Dollars and Sense: The Financial Argument for Dedicated Posttrauma Center Care.

OBJECTIVE: To demonstrate that the creation of a Center for Trauma Survivorship (CTS) is not cost-prohibitive but is a revenue generator for the institution. BACKGROUND: A dedicated CTS has been demonstrated to increase adherence with follow-up visits and improve overall aftercare in severely injured patients discharged from the trauma center. A potential impediment to the creation of similar centers is its assumed prohibitive cost. METHODS: This pre and post-cohort study examines the financial impact of patients treated by the CTS. Patients in the PRE cohort were those treated in the year before CTS inception. Eligibility criteria are trauma patients admitted who are ≥18 years of age and have a New Injury Severity Score ≥16 or intensive care unit stay ≥2 days. Financial data were obtained from the hospital's billing and cost accounting systems for a 1-year time period after discharge. RESULTS: There were 176 patients in the PRE and 256 in the CTS cohort. The CTS cohort generated 1623 subsequent visits versus 748 in the PRE cohort. CTS patients underwent more follow-up surgery in their first year of recovery as compared with the PRE cohort (98 vs 26 procedures). Each CTS patient was responsible for a $7752 increase in net revenue with a positive contribution margin of $4558 compared with those in the PRE group. CONCLUSIONS: A dedicated CTS increases subsequent visits and necessary procedures and is a positive revenue source for the trauma center. The presumptive financial burden of a CTS is incorrect and the creation of dedicated centers will improve patients' outcomes and the institution's bottom line.

Unveiling the Lasting Impact: A 15-Year Follow-Up of Short-Term Surgical Mission Experiences.

INTRODUCTION: Resident interest in global surgery has increased over recent years. Incorporating short-term surgical missions (STSMs) into training improves Accreditation Council for Graduate Medical Education (ACGME) competencies and aids in understanding of global health infrastructure. We aim to investigate the impact of STSM participation during residency on the desire for participation after residency, and barriers in doing so. METHODS: Eighteen general surgery residents who participated in STSM with the International Surgical Health Initiative from 2009 to 2017 were surveyed. An 18-question survey encompassing demographics, mission-specific data, ACGME competencies, current perspectives, barriers, and areas for improvement was distributed. RESULTS: The group averaged 5.4 y out of residency and 89% (n = 16) completed the survey. Mean age was 38.5 y with a female predominance (62.5%). During residency, 10 (62.5%) participated in ≥ two STSMs and six (37.5%) participated in one STSM. On average, each resident performed 24 cases per mission. All reported that after their resident STSM experience, they were more inclined to participate as an attending. Twenty-five percent (n = 4) participated in STSMs after residency. Vacation, scheduling, and family factors were ranked the highest barriers. All ACGME competencies were felt to be significantly improved by STSMs. CONCLUSIONS: This is the first long-term follow-up study of general surgery residents who participated in STSMs confirming that resident involvement increases desire for continued participation. Although 100% of residents wanted to participate as attendings, only 25% were successful in doing so. While operative experience is salient in surgical residency, there are other valuable experiences to be gained. Further work should focus on enhancing experiences and mitigation of barriers to continued participation in global humanitarian initiatives.

Brain Endurance Training Improves Dynamic Calisthenic Exercise and Benefits Novel Exercise and Cognitive Performance: Evidence of Performance Enhancement and Near Transfer of Training.

ABSTRACT: Dallaway, N, Mortimer, H, Gore, A, and Ring, C. Brain endurance training improves dynamic calisthenic exercise and benefits novel exercise and cognitive performance: Evidence of performance enhancement and near transfer of training. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this dual study was to evaluate whether brain endurance training (BET)-a mental fatigue countermeasure involving physical and cognitive training-enhanced exercise compared with physical training alone. Two studies (N = 29) used a pretest/training/posttest design, with participants randomized to BET or control groups. During testing, participants performed calisthenic exercises (study 1: press-ups, wall sit, and plank; study 2: burpees, jump squats, leg raises, press-ups, and plank) to failure before and after completing 20-minute cognitive tasks (study 1: memory updating; study 2: memory updating, response inhibition, and nonexecutive functions). Training comprised 3 sessions per week for 4 weeks. In study 1 training sessions, participants completed 2 submaximal exercise sets; each exercise was followed by a 3-minute cognitive task with high (BET) or low (control) cognitive loads. In study 2 training sessions, participants completed 1 submaximal exercise set; after 12-minute cognitive tasks (BET) or rest (control), each exercise was preceded by a 3-minute cognitive task (BET) or rest (control). These cognitive tasks involved response inhibition and memory updating. Performance (exercise repetitions/duration), perceived exertion, and mental fatigue were assessed. In pretesting, exercise performance was matched between groups. In posttesting, BET groups performed more dynamic exercises than control groups but the same number of static exercises. Cognitive task performance was either greater for BET or not different between groups. Neither perceived exertion nor mental fatigue differed between groups and tests. Brain endurance training enhanced dynamic but not static calisthenic exercise performance compared with physical training alongside near transfer of training benefits for novel physical and cognitive task performance.

The Efficacy and Safety of Transversus Abdominis Plane Blocks After Open Cholecystectomy in Low- and Middle-Income Countries.

BACKGROUND: Postoperative pain management is challenging in low- and middle-income countries (LMICs). This study assesses the safety and efficacy of transversus abdominis plane (TAP) blocks as an adjunct for postoperative pain control after an open cholecystectomy in LMICs during short-term surgical missions (STSMs). TAP block is a regional anesthesia technique that has been shown to be effective in providing supplementary analgesia to the anterolateral wall post abdominal surgery. METHODS: A retrospective chart review of patients undergoing open cholecystectomy during STSMs was performed. STSMs took place in Guatemala, the Philippines, and Peru from 2009 to 2019. Measured outcomes including pain scores, presence of postoperative nausea or vomiting, and opioid consumption were compared between TAP block and non-TAP block groups. RESULTS: Of the 48 patients analyzed, 28 underwent TAP block (58%). Non-TAP block patients received, on average, 8 mg of oral morphine equivalents more than the TAP patients (P = 0.035). No significant difference was noted in pain scores, which were taken immediately after surgery, 2 h after surgery, and at multiple times between these time points to calculate an average. Of the patients who received a TAP block, 11% reported nausea or vomiting compared with 45% in the standard group (P < 0.01). There were no reported procedure-related complications. CONCLUSIONS: TAP blocks are safe and effective adjuncts for postoperative pain management on STSMs to LMICs. Additional studies are needed to investigate the potential advantages and disadvantages of more widespread use of TAP blocks in LMICs.

Gender Equity in Humanitarian Surgical Outreach: A Decade of Volunteer Surgeons.

BACKGROUND: Workforce trends in surgery demonstrate persistent gender inequity. Humanitarian surgical outreach opportunities exist for surgeons; however, it is unclear as to whether gender disparities exist in this arena. This pilot study examines gender equity among volunteer surgeons using a decade of compiled data from a surgical nongovernmental organization (NGO) that hosts multinational surgical outreach. We aim to evaluate gender proportions among surgical volunteers, compare the gender profiles of NGO surgeons with local and nationwide cohorts, and examine the productive output of surgical volunteers by gender. MATERIALS AND METHODS: A retrospective review was conducted of the records of the International Surgical Health Initiative, an NGO that hosts short-term surgical missions, to generate a demographic roster of volunteers between 2009 and 2018. Comparisons were made of gender profiles within volunteer cohorts against local institutional data and nationwide surgical workforce data. Productivity outputs of surgical volunteers were compared. Chi-square tests and Wilcoxon two-sample statistical t-tests were used. RESULTS: A total of 23 short-term surgical trips were inclusive of 227 volunteers, and 61% (139) were female. Physicians were less likely to be female than other volunteers. In addition, nonsurgical volunteers were more likely to be female compared with surgical volunteers (67% versus 44%, P < 0.01). No gender differences were observed by average number of trips or propensity for repeat trips among surgical volunteers. No differences were found in proportions of female surgical attendings and residents in the NGO cohort compared with the local and national cohorts. CONCLUSIONS: Females contribute substantially to surgical outreach, representing more than half the volunteers in this organization. Gender profiles of female surgeons in this NGO are in parity with those of surgical attendings and residents in the national census. Male and female volunteer surgeons are equally productive. There is an equitable gender representation among volunteer surgeons in this NGO. Further studies of other surgical organizations participating in surgical outreach are required toward a more complete understanding of female participation in international humanitarian efforts.

Mesenchymal stem cells reverse trauma and hemorrhagic shock-induced bone marrow dysfunction.

BACKGROUND: Lung contusion (LC) followed by hemorrhagic shock (HS) causes persistent bone marrow (BM) dysfunction lasting up to 7 d after injury. Mesenchymal stem cells (MSCs) are multipotent cells that can hasten healing and exert protective immunomodulatory effects. We hypothesize that MSCs can attenuate BM dysfunction after combined LCHS. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 5-6 per group) underwent LC plus 45 min of HS (mean arterial pressure of 30-35). Allogeneic MSCs (5 × 10(6) cells) were injected intravenously after resuscitation. At 7 d, BM was analyzed for cellularity and growth of hematopoietic progenitor cell (HPC) colonies (colony-forming unit-erythroid; burst-forming unit-erythroid; and colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte). Flow cytometry measured %HPCs in peripheral blood; plasma granulocyte colony-stimulating factor (G-CSF) levels were measured via enzyme-linked immunosorbent assay. Data were analyzed by one-way analysis of variance followed by the Tukey multiple comparison test. RESULTS: As previously shown, at 7 d, LCHS resulted in 22%, 30%, and 24% decreases in colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte, burst-forming unit-erythroid, and colony-forming unit-erythroid colony growth, respectively, versus naive. Treatment with MSCs returned all BM parameters to naive levels. There was no difference in %HPCs in peripheral blood between groups; however, G-CSF remained increased up to 7 d after LCHS. MSCs returned G-CSF to naive levels. Plasma from animals receiving MSCs was not suppressive to the BM. CONCLUSIONS: One week after injury, the persistent BM dysfunction observed in animals undergoing LCHS is reversed by treatment with MSCs with an associated return of plasma G-CSF levels to normal. Plasma from animals undergoing LCHS plus MSCs was not suppressive to BM cells in vitro. Treatment with MSCs after injury and shock reverses BM suppression and returns plasma G-CSF levels to normal.

Evaluation of coagulopathy in cirrhotic patients: A scoping review of the utility of viscoelastic testing.

BACKGROUND: Cirrhosis causes significant coagulopathy. Traditional coagulation tests may not accurately measure coagulopathy in well-compensated patients with cirrhosis. Viscoelastic tests are functional tests that may better assess coagulopathy in cirrhotic patients. METHODS: We searched PubMed, ScienceDirect, Google Scholar, and grey literature using terms meaning viscoelastic testing and cirrhosis. After reviewing over 500 titles and abstracts, 40 full-text papers met inclusion criteria. RESULTS: Twenty-two papers found viscoelastic testing was a better indicator of baseline coagulation than traditional testing in cirrhosis. Nineteen additional papers evaluated the utility of peri-procedural viscoelastic testing and found they led to a reduction in blood product administration without increasing risk of hemorrhage, thrombotic events, or other complications. CONCLUSIONS: The usage of viscoelastic testing in patients with cirrhosis allows for better assessment of coagulopathy, resulting in improved outcomes. Educating physicians to optimize care of this high-risk group is necessary to further improve their treatment.

Value in acute care surgery, part 3: Defining value in acute surgical care-It depends on the perspective.

ABSTRACT: The prior articles in this series have focused on measuring cost and quality in acute care surgery. This third article in the series explains the current ways of defining value in acute care surgery, based on different stakeholders in the health care system-the patient, the health care organization, the payer and society. The heterogenous valuations of the different stakeholders require that the framework for determining high-value care in acute care surgery incorporates all viewpoints. LEVEL OF EVIDENCE: Expert Opinion; Level V.

Renoduodenal Fistula Following Penetrating Abdominal Injury.

Renoduodenal fistula is an uncommon occurrence and usually results as a complication of injury or inflammatory process. Here, we describe a case of renoduodenal fistula formation after traumatic injury via gunshot wound to the abdomen. The patient suffered right renal and ureteral injury, complicated by urine leak, managed by surgery, interventional radiology, and urology. His post-hospital course was complicated by recurrent urinary tract infections and was found to have a renoduodenal fistula 3 months after the initial operation. Patient underwent uncomplicated right nephrectomy and repair of fistula. Etiology, presentation, diagnosis, and treatment options of renoduodenal fistula are discussed.

Center for Trauma Survivorship improves postdischarge follow-up and retention.

BACKGROUND: Although the need for high-level care persists postdischarge, severely injured trauma survivors have historically poor adherence to follow-up. We hypothesized that a dedicated Center for Trauma Survivorship (CTS) improves follow-up and facilitates postdischarge specialty care. METHODS: A retrospective study of "CTS eligible" trauma patients before (January to December 2017) and after (January to December 2019) creation of the CTS was performed. Patients with an intensive care unit stay ≥2 days or a New Injury Severity Score of ≥16 are CTS eligible. The before (PRE) cohort was followed through December 2018 and the after (CTS) cohort through December 2020. Primary outcome was follow-up within the hospital system exclusive of mental health and rehabilitative therapy appointments. Secondary outcomes include postdischarge surgical procedures and specialty-specific follow-up. RESULTS: There were no significant differences in demographics or hospital duration in the PRE (n = 177) and CTS (n = 119) cohorts. Of the CTS group, 91% presented for outpatient follow-up within the hospital system, compared with 73% in the PRE group (p < 0.001). In the PRE cohort, only 39% were seen by the trauma service compared with 62% in the CTS cohort (p < 0.001). Center for Trauma Survivorship patients also had increased follow-up with other providers (80% vs. 65%; p = 0.006). Notably, 33% of CTS patients had additional surgery compared with only 20% in the PRE group (p = 0.011). Center for Trauma Survivorship patients had more than 20% more outpatient visits (1,280 vs. 1,006 visits). CONCLUSION: Despite the follow-up period for the CTS cohort occurring during the peak of the COVID-19 pandemic, limiting availability of outpatient services, our CTS significantly improved follow-up with trauma providers, as well as with other specialties. The CTS patients also underwent significantly more secondary operations. These data demonstrate that creation of a CTS can improve the postdischarge care of severely injured trauma survivors, allowing for care coordination within the health care system, retaining patients, generating revenue, and providing needed follow-up care. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Data resources for evaluating the economic and financial consequences of surgical care in the United States.

ABSTRACT: Evaluating the relationship between health care costs and quality is paramount in the current health care economic climate, as an understanding of value is needed to drive policy decisions. While many policy analyses are focused on the larger health care system, there is a pressing need for surgically focused economic analyses. Surgical care is costly, and innovative technology is constantly introduced into the operating room, and surgical care impacts patients' short- and long-term physical and economic well-being. Unfortunately, significant knowledge gaps exist regarding the relationship between cost, value, and economic impact of surgical interventions. Despite the plethora of health care data available in the forms of claims databases, discharge databases, and national surveys, no single source of data contains all the information needed for every policy-relevant analysis of surgical care. For this reason, it is important to understand which data are available and what can be accomplished with each of the data sets. In this article, we provide an overview of databases commonly used in surgical health services research. We focus our review on the following five categories of data: governmental claims databases, commercial claims databases, hospital-based clinical databases, state and national discharge databases, and national surveys. For each, we present a summary of the database sampling frame, clinically relevant variables, variables relevant to economic analyses, strengths, weaknesses, and examples of surgically relevant analyses. This review is intended to improve understanding of the current landscape of data available, as well as stimulate novel analyses among surgical populations. Ongoing debates over national health policy reforms may shape the delivery of surgical care for decades to come. Appropriate use of available data resources can improve our understanding of the economic impact of surgical care on our health care system and our patients. LEVEL OF EVIDENCE: Regular Review, Level V.

Trust the FAST: Confirmation that the FAST examination is highly specific for intra-abdominal hemorrhage in over 1,200 patients with pelvic fractures.

BACKGROUND: Use of the focused assessment with sonography for trauma (FAST) examination in patients with pelvic fractures has been reported as unreliable. We hypothesized that FAST is a reliable method for detecting clinically significant intra-abdominal hemorrhage in patients with pelvic fractures. METHODS: All patients with pelvic fractures over a 10-year period were reviewed at a Level I trauma center. The predictive ability of FAST was assessed by calculating the sensitivity, specificity, positive predictive value and negative predictive value against the criterion standard of either computed tomography (CT) or laparotomy findings. The FAST examination was considered "false negative" if findings at laparotomy indicated traumatic intra-abdominal hemorrhage. Likewise, the FAST examination was considered "false positive" if either CT or findings at laparotomy indicated no intra-abdominal hemorrhage. Hemodynamic instability scores were calculated for all patients. RESULTS: There were 1,456 patients with pelvic fractures and an initial FAST reviewed; 1,219 (83.7%) underwent FAST and either CT or operative exploration. Median age was 43 years (interquartile range, 26-56 years) and mean Injury Severity Score was 18.5 ± 12.3. The sensitivity and specificity for FAST in this group of patients with pelvic fracture was 85.4% and 98.1%, respectively. The positive predictive value and negative predictive value were 78.4% and 98.8%, respectively. Of 21 patients with a false-positive FAST, 15 (71.4%) were confirmed with a negative CT scan, and 6 (28.6%) underwent laparotomy without findings of intra-abdominal hemorrhage. Of 13 patients with a false-negative FAST, all were identified with positive findings at the time of laparotomy. The specificity of the FAST examination remained high regardless of hemodynamic instability score grade. CONCLUSION: The false positive rate of FAST examination for intra-abdominal hemorrhage is 1.1%. These data suggest that a positive FAST in this clinical scenario should be considered to represent intra-abdominal fluid. This series contradicts prior reports that FAST is unreliable in patients with pelvic fracture. LEVEL OF EVIDENCE: Diagnostic, level III.

Mesenchymal stem cells enhance lung recovery after injury, shock, and chronic stress.

BACKGROUND: Normal lung healing is impaired when lung contusion (LC) is followed by hemorrhagic shock (HS), and chronic stress (CS). Mesenchymal stem cells (MSCs) are immunomodulatory, pluripotent cells that are under investigation for use in wound healing and tissue regeneration. We hypothesized that treatment with MSCs can reverse the impaired healing seen after LC combined with HS and CS (LCHS/CS). METHODS: Male Sprague-Dawley rats (n = 6/group) underwent LCHS with or without a single intravenous dose of 5 × 10(6) Sprague-Dawley rat MSCs after resuscitation. Thereafter, rats were subjected to 2 hours of CS daily on days 1-6 and were humanely killed on day 7. Lung histology was scored according to a well-established lung injury score (LIS) that included interstitial and pulmonary edema, alveolar integrity, and inflammatory cells. Scoring ranges from 0 (normal lung) to 11 (most severely injured). Whole blood was analyzed for the presence of CD4(+)CD25(+)FoxP3(+) T-regulatory cells (Treg) by flow cytometry. RESULTS: Seven days after isolated LC, LIS had returned to 0.8 ± 0.4; however, after LCHS/CS healing is significantly delayed (7.2 ± 2.2; P < .05). Addition of MSC to LCHS/CS decreased LIS to 2.0 ± 1.3 (P < .05) and decreased all subgroup scores (inflammatory cells, interstitial and pulmonary edema, and alveolar integrity) significantly compared with LCHS/CS (P < .05). The percentage of Tregs found in the peripheral blood of animals undergoing LCHS/CS did not change from LC alone (10.5 ± 3.3% vs 6.7 ± 1.7%; P > .05). Treatment with MSCs significantly increased the Treg population compared with LCHS/CS alone (11.7 ± 2.7% vs 6.7 ± 1.7%; P < .05) CONCLUSION: In this model, severe impairment of wound healing observed 1 week after LCHS/CS is reversed by a single treatment with MSCs immediately after resuscitation. This improvement in lung healing is associated with a decrease in the number of inflammatory cells and lung edema and a significant increase in peripheral Tregs. Further study into the timing of administration and mechanisms by which cell-based therapy using MSCs modulate the immune system and improve wound healing is warranted.

Mesenchymal stem cells reverse bone marrow dysfunction following injury and stress.

BACKGROUND: Bone marrow (BM) dysfunction following experimental lung contusion (LC) resolves in 7 days; however, if followed by chronic stress (CS) following, BM dysfunction is persistent. Mesenchymal stem cells (MSCs) have protective immunomodulatory effects. We hypothesize that MSC can protect the BM against the deleterious effect of CS following LC. METHODS: Male Sprague-Dawley rats (n = 6-7 per group) underwent LC or LC/CS ± MSC injection. CS consisted of a daily 2-hour period of restraint with repositioning and alarming every 30 minutes to prevent habituation. A single intravenous dose of 5 × 10 MSCs was given within 10 minutes following LC. Animals were sacrificed at Day 7, and peripheral blood (PB) and BM were collected. Flow cytometry was used to assess hematopoietic progenitor cells (HPCs) mobilized to PB. Plasma granulocyte colony-stimulating factor (G-CSF) levels were measured by enzyme-linked immunosorbent assay. BM cellularity and growth of BM HPC colonies (colony-forming unit-erythroid [CFU-E], burst-forming unit-erythroid [BFU-E], colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte [CFU-GEMM]) were also evaluated. RESULTS: As previously reported, the addition of CS to LC resulted in a 32% decrease in BM cellularity; significant decreases in CFU-GEMM, BFU-E, and CFU-E; and marked increase in HPC in the PB as compared with the naive animals. The addition of MSC to LC/CS resulted in a 22% increase in BM cellularity and significant increases in CFU-GEMM, BFU-E, and CFU-E cultured from the BM. MSCs additionally reduced plasma G-CSF, prevented prolonged mobilization of HPC to PB, and restored colony growth to naive levels. CONCLUSION: CS following LC results in persistent BM dysfunction manifested by a significant decrease in cellularity, HPC colony growth, and increased G-CSF levels and HPC mobilization to the PB at 7 days following injury. The addition of a single dose of MSCs following acute traumatic injury reverses the deleterious effects of CS on BM function. Further study is warranted to better understand the mechanisms behind MSC-mediated protection of BM function in the setting of CS.

Can mesenchymal stem cells reverse chronic stress-induced impairment of lung healing following traumatic injury?

BACKGROUND: One week following unilateral lung contusion (LC), rat lungs demonstrate full histologic recovery. When animals undergo LC plus the addition of chronic restraint stress (CS), wound healing is significantly delayed. Mesenchymal stem cells (MSCs) are pluripotent cells capable of immunomodulation, which have been the focus of much research in wound healing and tissue regeneration. We hypothesize that the addition of MSCs will improve wound healing in the setting of CS. METHODS: Male Sprague-Dawley rats (n = 6-7 per group) were subjected to LC/CS with or without the injection of MSCs. MSCs were given as a single intravenous dose of 5 × 10 cells in 1 mL Iscove's Modified Dulbecco's Medium at the time of LC. Rats were subjected to 2 hours of restraint stress on Days 1 to 6 following LC. Seven days following injury, rats were sacrificed, and the lungs were examined for histologic evidence of wound healing using a well-established histologic lung injury score (LIS) to grade injury. LIS examines inflammatory cells/high-power field (HPF) averaged over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity, with scores ranging from 0 (normal) to 11 (highly damaged). Peripheral blood was analyzed by flow cytometry for the presence of T-regulatory (C4CD25FoxP3) cells. Data were analyzed by analysis of variance followed by Tukey's multiple comparison test, expressed as mean (SD). RESULTS: As previously shown, 7 days following isolated LC, LIS has returned to 0.83 (0.41), with a subscore of zero for inflammatory cells/HPF. The addition of CS results in an LIS of 4.4 (2.2), with a subscore of 1.9 (0.7) for inflammatory cells/HPF. Addition of MSC to LC/CS decreased LIS to 1.7 (0.8), with a subscore of zero for inflammatory cells/HPF. Furthermore, treatment of animals undergoing LC/CS with MSCs increased the %T-regulatory cells by 70% in animals undergoing LC/CS alone (12.9% [2.4]% vs. 6.2% [1.3%]). CONCLUSION: Stress-induced impairment of wound healing is reversed by the addition of MSCs given at the time of injury in this rat LC model. This improvement in lung healing is associated with a decrease in the number of inflammatory cells and an increase in the number of T-regulatory cells. Further study into the mechanisms by which MSCs hasten wound healing is warranted.

Mesenchymal stem cells increase T-regulatory cells and improve healing following trauma and hemorrhagic shock.

BACKGROUND: Rodent lungs undergo full histologic recovery within 1 week following unilateral lung contusion (LC). However, when LC is followed by hemorrhagic shock (HS), healing is impaired. We hypothesize that the intravenous administration of mesenchymal stem cells (MSCs) in animals undergoing combined LC followed by HS (LCHS) will improve wound healing. METHODS: Male Sprague-Dawley rats (n = 5-6 per group) were subjected to LCHS with or without the injection of a single intravenous dose of 5 × 10 MSCs following return of shed blood after HS. Rats were sacrificed 7 days following injury. Flow cytometry was used to determine the T-regulatory cell (Treg) population in peripheral blood. Lung histology was graded using a well-established lung injury score (LIS). Components of the LIS include average inflammatory cells per high-power field over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity, with total scores ranging from 0 to 11. Data were analyzed by analysis of variance followed by Tukey's multiple comparison test, expressed as mean (SD). p < 0.05 was considered significant. RESULTS: Seven days following isolated LC, animals demonstrated lung healing with an LIS unchanged from naive. The addition of HS resulted in a persistently elevated LIS score, whereas the addition of MSCs to LCHS decreased the LIS score back to naive levels. The change in LIS was driven by a significant decrease in edema scores. In rats undergoing LC alone, 10.5% (3.3%) of CD4 cells were Tregs. The addition of HS caused no significant change in Treg population (9.3% [0.7%]), whereas LCHS + MSC significantly increased the population to 18.2% (6.8%) in peripheral blood (p < 0.05 vs. LCHS). CONCLUSION: Impaired wound healing following trauma and HS is improved by a single dose of MSCs given immediately after injury. This enhanced healing is associated with an increase in the Treg population and a significant decrease in lung edema score as compared with animals undergoing LCHS. Further study into the role of Tregs in MSC-mediated wound healing is warranted.

Chronic restraint stress after injury and shock is associated with persistent anemia despite prolonged elevation in erythropoietin levels.

BACKGROUND: Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (chronic stress [CS]) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia and prolong the initial anemia, despite elevated erythropoietin (EPO) levels. METHODS: Male Sprague-Dawley rats (n = 6-8 per group) underwent lung contusion (LC) or combined LC/hemorrhagic shock (LCHS) followed by 6 days of CS. CS consisted of a 2-hour restraint period interrupted with repositioning and alarms every 30 minutes. At 7 days, urine was assessed for norepinephrine (NE) levels, blood for EPO and hemoglobin (Hgb), and BM for erythroid progenitor growth. RESULTS: Animals undergoing LC or combined LCHS predictably recovered by Day 7; urine NE, EPO, and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on Day 6. The addition of CS to LC led to a persistent 20% to 25% decrease in the growth of BM hematopoietic progenitor cells. These findings were further exaggerated when CS was added following LCHS, resulting in a 20%q to 40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared with LCHS alone. CONCLUSION: Exposing injured animals to CS results in prolonged elevation of NE and EPO, which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating CS after severe injury is a potential therapeutic target to improve BM dysfunction and anemia.

Daily propranolol prevents prolonged mobilization of hematopoietic progenitor cells in a rat model of lung contusion, hemorrhagic shock, and chronic stress.

INTRODUCTION: Propranolol has been shown previously to decrease the mobilization of hematopoietic progenitor cells (HPCs) after acute injury in rodent models; however, this acute injury model does not reflect the prolonged period of critical illness after severe trauma. Using our novel lung contusion/hemorrhagic shock/chronic restraint stress model, we hypothesize that daily administration of propranolol will decrease prolonged mobilization of HPCs without worsening lung healing. METHODS: Male Sprague-Dawley rats underwent 6 days of restraint stress after undergoing lung contusion or lung contusion/hemorrhagic shock. Restraint stress consisted of a daily 2-hour period of restraint interrupted every 30 minutes by alarms and repositioning. Each day after the period of restraint stress, the rats received intraperitoneal propranolol (10 mg/kg). On day 7, peripheral blood was analyzed for granulocyte-colony stimulating factor (G-CSF) and stromal cell-derived factor 1 via enzyme-linked immunosorbent assay and for mobilization of HPCs using c-kit and CD71 flow cytometry. The lungs were examined histologically to grade injury. RESULTS: Seven days after lung contusion and lung contusion/hemorrhagic shock, the addition of chronic restraint stress significantly increased the mobilization of HPC, which was associated with persistently increased levels of G-CSF and increased lung injury scores. The addition of propranolol to lung contusion/chronic restraint stress and lung contusion/hemorrhagic shock/chronic restraint stress models greatly decreased HPC mobilization and restored G-CSF levels to that of naïve animals without worsening lung injury scores. CONCLUSION: The daily administration of propranolol after both lung contusion and lung contusion/hemorrhagic shock subjected to chronic restraint stress decreased the prolonged mobilization of HPC from the bone marrow and decreased plasma G-CSF levels. Despite the decrease in mobilization of HPC, lung healing did not worsen. Alleviating chronic stress with propranolol may be a future therapeutic target to improve healing after severe injury.

Early propranolol administration to severely injured patients can improve bone marrow dysfunction.

BACKGROUND: Bone marrow (BM) dysfunction is common in severely injured trauma patients, resulting from elevated catecholamines and plasma granulocyte colony-stimulating factor (G-CSF) as well as prolonged mobilization of hematopoietic progenitor cells (HPCs). We have previously shown that propranolol (ß-blocker [BB]) reduces HPC mobilization in a rodent model of injury and hemorrhagic shock. We hypothesize that BB would prevent BM dysfunction in humans following severe injury. METHODS: Forty-five severely injured trauma patients were studied in a prospective, randomized pilot trial. Twenty-five patients received BB, and 20 served as untreated controls. The dose of propranolol was adjusted to decrease the heart rate by 10% to 20% from baseline. Blood was analyzed for the presence of HPC (blast-forming unit erythroid cells [BFU-E] and colony-forming unit erythroid cells) and G-CSF. Demographic data, Injury Severity Score (ISS), hemoglobin, reticulocyte number, and outcome data were obtained. RESULTS: The mean age of the study population was 33 years; 87% were male, with a mean ISS of 29. There is a significant increase in BFU-E in peripheral blood immediately following traumatic injury, and this mobilization persists for 30 days. The use of BB significantly decreases BFU-E and colony-forming unit erythroid cells at all time points. G-CSF is significantly elevated in both groups on admission; the use of BB decreases G-CSF levels by 51% as compared with 37% for controls. The average hemoglobin is nearly 1 g higher on the day of discharge with propranolol treatment (BB, 9.9 ± 0.4 g/dL vs. no BB, 9.1 ± 0.6 g/dL). CONCLUSION: Following severe trauma, early treatment with propranolol following resuscitation is safe. The use of propranolol blunts early tachycardia, reduces HPC mobilization, and results in a faster return to baseline of the G-CSF peak seen after injury. There is also a trend toward faster recovery and resolution of anemia. Propranolol may be the first therapeutic agent to show improved BM function after severe injury. LEVEL OF EVIDENCE: Therapeutic study, level III.