study does not change the way patients are treated, thus, there is no direct benefit associated with study participation. However, there is the possibility from the data gathered in this study that future patients with BSI may benefit.
Risks to subject and/or fetus
There are no physical risks associated with this study because there are no medications or treatments being given to subjects for this study. There is, however, the potential risk of loss of confidentiality. Every effort will be made to keep each subject ’s information confidential; however, this cannot be guaranteed.
Drug/Device Information
There are no devices used in this study.
Safety
Since there are no treatments prescribed in the protocol there is minimal risk to subjects. Subject confidentiality is paramount in this study since we will be obtaining
Page 5 of 10

protected health information. The details of how study related data are to be handled are outlined in the confidentiality section below.
Data Integrity/ Data Management / Monitoring Plan
Data will be maintained in an online, secure, HIPAA-compliant database administered by the American Association for the Surgery of Trauma. The website is password protected. Each site PI will have access to subjects enrolled from their site only. No PI will have access to the entire database. The study PI, however, will have the ability to monitor data input from each participating site. At least monthly, the number of subjects enrolled will be determined and the amount of missing data will be determined by the study PI. To ensure consistency among sites regarding data entry, a study related data dictionary will be developed. These efforts will help to ensure that the data gathered as part of this study is of the highest quality possible.
DSMB
Since this is a retrospective data collection study with no study related interventions, there is no need for a DSMB.
Alternative treatments
Subjects will receive treatment in accordance with the local standard of care for their injuries, including the injury to the spleen, regardless of study participation status.
Confidentiality
All paper research records will be stored in locked file cabinets and will be accessible only to research personnel. All electronic research records will be computer password protected and also accessible only to research personnel. Research records will be entered into a computerized study database and will be labeled with a code. A master key which links the subjects ’ names with the codes for each research record will be maintained at the local investigative site until the study has ended and all the information has been collected and verified with the hospital chart.
PHI collected in this study may include medical history, the results of physical exams, lab tests, x-ray exams, and other diagnostic and treatment procedures, as well as basic demographic information. Institutional Review Boards (IRB) may review PHI as part of their responsibility to protect the rights and welfare of research subjects. PHI will not be used or disclosed to any other person or entity, except as required by law, or for authorized oversight of this research study by other regulatory agencies, or for other research for which the use and disclosure of your PHI has been approved by the IRB.
PHI will be used until the study is completed.
Page 6 of 10

No HIPAA will be collected as part of the data set for this study. Subject data sets will be assigned a unique number. Subjects will not be identified in any presentations or publications based on the results of this research study.
Compensation
Subjects will not be compensated for participation in this study.
Costs to Subjects
No additional costs will be incurred by a subject who participates in this study.
Plans for data analysis, including justification of sample size
Descriptive and Preliminary Analyses: Means, standard deviations and frequencies
(where appropriate) will be calculated for the entire cohort for demographic data, the
CCI, as well as admission ISS, and baseline injury characteristics.
Specific Aim #1: Ascertain the in-hospital risk of splenectomy for adult patients with BSI who present with or develop a splenic pseudoaneurysm, contrast blush or both while in-hospital.
Main Outcome: Splenectomy at anytime after study enrollment up to discharge.
Analysis Method: Splenectomy rates will be calculated at various time points after injury.
The numerator for each calculation will be the person time contributed by the patients who have had a splenectomy by the time point. The denominator will be person-time at risk for the cohort up to that time point. The risk of splenectomy at each time-point will also be calculated. For these calculations the numerator will be the number of patients who have had a splenectomy up to the time point of interest. The denominator will be the total number of persons at risk for the outcome.
Secondary Outcome: Any spleen related intervention from time of study enrollment up to discharge.
Specific Aim #2: Determine factors related to failure of non-operatively managed blunt splenic injuries with splenic pseudoaneurysm or contrast blush or both.
Main Outcome: Splenectomy at anytime after study enrollment up to hospital discharge.
Analysis Method: Variables that may influence the in-hospital risk of splenectomy will be tested using univariate and multivariable regression using hierarchical modeling techniques. Because individual patients are clustered within hospitals, we will use hierarchical regression analysis to account for patient clustering. Hierarchical regression analysis is a statistical methodology that provides information on variables that are distributed between the individual and the hospital levels, quantifies the clustering of individual factors within hospitals, and permits the examination of cross level interactions between the effects of hospitals and individual level factors. Models will be built utilizing standard model building strategies. Factors that are associated with delayed splenectomy on univariate analysis (p<0.20) will be eligible for entry into the
Page 7 of 10

multivariable model. Factors with a p<0.05 on multivariable analysis will be considered independent predictors of delayed splenectomy after non-operative management of
BSI.
Secondary Outcomes: Early splenectomy (≤ 10 days after injury) and Late splenectomy
(≥10 days after injury).
Analysis Method: Factors associated with risk of early splenectomy will be determined using similar techniques as described for the main outcome. A similar analysis will be performed for the late splenectomy outcome.
Power Calculation: Based on preliminary data, we expect that for every 1000 admissions at a participating center that 36 patients will be admitted with BSI. Of those, nearly 10% will have splenectomy within 24 hours leaving 33 patients eligible for study enrollment per 1000 admissions. We estimate that in order to observe 60 in-hospital ruptures within 6 months at least of 1000 patients will be needed.
To estimate our ability to detect relationships between multiple variables and our outcomes, we used power analysis methods suggested by Cohen for multiple correlations (24). We set the alpha level at 0.05 and power at 0.80. The following table indicates the sample sizes for moderate (r 2 =0.09) and large (r 2 =0.25) proportions of explained variance that we could detect for varying numbers of predictors in the models.
As Table 1 indicates, with 1000 subjects with complete data we expect to be able to detect moderate and large proportions of explained variance in our models even if we use up to 15 predictors.
Table 1. Sample Sizes for multiple correlations.
Number of
Predictors
Moderate
Proportion of explained
Variance r 2 =0.09
Large proportion of explained variance r 2 =0.25
5
136
45
10
174
59
15
204
70
Literature cited
1. WISQARS [database online]. Atlanta, GA: Centers for Disease Control National
Center For Injury Prevention and Control. Available at: http://www.cdc.gov/ncipc/wisqars/. Accessed August 1, 2008.
Page 8 of 10

2. Peitzman AB, Heil B, Rivera L, et al. Blunt splenic injury in adults: multi-institutional study of the eastern association for the surgery of trauma. J Trauma 2000;49:177-
189.
3. Cogbill TH, Moore EE, Jurkovich GJ, Morris JA, Mucha P Jr, Shackford SR.
Nonoperative management of blunt splenic trauma: a multicenter experience. J
Trauma 1989;29:1312-7.
4. Alonso M, Brathwaite C, Garcia V, et al. Practice management guidelines for the nonoperative management of blunt liver and spleen [database online]. Eastern
Association for the Surgery of Trauma. Available at: http://www.east.org/tpg/livspleen.pdf. Accessed July 1, 2010.
5. Sclafani SJA, Shaftan GW, Scalen TM, et al. Nonoperative salvage of computed tomography-diagnosed splenic injuries: utilization of angiography for triage and embolization for hemostasis. J Trauma 1995;39:818-27.
6. Haan J, Scott J, Boyd-Kranis RL, Ho S, Kramer M, Scalea TM. Admission angiography for blunt splenic injury: advantages and pitfalls. J Trauma
2001;51:1161-5.
7. Davis KA, Fabian TC, Croce MA, et al. Improved success in nonoperative management of blunt splenic injuries: embolization of splenic artery pseudoaneurysms. J Trauma 1998;44:1008-15.
8. Gavant ML, Schurr M, Flick PA, et al. Predicting clinical outcome of nonsurgical management of blunt splenic injury: using CT to reveal abnormalities of splenic vasculature. Am J Radiol 1997;168:207-12.
9. Harbrecht BG, Ko SH, Watson GA, Forsythe RM, Rosengart MR, Peitzman AB.
Angiography for blunt splenic trauma does not improve the success rate of nonoperative management. J Trauma 2007;63:44-9.
10. Zarzaur BL, Kozar RA, Fabian TC, Coimbra R. A survey of American Association for the Surgery of Trauma member practices in the management of adult blunt splenic injury. (Unpublished).
11. Peitzman AB, Harbrecht BG, Rivera L, Heil B, and the Eastern Association for the
Surgery of Trauma Multiinstitutional Trials Workgroup. Failure of observation of blunt splenic injury in adults: variability in practice and adverse consequences. J
Am Coll Surg 2005;201:179-187.
12. Bee TK, Croce MA, Miller PR, Pritchard FE, Fabian TC. Failures of splenic nonoperative management: is the glass half empty or half full? J Trauma
2001;50:230-6.
Page 9 of 10

13. Savage SA, Zarzaur BL, Magnotti LJ, et al. The evolution of blunt splenic injury: resolution and progression. J Trauma 2008;64:1085
– 1092.
14. Crawford RS, Tabbara M, Sheridan R, Spaniolas K, Velmahos GC. Early discharge after nonoeprative management for splenic injuries: increased patient risk caused by late failure? Surgery 2007;142:337-42.
15. Zarzaur BL, Vashi S, Magnotti LJ, Croce MA, Fabian TC. The real risk of splenectomy after discharge home following non-operative management of blunt splenic injury. J Trauma 2009 Jun;66(6):1531-6.
16. Cocanour CS, Moore FA, Ware DN et al. Delayed complications of nonoperative management of blunt adult splenic trauma. Arch Surg 1998;133:619 – 625.
17. Harbrecht BG, Zenati M S, Ochoa JB, et al. Evaluation of a 15-year experience with splenic injuries in a state trauma system. Surgery 2007;141:229-38.
18. Charlson ME, Pompei P, Ales KL, McKenzie CR. 1987. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40: 373-383.
19. Chaudhry S, Jin L, Meltzer D. 2002. Use of a self-report generated charlson comorbidity index for predicting mortality. Abstr Acad Health Serv Res Health
Policy Meet. 2002; 19:5.
20. Nathens AB, Jurkovich GJ, Maier RV, Grossman DC, MacKenzie EJ, Moore M,
Rivara FP. 2001. Relationship between trauma center volume and outcomes.
JAMA 285:1164-71.
21. Hemmila MR, Birkmeyer NJ, Arbabi S, Osborne NH, Wahl WL, Dimick JB.
Introduction to propensity scores: A case study on the comparative effectiveness of laparoscopic vs open appendectomy. Arch Surg. 2010 Oct;145(10):939-45.
22. Braitman LE, Rosenbaum PR. Rare outcomes, common treatments: analytic strategies using propensity scores. Ann Intern Med. 2002;137(8):693-695.
23. Cepeda MS, Boston R, Farrar JT, Strom BL. Comparison of logistic regression versus propensity score when the number of events is low and there are multiple confounders. Am J Epidemiol 2003; 158: 280-287.
24. Cohen, J. 1988. Statistical power analysis for the behavioral sciences. Lawrence
Erlbaum Associates. Hillsdale, NJ.
Page 10 of 10