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Background: The combined injury of traumatic brain injury and hemorrhagic shock has been shown to worsen coagulopathy and systemic inflammation, thereby increasing posttraumatic morbidity and mortality. Aeromedical evacuation to definitive care may exacerbate postinjury morbidity because of the inherent hypobaric hypoxic environment. We hypothesized that blood product resuscitation may mitigate the adverse physiologic effects of postinjury flight., Methods: An established porcine model of controlled cortical injury was used to induce traumatic brain injury. Intracerebral monitors were placed to record intracranial pressure, brain tissue oxygenation, and cerebral perfusion. Each of the 42 pigs was hemorrhaged to a goal mean arterial pressure of 40 ± 5 mm Hg for 1 hour. Pigs were grouped according to resuscitation strategy used-Lactated Ringer's (LR) or shed whole blood (WB)-then placed in an altitude chamber for 2 hours at ground, 8,000 ft, or 22,000 ft, and then observed for 4 hours. Hourly blood samples were analyzed for proinflammatory cytokines and lactate. Internal jugular vein blood flow was monitored continuously for microbubble formation with altitude changes., Results: Cerebral perfusion, tissue oxygenation, and intracranial pressure were unchanged among the six study groups. Venous microbubbles were not observed even with differing altitude or resuscitation strategy. Serum lactate levels from hour 2 of flight to the end of observation were significantly elevated in 22,000 + LR compared with 8,000 + LR and 22,000 + WB. Serum IL-6 levels were significantly elevated in 22,000 + LR compared with 22,000 + WB, 8,000 + LR and ground+LR at hour 1 of observation. Serum tumor necrosis factor-α was significantly elevated at hour 2 of flight in 8,000 + LR versus ground+LR, and in 22,000 + LR vs. 22,000 + WB at hour 1 of observation. Serum IL-1β was significantly elevated hour 1 of flight between 8,000 + LR and ground+LR., Conclusion: Crystalloid resuscitation during aeromedical transport may cause a prolonged lactic acidosis and proinflammatory response that can predispose multiple-injury patients to secondary cellular injury. This physiologic insult may be prevented by using blood product resuscitation strategies., (Copyright © 2021 American Association for the Surgery of Trauma.)

Background: The management of hypotensive patients with severe combined head and abdominal trauma is challenging, regarding the need, timing, and sequence of craniotomy or laparotomy. The purpose of the present study was to determine whether rare situations requiring craniotomy prior to laparotomy can be identified on admission with simple clinical parameters. We hypothesized that hypotension is rarely associated with the need of a combined procedure, especially in patients with mildly depressed consciousness., Methods: National Trauma Data Bank study, including adult blunt trauma patients with combined severe head (Abbreviated Injury Scale score, ≥ 3) and abdominal injury (Abbreviated Injury Scale score, ≥ 3). Data collection included demographic and clinical characteristics, laparotomy, and craniotomy within 24 hours of admission, types of intracranial pathologies, survival, and hospital stay. Multivariate regression analysis was used to determine factors predictive for the need of both operative procedures., Results: Of 25,585 patients with severe combined head and abdominal trauma, 8,744 (34.2%) needed only laparotomy, 534 (2.1%) only craniotomy, and 394 (1.5%) required both procedures within 24 hours of admission. In the subgroup of 4,667 hypotensive patients, 2,421 (51.9%) underwent only laparotomy, 54 (1.2%) only craniotomy, and 79 (1.7%) both procedures within 24 hours of admission. Only 5 (0.7%) of 711 hypotensive patients with Glasgow Coma Scale (GCS) score above 8 who required a laparotomy also needed a craniotomy. Among clinical parameters available on patient's arrival, GCS score of 7 to 8 was independently associated with the highest need for craniotomy in hypotensive patients requiring laparotomy (odds ratio, 7.94; p = 0.004)., Conclusion: The need for craniotomy in patients with severe combined head and abdominal injury requiring exploratory laparotomy is very low. In hypotensive patients requiring laparotomy, GCS score of 7 to 8 was an independent predictor of the need for craniotomy. In hemodynamically unstable patients with a GCS score greater than 8, it may be safer to proceed with a laparotomy first and address the head with a computed tomography scan at a later stage., Level of Evidence: Therapeutic, Level IV., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Multiply injured patients are at risk of developing hemorrhagic shock and organ dysfunction. We determined how cumulative hypoperfusion predicted organ dysfunction by integrating serial Shock Index measurements., Methods: In this study, we calculated shock volume (SHVL) which is a patient-specific index that quantifies cumulative hypoperfusion by integrating abnormally elevated Shock Index (heart rate/systolic blood pressure ≥ 0.9) values acutely after injury. Shock volume was calculated at three hours (3 hr), six hours (6 hr), and twenty-four hours (24 hr) after injury. Organ dysfunction was quantified using Marshall Organ Dysfunction Scores averaged from days 2 through 5 after injury (aMODSD2-D5). Logistic regression was used to determine correspondence of 3hrSHVL, 6hrSHVL, and 24hrSHVL to organ dysfunction. We compared correspondence of SHVL to organ dysfunction with traditional indices of shock including the initial base deficit (BD) and the lowest pH measurement made in the first 24 hr after injury (minimum pH)., Results: SHVL at all three time intervals demonstrated higher correspondence to organ dysfunction (R = 0.48 to 0.52) compared to initial BD (R = 0.32) and minimum pH (R = 0.32). Additionally, we compared predictive capabilities of SHVL, initial BD and minimum pH to identify patients at risk of developing high-magnitude organ dysfunction by constructing receiver operator characteristic curves. SHVL at six hours and 24 hours had higher area under the curve compared to initial BD and minimum pH., Conclusion: SHVL is a non-invasive metric that can predict anticipated organ dysfunction and identify patients at risk for high-magnitude organ dysfunction after injury., Level of Evidence: Prognostic study, level III.

Background: We have previously shown that treatment with valproic acid (VPA) decreases brain lesion size in swine models of traumatic brain injury (TBI) and controlled hemorrhage. To translate this treatment into clinical practice, validation of drug efficacy and evaluation of pharmacologic properties in clinically realistic models of injury are necessary. In this study, we evaluate neurologic outcomes and perform pharmacokinetic analysis of a single dose of VPA in swine subjected to TBI, hemorrhagic shock, and visceral hemorrhage., Methods: Yorkshire swine (n = 5/cohort) were subjected to TBI, hemorrhagic shock, and polytrauma (liver and spleen injury, rib fracture, and rectus abdominis crush). Animals remained in hypovolemic shock for 2 hours before resuscitation with isotonic sodium chloride solution (ISCS; volume = 3× hemorrhage) or ISCS + VPA (150 mg/kg). Neurologic severity scores were assessed daily for 30 days, and brain lesion size was measured via magnetic resonance imaging on postinjury days (PID) 3 and 10. Serum samples were collected for pharmacokinetic analysis., Results: Shock severity and response to resuscitation were similar in both groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment between PID 1 to 5 and smaller brain lesions on PID 3 (mean lesion size ± SEM, mm: ISCS = 4,956 ± 1,511 versus ISCS + VPA = 828 ± 279; p = 0.047). No significant difference in lesion size was identified between groups at PID 10 and all animals recovered to baseline neurologic function during the 30-day observation period. Animals treated with VPA had faster neurocognitive recovery (days to initiation of testing, mean ± SD: ISCS = 6.2 ± 1.6 vs ISCS + VPA = 3.6 ± 1.5; p = 0.002; days to task mastery: ISCS = 7.0 ± 1.0 vs ISCS + VPA = 4.8 ± 0.5; p = 0.03). The mean ± SD maximum VPA concentrations, area under the curve, and half-life were 145 ± 38.2 mg/L, 616 ± 150 hour·mg/L, and 1.70 ± 0.12 hours., Conclusions: In swine subjected to TBI, hemorrhagic shock, and polytrauma, VPA treatment is safe, decreases brain lesion size, and reduces neurologic injury compared to resuscitation with ISCS alone. These benefits are achieved at clinically translatable serum concentrations of VPA., Level of Evidence: Therapeutic (preclinical study).

Background: Platelet dysfunction has been described as an early component of trauma-induced coagulopathy. The platelet component of trauma-induced coagulopathy remains to be fully elucidated and translatable animal models are required to facilitate mechanistic investigations. We sought to determine if the early platelet dysfunction described in trauma patients could be recapitulated in a nonhuman primate model of polytraumatic hemorrhagic shock., Methods: Twenty-four male rhesus macaques weighting 7 to 14 kg were subjected to 60 minutes (min) of severe pressure-targeted controlled hemorrhagic shock (HS) with and without other injuries. After 60 min, resuscitation with 0.9% NaCl and whole blood was initiated. Platelet counts and platelet aggregation assays were performed at baseline (BSLN), end of shock (EOS; T = 60 min), end of resuscitation (EOR; T = 180 min), and T = 360 min on overall cohort. Results are reported as mean ± standard deviation (SD) or median (interquartile range). Statistical analysis was conducted using Spearmen correlation, one-way analysis of variance, two-way repeated-measures analysis of variance, paired t-test or Wilcoxon nonparametric test, with p < 0.05 considered significant., Results: Platelet count in all injury cohorts decreased over time, but no animals developed thrombocytopenia. Correlations were observed between platelet aggregation and platelet count for all agonists: adenosine diphosphate, thrombin recognition-activating peptide-6, collagen, and arachidonic acid. Overall, compared to BSLN, platelet aggregation decreased for all agonist at EOS, EOR, and T = 360 min. When normalized to platelet count, platelet aggregation in response to agonist thrombin recognition-activating peptide-6 demonstrated no change from BSLN at subsequent time points. Aggregation to adenosine diphosphate was significantly less at EOR but not EOS or T = 360 min compared to BSLN. Platelet aggregation to collagen and arachidonic acid was not significantly different at EOS compared to BSLN but was significantly less at EOR and T = 360 min., Conclusion: Nonhuman primates manifest early platelet dysfunction in response to polytraumatic hemorrhagic shock, consistent with that reported in severely injured human patients. Nonhuman primate models potentially are translationally valuable for understanding the mechanisms and pathophysiology of trauma-induced platelet dysfunction.

Background: Accidental hypothermia (AH) endangers the patient after polytrauma. Past studies have emphasized this entity as a major risk factor. The aim of this study was to describe the epidemiology of AH in major trauma considering the preclinical and clinical course. Predictors should be elucidated., Methods: This is a retrospective investigation from the TraumaRegister DGU. Patients were documented in the period between 2002 and 2012. The study compared multiple-injured patients with or without hypothermic temperatures. Different groups of body core temperature were analyzed. Preclinical and clinical parameters were documented., Results: Fifteen thousand two hundred thirty patients could be included. In 5,078 patients, temperature was below 36.0°C. Blunt trauma mechanisms surpassed penetrating injuries. The majority of patients sustained car accidents, accidents involving pedestrians, and falls from heights of greater than 3 m. Preclinical rescue procedures were extensively long in patients with low body temperature. Female gender, Glasgow Coma Scale score of 8 or less, nighttime, winter, motorcycle/bicycle accidents, Injury Severity Score 9 or greater, shock on site and in the emergency room, preclinical volume therapy, and time until admission to emergency room are significant risk factors to develop AH of 33°C. Volume management ranged between 1,453 ± 1,051 mL (33°C) and 1,058 ± 768 mL (36°C). Treatment in emergency room was extensively long. In further clinical course, severe AH advanced the clinical development of sepsis and multiple organ failure. The overall mortality inclined with decreasing body temperatures., Conclusions: Accidental hypothermia regularly occurred in polytrauma patients. Certain predictors exist, that is, female gender, which facilitate a body core temperature of 33°C. Preclinical and clinical courses match with other polytrauma studies. High incidence rates of sepsis, multiple organ failure, and mortality in hypothermic patients (33°C) demonstrate the severity of injury. Unfortunately, documentation of body core temperature remains challenging as the number of recorded hypothermic patients appears to be too small. We favor a strict focus on body core temperature on arrival in the emergency room., Level of Evidence: Prognostic and epidemiological study, level III.

Background: Many traumatic brain injury (TBI) patients experience additional injuries, including those that result in hemorrhagic shock (HS). Interactions between HS and TBI can include reduced brain O2 delivery, resulting in partial cerebral ischemia and worse neurologic outcome. This study tested the hypothesis that inspiration of 100% O2 during resuscitation following TBI and HS improves survival, reduces brain lesion volume, and improves neurologic outcome compared with resuscitation in the absence of supplemental O2., Methods: The adult male rat polytrauma model consisted of controlled cortical impact-induced TBI followed by 30 minutes of HS (mean arterial pressure, 35-40 mm Hg) induced by blood withdrawal. The HS phase was followed by a 1-hour "prehospital" Hextend fluid resuscitation phase and then a 1-hour "hospital phase" when shed blood was reinfused. Rats were randomized on the day of surgery to three groups with 10 per group: sham, polytrauma normoxic, and polytrauma hyperoxic. Normoxic animals inspired room air, and hyperoxic animals inspired 100% O2 during both resuscitation phases. Neurobehavioral tests were conducted weekly until the rats were perfused with fixative at 30 days after injury. Brain sections were stained with Fluoro Jade B and used for quantification of contusion, penumbral, and healthy cortical volumes., Results: Survival was greater following hyperoxic compared with normoxic resuscitation. Composite neuroscores obtained at 2 weeks to 4 weeks following hyperoxic resuscitation were lower than those of shams. Balance beam foot faults measured at 2 weeks after injury were greater following hyperoxic resuscitation compared with normoxic resuscitation and those of shams. There was no significant difference in cerebrocortical pathology between the normoxic and hyperoxic polytrauma groups., Conclusion: The survival of rats following controlled cortical impact plus HS was greater following hyperoxic resuscitation. In contrast, neurologic outcomes were better following normoxic resuscitation.

Background: Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients., Methods: Patients were enrolled and randomized in the out-of-hospital setting. Nineteen emergency medical services (EMS) systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of-hospital systolic blood pressure (SBP) of 90 mm Hg or lower. CR patients received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg and additional 250-mL boluses to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or greater. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival., Results: A total of 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. The mean (SD) crystalloid volume administered during the study period was 1.0 L (1.5) in the CR group and 2.0 L (1.4) in the SR group, a difference of 1.0 L (95% confidence interval [CI], 0.6-1.4). Intensive care unit-free days, ventilator-free days, renal injury, and renal failure did not differ between the groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio, 0.39; 95% CI, 0.12-1.26). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted odds ratio of 0.17 (0.03-0.92). There was no difference among patients with penetrating trauma (9% vs. 9%; adjusted odds ratio, 1.93; 95% CI, 0.19-19.17)., Conclusion: CR is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large-scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted., Level of Evidence: Therapeutic study, level I.

Background: People who have sustained severe multiple injuries have reduced health and functioning years after the injury. For people who have sustained severe injuries, an optimal degree of predictability in future functioning and health-related quality of life is important. The main aim was to study the impacts of demographic- and injury-related factors as well as functioning at 1 year and 2 years after injury on physical and mental health 10 years after injury., Methods: Fifty-eight participants completed a 10-year follow-up (55.2% of all included patients). Demographic and injury severity characteristics were collected, and assessments at 1, 2, 5, and 10 years after injury were performed. Patient-reported outcome measures were the Short Form 36 (SF-36), the Brief Approach/Avoidance Coping Questionnaire, and the cognitive function scale (COG). The SF-36 Physical and Mental Component Summaries (PCS and MCS, respectively) were the main outcome variables. We performed hierarchical multiple regression analyses to assess functioning on the PCS and MCS., Results: Mean (SD) age at injury was 37.8 (14.7) years, 74% were male. Mean (SD) New Injury Severity Score (NISS) was 33.7 (13.0). Mean (SD) PCS score was 41.8 (11.7). Mean (SD) MCS was 48.8 (10.7). Predictors of the PCS were change in coping from 2 years to 10 years (p = 0.032), physical functioning (p < 0.001) and cognitive functioning at 1 year (p = 0.011), as well as bodily pain at 2 years (p = 0.005). Adjusted R was 0.57. Predictors of the MCS were change in coping (p = 0.031), vitality (p = 0.008) at 1 year, as well as social functioning (p = 0.034) and mental health (p = 0.043) at 2 years. Adjusted R was 0.64., Conclusion: Physical health was reduced compared with the adjusted general population at 10 years after injury. The mental health did not differ from that of the general population. In addition to physical functioning, coping strategies, vitality, social functioning, and mental health should be considered in the long-term rehabilitation perspective. A more comprehensive approach should be used for rehabilitation after multiple injuries.

Background: The exact alterations of the immune system after polytrauma leading to sepsis and multiple-organ failure are poorly understood. Thus, the early local and systemic inflammatory and apoptotic response was characterized in a new polytrauma model and compared with the alterations seen after single or combined injuries., Methods: Anesthetized C57BL/6 mice were subjected to either blunt bilateral chest trauma (Tx), closed head injury, right femur fracture including contralateral soft tissue injury, or a combination of injuries (PTx). After 2 hours or 6 hours, animals were sacrificed, and the systemic as well as the local pulmonary immune response (bronchoalveolar lavage [BAL]/plasma cytokines, lung myeloperoxidase [MPO] activity, and alveolocapillary barrier dysfunction) were evaluated along with lung/brain apoptosis (lung caspase 3 Western blotting, immunohistochemistry, and polymorphonuclear leukocytes [PMN] Annexin V)., Results: Hemoglobin, PO2 saturation, and pH did not differ between the experimental groups. Local BAL cytokines/chemokines were significantly increased in almost all groups, which included Tx. There was no further enhancement of this local inflammatory response in the lungs in case of PTx. At 2 hours, all groups except sham and closed head injury alone revealed an increased activity of lung MPO. However, 6 hours after injury, lung MPO remained increased only in the PTx group. Increased BAL protein levels were found, reflecting enhanced lung leakage in all groups with Tx 6 hours after trauma. Only after PTx was neutrophil apoptosis significantly decreased, whereas lung caspase 3 and plasma interleukin 6/keratinocyte chemoattractant (KC) were substantially increased., Conclusion: The combination of different injuries leads to an earlier systemic inflammatory response when compared with the single insults. Interestingly, only after PTx but not after single or double hits was lung apoptosis increased, and PMN apoptosis was decreased along with a prolonged presence of neutrophils in the lungs, which may therefore represent a possible pathomechanism for lung injury after polytrauma.

Background: We recently demonstrated that a blunt chest trauma, a strong inducer of the posttraumatic systemic inflammatory response and one of the most critical injuries in polytrauma patients, significantly delayed fracture healing in rats, possibly by the interaction of the systemic inflammation with early regeneration processes locally at the fracture site. The underlying cellular mechanisms, however, have as yet remained unknown. Therefore, the aim of this study was to analyze the cellular and morphologic composition of the early fracture callus after a blunt chest trauma., Methods: Rats received an osteotomy of the right femur stabilized by an external fixator in combination with a blunt chest trauma or not. The animals were killed after 3, 7, and 35 days, and the fracture calli were analyzed histologically for new tissue formation, polymorphonuclear leucocytes, macrophages, osteoclasts, and the presence of the proinflammatory cytokine interleukin 6., Results: The blunt chest trauma considerably increased the number of polymorphonuclear leucocytes in the callus by Day 3 compared with animals with isolated fractures. The number of macrophages was significantly reduced by the thoracic trauma at Days 3 and 7. The number of osteoclasts was not changed at any postoperative time point. After 3 days, the blunt chest trauma led to a significantly stronger interleukin 6 staining within the periosteal callus in zones of intramembranous ossification. During the time of cortical bridging at Day 35, the amount of newly formed bone was significantly decreased after blunt chest trauma., Conclusion: Our results suggest that the systemic posttraumatic inflammation induced by a thoracic trauma disturbed the inflammatory balance during the early healing stage by altering the recruitment of inflammatory cells and cytokine expression locally at the fracture site and thus impaired fracture healing. These findings provide new insights in the pathomechanisms of impaired fracture healing in patients experiencing severe trauma.

Introduction: Intravenous contrast extravasation (IVCE) on a trauma computed tomography has been quoted as a reason for intervention (angiographic embolization or operation). The new-generation computed tomographic (CT) scanners identify IVCE with increasing frequency. We hypothesized that most IVCEs do not require an intervention., Methods: This study was a retrospective evaluation of trauma patients with IVCE on abdomen or pelvis CT scan (January 2005-December 2009). Along with demographic and hemodynamic variables, the following characteristics of IVCE were examined as potential risk factors for intervention: maximal dimension, small (≤ 1.5 cm) versus large (>1.5 cm), contained versus free, and single versus multiple and location., Results: Sixty-nine patients with 81 IVCEs were identified: 48 IVCEs occurred in intra-abdominal solid organs, 18 IVCEs in the pelvic retroperitoneal space, and 15 IVCEs in the soft tissues or other locations. Thirty patients (43.5%) were managed without an intervention, and 39 patients (56.5%) required either an immediate (30 patients) or a delayed (9 patients) intervention. Multivariate analysis identified three independent predictors of an intervention: an admission systolic blood pressure of 100 mm Hg or lower, a large ICVE, and an Abbreviated Injury Score of the abdomen of 3 or higher. If all three independent predictors were present, 100% of patients received an intervention., Conclusion: Nearly half of IVCEs on CT scan did not require an intervention. A hypotension at admission, a severe abdominal trauma, and a blush diameter of 1.5 cm or greater predicted the need for intervention., Level of Evidence: Therapeutic study, level IV; prognostic study, level III.