Scott C. Brakenridge

Evaluation and Management of Blunt Traumatic Aortic Injury: A Practice Management Guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND Blunt traumatic aortic injury (BTAI) is the second most common cause of death in trauma patients. Eighty percent of patients with BTAI will die before reaching a trauma center. The issues of how to diagnose, treat, and manage BTAI were first addressed by the Eastern Association for the Surgery of Trauma (EAST) in the practice management guidelines on this topic published in 2000. Since that time, there have been advances in the management of BTAI. As a result, the EAST guidelines committee decided to develop updated guidelines for this topic using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework recently adopted by EAST. METHODS A systematic review of the MEDLINE database using PubMed was performed. The search retrieved English language articles regarding BTAI from 1998 to 2013. Letters to the editor, case reports, book chapters, and review articles were excluded. Topics of investigation included imaging to diagnose BTAI, type of operative repair, and timing of operative repair. RESULTS Sixty articles were identified. Of these, 51 articles were selected to construct the guidelines. CONCLUSION There have been changes in practice since the publication of the previous guidelines in 2000. Computed tomography of the chest with intravenous contrast is strongly recommended to diagnose clinically significant BTAI. Endovascular repair is strongly recommended for patients without contraindications. Delayed repair of BTAI is suggested, with the stipulation that effective blood pressure control must be used in these patients.

A randomized, double-blinded, placebo-controlled pilot trial of anticoagulation in low-risk traumatic brain injury: The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP I) study.

BACKGROUND Our group has created an algorithm for venous thromboembolism prophylaxis after traumatic brain injury (TBI), which stratifies patients into low, moderate, and high risk for spontaneous injury progression and tailors a prophylaxis regimen to each arm. We present the results of the Delayed Versus Early Enoxaparin Prophylaxis I study, a double-blind, placebo-controlled, randomized pilot trial on the low-risk arm. METHODS In this two-institution study, patients presenting within 6 hours of injury with prespecified small TBI patterns and stable scans at 24 hours after injury were randomized to receive enoxaparin 30 mg bid or placebo from 24 to 96 hours after injury in a double-blind fashion. An additional computed tomography scan was obtained on all subjects 24 hours after starting treatment (and therefore 48 hours after injury). The primary end point was the radiographic worsening of TBI; secondary end points were venous thromboembolism occurrence and extracranial hemorrhagic complications. RESULTS A total of 683 consecutive patients with TBI were screened during the 28 center months. The most common exclusions were for injuries larger than the prespecified criteria (n = 199) and preinjury anticoagulant use (n = 138). Sixty-two patients were randomized to enoxaparin (n = 34) or placebo (n = 28). Subclinical, radiographic TBI progression rates on the scans performed 48 hours after injury and 24 hours after start of treatment were 5.9% (95% confidence interval [CI], 0.7–19.7%) for enoxaparin and 3.6% (95% CI, 0.1–18.3%) for placebo, a treatment effect difference of 2.3% (95% CI, −14.42–16.5%). No clinical TBI progressions occurred. One deep vein thrombosis occurred in the placebo arm. CONCLUSION TBI progression rates after starting enoxaparin in small, stable injuries 24 hours after injury are similar to those of placebo and are subclinical. The next Delayed Versus Early Enoxaparin Prophylaxis studies will assess efficacy of this practice in a powered study on the low-risk arm and a pilot trial of safety of a 72-hour time point in the moderate-risk arm. LEVEL OF EVIDENCE Therapeutic study, level II.

Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-immunosuppression and Catabolism Syndrome

Objectives: To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design: Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Measurements and Main Results: Sepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit “a persistent inflammation-immunosuppression and catabolism syndrome,” and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusions: Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.

Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock.

Objective: We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. Background: Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Methods: Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. Results: After SS/SS, CD33+CD11b+HLA-DR−/low MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05). Conclusions: After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

Early blood product and crystalloid volume resuscitation: Risk association with multiple organ dysfunction after severe blunt traumatic injury

BACKGROUND Elements of volume resuscitation from hemorrhagic shock, such as amount of blood product and crystalloid administration, have been shown to be associated with multiple organ dysfunction (MOD). However, it is unknown whether these are causative factors or merely markers of an underlying requirement for large-volume resuscitation. We sought to further delineate the relevance of the major individual components of early volume resuscitation to onset of MOD after severe blunt traumatic injury. METHODS We performed a secondary analysis of a large, multicenter prospective observational cohort of severely injured blunt trauma patients, the NIGMS Trauma Glue Grant, to assess the relevance of individual components of resuscitation administered in the first 12 hours of resuscitation including packed red blood cells (PRBC), fresh frozen plasma (FFP), and isotonic crystalloid, to the onset of MOD within the first 28 days after injury. Deaths within 48 hours of injury were excluded. We used a two tiered, exhaustive logistic regression model search technique to adjust for potential confounders from clinically relevant MOD covariates, including indicators of shock severity, injury severity, comorbidities, age, and gender. RESULTS The study cohort consisted of 1,366 severely injured blunt trauma patients (median new Injury Severity Score = 34). Incidence of 28-day Marshall MOD was 19.6%. Transfusion of ≥10 Units of PRBC in the first 12 hours (odds ratio, 2.06; 95% confidence interval 1.44-2.94), but not FFP (≥8 U) or large volume crystalloid administration (≥12 L), was independently associated with onset of 28-day Marshall MOD. PRBC:FFP ratio in the first 12 hours was not significantly associated with MOD. CONCLUSIONS When controlling for all major components of acute volume resuscitation, massive-transfusion volumes of PRBCs within the first 12 hours of resuscitation are modestly associated with MOD, whereas FFP and large volume crystalloid administration are not independently associated with MOD. Previous reported associations of blood products and large-volume crystalloid with MOD may be reflecting overall resuscitation requirements and burden of injury rather than independent causation.

Comparing clinical predictors of deep venous thrombosis versus pulmonary embolus after severe injury: A new paradigm for posttraumatic venous thromboembolism?

BACKGROUND: The traditional paradigm is that deep venous thrombosis (DVT) and pulmonary embolus (PE) are different temporal phases of a single disease process, most often labeled as the composite end point venous thromboembolism (VTE). However, we theorize that after severe blunt injury, DVT and PE may represent independent thrombotic entities rather than different stages of a single pathophysiologic process and therefore exhibit different clinical risk factor profiles. METHODS: We examined a large, multicenter prospective cohort of severely injured blunt trauma patients to compare clinical risk factors for DVT and PE, including indicators of injury severity, shock, resuscitation parameters, comorbidities, and VTE prophylaxis. Independent risk factors for each outcome were determined by cross‐validated logistic regression modeling using advanced exhaustive model search procedures. RESULTS: The study cohort consisted of 1,822 severely injured blunt trauma patients (median Injury Severity Score [ISS], 33; median base deficit, ‐9.5). Incidence of DVT and PE were 5.1% and 3.9%, respectively. Only 9 (5.7%) of 73 patients with a PE were also diagnosed with DVT. Independent risk factors associated with DVT include prophylaxis initiation within 48 hours (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.36–0.90) and thoracic Abbreviated Injury Scale (AIS) score of 3 or greater (OR, 1.82; 95% CI, 1.12–2.95), while independent risk factors for PE were serum lactate of greater than 5 (OR, 2.33; 95% CI, 1.43–3.79) and male sex (OR, 2.12; 95% CI, 1.17–3.84). Both DVT and PE exhibited differing risk factor profiles from the classic composite end point of VTE. CONCLUSION: DVT and PE exhibit differing risk factor profiles following severe injury. Clinical risk factors for diagnosis of DVT after severe blunt trauma include the inability to initiate prompt pharmacologic prophylaxis and severe thoracic injury, which may represent overall injury burden. In contrast, risk factors for PE are male sex and physiologic evidence of severe shock. We hypothesize that postinjury DVT and PE may represent a broad spectrum of pathologic thrombotic processes as opposed to the current conventional wisdom of peripheral thrombosis and subsequent embolus. LEVEL OF EVIDENCE: Prognostic study, level III.

A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die of infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared with their younger counterparts, the elderly do not respond to severe infection or injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects do. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after posttrauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24-mo-old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an emergency myelopoietic response, engendering myeloid cells that fail to clear secondary infection. In addition, elderly people appeared unable to resolve their inflammatory response to severe injury effectively.

Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock

IntroductionWe wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.MethodsWe performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.ResultsWe found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients’ plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.ConclusionsWe concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population’s age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

A protocol for the management of adhesive small bowel obstruction

BACKGROUND Differentiating between partial adhesive small bowel obstruction (aSBO) likely to resolve with medical management and complete obstruction requiring operative intervention remains elusive. We implemented a standardized protocol for the management of aSBO and reviewed our experience retrospectively. METHODS Patients with symptoms of aSBO were admitted for intravenous fluid resuscitation, bowel rest, nasogastric tube decompression, and abdominal examinations every 4 hours. Laboratory values and a computed tomography scan of the abdomen and pelvis with intravenous contrast were obtained. Patients with peritonitis or computed tomography scan findings suggesting bowel compromise were taken to the operating room for exploration following resuscitation. All other patients received 80 mL of Gastroview (GV) and 40 mL of sterile water via nasogastric tube. Abdominal plain films were obtained at 4, 8, 12, and 24 hours. If contrast did not reach the colon within 24 hours, then operative intervention was performed. RESULTS Over 1 year, 91 patients were admitted with aSBO. Sixty-three patients received GV, of whom 51% underwent surgery. Twenty-four patients went directly to the operating room because of clinical or imaging findings suggesting bowel ischemia. Average time to surgery was within 1 day for the no-GV group and 2 days for the GV group. Patients passing GV to the colon within 5 hours of administration had a 90% rate of resolution of obstruction. There was a direct relationship between the duration of time before passing GV to the colon and hospital length of stay (HLOS) (r2 = 0.459). Patients who received GV and did not require surgery had lower HLOS (3 days vs. 11 days, p < 0.0001). CONCLUSION The GV protocol facilitated early recognition of complete obstruction. Administration of GV had diagnostic and therapeutic value and did not increase HLOS, morbidity, or mortality. LEVEL OF EVIDENCE Therapeutic study, level V. Epidemiologic study, level V.

Predictors of early versus late timing of pulmonary embolus after traumatic injury

OBJECTIVE To identify risk factors predictive of pulmonary embolus (PE) timing after a traumatic injury. METHODS One hundred eight traumatic injury patients with a confirmed diagnosis of PE were classified as early PE (≤4 days, n = 54) or late PE (>4 days, n = 54). Independent predictors of early versus late PE were identified using multivariate logistic regression. RESULTS Half the PEs were diagnosed ≤4 days of injury. Only long bone fractures independently predicted early PE (odds ratio 2.8; 95% confidence interval, 1.1-7.1). Severe head injuries were associated with late PE (odds ratio 11.1; 95% confidence interval, 3.9-31). Established risk factors such as age did not affect timing. CONCLUSIONS Half the PEs were diagnosed ≤4 days after injury. The risk of early PE appeared highest in patients with long bone fractures, and the benefits of immediate prophylaxis may outweigh risks. Patients with severe head injuries appear to have later PE events. Prospective interventional trials in these injury populations are needed.