Early Fluid is Less Fluid: Comparing Early Versus Late Resuscitation in Severely Injured Trauma Patients.

Background: We aimed to characterize the temporal trends of crystalloid resuscitation in severely injured trauma patients after intensive care unit (ICU) admission. Using 500 mL/hr of crystalloid in the first 6 hours of ICU admission to distinguish early versus late resuscitation, we hypothesized early resuscitation was associated with less volume by 48 hours and better outcomes compared with late resuscitation. Methods: We performed a retrospective review of the trauma registry of a high-volume level 1 academic trauma center to examine adult trauma patients admitted to the ICU (2016-2019) with: with initial serum lactate ≥ 4 mmol/dL, elevated lactate (≥ 2 mmol/L) at ICU admission, and lactate normalization within 48 hours. We analyzed patient and injury characteristics, and the first 48 hours of ICU course. The primary outcome was ICU length of stay (LOS); secondary outcomes included ventilator days, acute kidney injury (AKI), and in-hospital death. We compared subjects who received early resuscitation to those received late resuscitation using unadjusted methods and multivariable regression models. Results: We analyzed 333 subjects. The late resuscitation group received less volume over the first 24 hours, but surpassed the early group by 48 hours (5.5 vs 4.1L, p ≤ 0.001). The late group had longer ICU LOS (9 vs 5 days, p ≤ 0.001) and ventilator days (5 vs 2 days, p ≤ 0.001), and higher incidence of AKI (38% vs 11%, p ≤ 0.001). On multivariable regression, late resuscitation remained associated with longer ICU LOS and ventilator days, and higher odds of AKI after adjusting for important confounders. Conclusions: After hemostasis, crystalloid can play an important role in restoration of organ perfusion. Delaying resuscitation is associated with both receipt of higher volumes of crystalloid by 48 hours and worse outcomes compared to early resuscitation. Judicious crystalloid given early in ICU admission could improve outcomes in the severely injured.

Predicting High-Intensity Resuscitation Needs in Injured Patients in the Post-Hemostasis Phase of Care Following Intervention.

BACKGROUND: Best resuscitation practices in the post-hemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this post-hemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at ICU admission. METHODS: Clinical data was extracted for consecutive injured patients (2016-19) admitted to the ICU following an immediate procedure in the operating room or angiography suite. HIR thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 Liters) use in the initial twelve hours of ICU care and/or vasoactive medication use between ICU hours 2-12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six-hundred-and-five patients were included. Patients were 79% male, young (median age: 39 years), severely injured (median ISS: 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSIONS: ICU admission data can identify subsequent HIR in the post-hemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Retrospective Cohort, Level IV.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

PREHOSPITAL CRYSTALLOID RESUSCITATION: PRACTICE VARIATION AND ASSOCIATIONS WITH CLINICAL OUTCOMES.

ABSTRACT: Introduction: Although resuscitation guidelines for injured patients favor blood products, crystalloid resuscitation remains a mainstay in prehospital care. Our understanding of contemporary prehospital crystalloid (PHC) practices and their relationship with clinical outcomes is limited. Methods: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial data set was used for this investigation. We sought to identify factors associated with PHC volume variation and hypothesized that higher PHC volume is associated with worse coagulopathy and a higher risk of acute respiratory distress syndrome (ARDS) but a lower risk of acute kidney injury (AKI). Subjects were divided into groups that received <1,000 mL PHC (PHC<1,000) and ≥1,000 mL PHC (PHC≥1,000); initial laboratory values and outcomes (ARDS and AKI risk) were summarized with medians and interquartile ranges or percentages and compared using Wilcoxon rank-sum tests and chi-square tests. The primary outcome was ARDS risk. Multivariable regression was used to characterize the association of each 500 mL aliquot of PHC with initial laboratory values and clinical outcomes. Results: PHC volume among study subjects (n = 680) varied (median, 0.3 L; interquartile range, 0-0.9 L) with weak associations demonstrated among prehospital hemodynamics, intubation, Glasgow Coma Score, and Injury Severity Score (0.008 ≤ R2 ≤ 0.09); prehospital time and enrollment site explained more variation in PHC volume with R2 values of 0.2 and 0.54, respectively. Compared with PHC<1,000, PHC≥1,000 had higher INR, PT, PTT, and base deficit and lower hematocrit and platelets. The proportion of ARDS in the PHC≥1,000 group was higher than PHC<1,000 (21% vs. 12%, P < 0.01), whereas the rate of AKI was similar between groups (23% vs. 23%, P = 0.9). In regression analyses, each 500 mL of PHC was associated with increased INR and PTT, and decreased hematocrit and platelet count (P < 0.05). Each 500 mL of PHC was associated with increased ARDS risk and decreased AKI risk (P < 0.05). Conclusion: PHC administration correlates poorly with prehospital hemodynamics and injury characteristics. Increased PHC volume is associated with greater anemia, coagulopathy, and increased risk of ARDS, although it may be protective against AKI.

HLA-A Locus is Associated With Sepsis and Septic Shock After Traumatic Injury.

OBJECTIVE: Determine whether variation in the HLA region is associated with the development of post-traumatic sepsis and septic shock. BACKGROUND: Sepsis-related deaths remain a major source of mortality after traumatic injury. Genetic characteristics may contribute to susceptibility to adverse outcomes including sepsis and septic shock. Recent advances in next-generation sequencing technology now allow comprehensive genotyping of the HLA region. METHODS: White adult trauma patients requiring more than 2 days of mechanical ventilation underwent HLA genotyping, and were followed for the development of sepsis and septic shock. Odds ratios (OR) for the associations between our outcomes and HLA variants were estimated, a correction for multiple comparisons was applied, and significant variants were included in regression models adjusting for potential confounders. RESULTS: A total of 1184 patients were included. Patients were severely injured (median injury severity score 33); 33% developed sepsis, 6% septic shock, and in-hospital mortality was 14%. An amino acid variant (156Q) within the HLA-A peptide-binding groove was associated with greater odds of sepsis [OR 1.50, (1.18-1.89)]. HLA-A∗02:01 was associated with lower odds of septic shock [OR 0.52, (0.32-0.82)]. These associations remained significant after adjusting for potential confounders. CONCLUSIONS: This is the first study to apply next-generation sequencing techniques to evaluate associations between immunogenetic factors and post-traumatic sepsis and septic shock. Associations with class I HLA variants are novel as they implicate adaptive immunity in post-traumatic sepsis. These findings are a step towards developing a panel of genetic markers assessing risk of infection-related complications as we move towards more personalized medicine.

Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

Acute intensive care unit resuscitation of severely injured trauma patients: Do we need a new strategy?

BACKGROUND: Unlike recent advances in blood product resuscitation, intravenous crystalloid (IVF) use after intensive care unit (ICU) admission in hemorrhagic shock has received less attention and current recommendations are based on limited evidence. To address this knowledge gap, we aimed to determine associations between IVF administration during acute ICU resuscitation and outcomes. We hypothesized that larger IVF volumes are associated with worse outcomes. METHODS: We linked our trauma registry with electronic health record data (2012-2015) to identify adults with an initial lactate level of ≥4 mmol/L and documented lactate normalization (≤2 mmol/L), excluding those with isolated head Abbreviated Injury Scale score ≥3. We focused on the period from ICU admission to lactate normalization, analyzing duration, volume of IVF, and proportion of volume as 1-L boluses. We used linear regression to determine associations with ICU length of stay and duration of mechanical ventilation in survivors, and logistic regression to identify associations with acute kidney injury and home discharge while adjusting for important covariates. RESULTS: We included 337 subjects. Median time to lactate normalization was 15 hours (interquartile range, 7-25 hours), and median IVF volume was 3.7 L (interquartile range, 1.5-6.4 L). The fourfold difference between the upper and lower quartiles of both duration and volume remained after stratifying by injury severity. Hourly volumes tapered over time but persistently aggregated at 0.5 and 1 L, with 167 subjects receiving at least one 0.5-L bolus for 6 hours after ICU admission. Administration of larger volumes was associated with longer ICU length of stay and duration of mechanical ventilation, as well as acute kidney injury. CONCLUSION: There is substantial variation in volume administered during acute ICU resuscitation, both absolutely and temporally, despite accounting for injury severity. Administration of larger volumes during acute ICU resuscitation is associated with worse outcomes. There is an opportunity to improve outcomes by further investigating and standardizing this important phase of care. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Persistent metabolomic alterations characterize chronic critical illness after severe trauma.

BACKGROUND: Following trauma, persistent inflammation, immunosuppression, and catabolism may characterize delayed recovery or failure to recover. Understanding the metabolic response associated with these adverse outcomes may facilitate earlier identification and intervention. We characterized the metabolic profiles of trauma victims who died or developed chronic critical illness (CCI) and hypothesized that differences would be evident within 1-week postinjury. METHODS: Venous blood samples from trauma victims with shock who survived at least 7 days were analyzed using mass spectrometry. Subjects who died or developed CCI (intensive care unit length of stay of ≥14 days with persistent organ dysfunction) were compared with subjects who recovered rapidly (intensive care unit length of stay, ≤7 days) and uninjured controls. We used partial least squares discriminant analysis, t tests, linear mixed effects regression, and pathway enrichment analyses to make broad comparisons and identify differences in metabolite concentrations and pathways. RESULTS: We identified 27 patients who died or developed CCI and 33 who recovered rapidly. Subjects were predominantly male (65%) with a median age of 53 years and Injury Severity Score of 36. Healthy controls (n = 48) had similar age and sex distributions. Overall, from the 163 metabolites detected in the samples, 56 metabolites and 21 pathways differed between injury outcome groups, and partial least squares discriminant analysis models distinguished injury outcome groups as early as 1-day postinjury. Differences were observed in tryptophan, phenylalanine, and tyrosine metabolism; metabolites associated with oxidative stress via methionine metabolism; inflammatory mediators including kynurenine, arachidonate, and glucuronic acid; and products of the gut microbiome including indole-3-propionate. CONCLUSIONS: The metabolic profiles in subjects who ultimately die or develop CCI differ from those who have recovered. In particular, we have identified differences in markers of inflammation, oxidative stress, amino acid metabolism, and alterations in the gut microbiome. Targeted metabolomics has the potential to identify important metabolic changes postinjury to improve early diagnosis and targeted intervention. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level III.

Application of the modified Nutrition Risk in Critically Ill score to nutritional risk stratification of trauma victims: A multicenter observational study.

BACKGROUND: The modified Nutrition Risk in Critically Ill (mNUTRIC) score was developed to identify patients most likely to benefit from nutritional therapies and to stratify or select study subjects for clinical trials. The score is not validated in trauma victims in whom adequate nutritional support is important and difficult to achieve. We sought to determine whether a higher mNUTRIC score was associated with worse outcomes and whether caloric and protein intake improved outcome more in patients classified as high risk relative to those classified as low risk. METHODS: We analyzed a prospectively collected database of patients from intensive care units globally. The primary outcome was 60-day hospital mortality, and the secondary outcome was time to discharge alive. We compared outcomes between high and low mNUTRIC score groups and also tested whether the association between outcome and nutrition intake was modified by the mNUTRIC score. RESULTS: A total of 771 trauma patients were included. Most (585; 76%) had a low-risk mNUTRIC (0-4) score, and 186 (24%) had a high-risk (5-9) mNUTRIC score. The overall 60-day mortality was 13%. Patients in the high mNUTRIC group had a higher risk of death than those in the low mNUTRIC group (adjusted odds ratio, 2.6; 95% confidence interval, 1.7-4.2). Overall, there was no relationship between caloric or protein intake and clinical outcomes. However, patients in the high mNUTRIC group fared better with increasing caloric and protein intake, whereas subjects in the low mNUTRIC score group did not (p values for interaction with the mNUTRIC score for time to discharge alive was p = 0.014 for calories and was p = 0.004 for protein). CONCLUSION: A high mNUTRIC score identifies trauma patients at higher risk for poor outcomes and those who may benefit from higher caloric and protein intake. LEVEL OF EVIDENCE: Epidemiological/Prognostic, level III.

Predictors of mortality, limb loss, and discharge disposition at admission among patients with necrotizing skin and soft tissue infections.

BACKGROUND: Necrotizing soft tissue infections (NSTI) represent a heterogeneous group of rapidly progressive skin and soft tissue infections associated with significant morbidity and mortality. Efforts to identify factors associated with death have produced mixed results, and little or no data is available for other adverse outcomes. We sought to determine whether admission variables were associated with mortality, limb loss, and discharge disposition in patients with NSTI. METHODS: We analyzed prospectively collected data of adult patients with surgically confirmed NSTI from an NSTI registry maintained at a quaternary referral center. Factors independently associated with mortality, amputation, and skilled nursing facility discharge were identified using logistic regression. RESULTS: Between 2015 and 2018, 446 patients were identified. The median age was 55 years (interquartile range, 43-62). The majority of patients were male (65%), white (77%), and transferred from another facility (90%). The perineum was most commonly involved (37%), followed by the lower extremity (34%). The median number of operative debridements was 3 (interquartile range, 2-4). Overall mortality was 15%, and 21% of extremity NSTI patients required amputation. Age greater than 60 years; creatinine greater than 2 mg/dL; white blood cell count greater than 30 x 10^ /µl, platelets less than 150 × 10/µL, and clostridial involvement were independently associated with greater odds of death; perineal involvement was associated with lower odds of death. Age greater than 60 years; sex, male; nonwhite race; diabetes; chronic wound as etiology; leg involvement; transfer status; and sodium, less than 130 mEq/L were independently associated with amputation. Age greater than 60 years; sex, female; nonwhite race; perineal involvement; and amputation were associated with skilled care facility discharge. CONCLUSION: Necrotizing soft tissue infections are a heterogeneous group of infections involving significantly different patient populations with different outcomes; efforts to differentiate and predict adverse outcomes in NSTI should include laboratory data, comorbidities, infection site, and/or etiology to improve predictions and better account for this heterogeneity. LEVEL OF EVIDENCE: Prognostic, Level III.

Enhanced Perioperative Care for Major Spine Surgery.

STUDY DESIGN: The enhanced perioperative care (EPOC) program is an institutional quality improvement initiative. We used a historically controlled study design to evaluate patients who underwent major spine surgery before and after the implementation of the EPOC program. OBJECTIVE: To determine whether multidisciplinary EPOC program was associated with an improvement in clinical and financial outcomes for elective adult major spine surgery patients. SUMMARY OF BACKGROUND DATA: The enhanced recovery after surgery (ERAS) programs successfully implemented in hip and knee replacement surgeries, and improved clinical outcomes and patient satisfaction. METHODS: We compared 183 subjects in traditional care (TRDC) group to 267 intervention period (EPOC) in a single academic quaternary spine surgery referral center. One hundred eight subjects in no pathway (NOPW) care group was also examined to exclude if the observed changes between the EPOC and TRDC groups might be due to concurrent changes in practice or population over the same time period. Our primary outcome variables were hospital and intensive care unit lengths of stay and the secondary outcomes were postoperative complications, 30-day hospital readmission and cost. RESULTS: In this highly complex patient population, we observed a reduction in mean hospital length of stay (HLOS) between TRDC versus EPOC groups (8.2 vs. 6.1 d, standard deviation [SD] = 6.3 vs. 3.6, P < 0.001) and intensive care unit length of stay (ILOS) (3.1 vs. 1.9 d, SD = 4.7 vs. 1.4, P = 0.01). The number (rate) of postoperative intensive care unit (ICU) admissions was higher for the TRDC n = 109 (60%) than the EPOC n = 129 (48%) (P = 0.02). There was no difference in postoperative complications and 30-day hospital readmissions. The EPOC spine program was associated with significant average cost reduction-$62,429 to $53,355 (P < 0.00). CONCLUSION: The EPOC program has made a clinically relevant contribution to institutional efforts to improve patient outcomes and value. We observed a reduction in HLOS, ILOS, costs, and variability. LEVEL OF EVIDENCE: 3.

Increasing Enteral Protein Intake in Critically Ill Trauma and Surgical Patients.

BACKGROUND: Published guidelines recommend providing at least 2 g/kg/d of protein for critically ill surgical patients. It may be difficult to achieve this level of intake using standard enteral formulas, thus necessitating protein or amino acid supplementation. Herein, we report our approach to enteral protein supplementation and its relationship with urinary nitrogen excretion and serum transthyretin concentrations. METHODS: This was a retrospective cohort study in which we reviewed critically ill trauma and surgical patients treated with supplemental enteral protein according to a protocol aiming to deliver a total of 2 g/kg/d of protein. We collected detailed nutrition data over a 2-week period after admission and obtained additional data through discharge to determine caloric and protein intake as well as complications. We also compared urine nitrogen excretion and transthyretin concentrations between these patients and a control group who did not receive supplemental protein. RESULTS: Fifty-three subjects received early protein supplementation. Formula and protein supplement each provided ≈1.2 g/kg/d of protein by intensive care unit day 4. This resulted in a median total protein intake of 2.2 g/kg/d through day 14. One patient developed acute kidney injury, and 1 patient had 3 episodes of vomiting. By the third week, serum transthyretin concentrations increased to a median of 21 mg/dL compared with 13 mg/dL in subjects not receiving early supplementation. CONCLUSION: It is safe to deliver supplemental protein enterally to critically ill surgical and trauma patients and reach 2 g/kg/d of protein intake during the first week of illness.

Injury in the transgender population: What the trauma surgeon needs to know.

Gender dysphoria, or the distress caused by the incongruence between a person's assigned and experienced gender, can lead to significant psychosocial sequelae and increased risk of suicide (>40% of this population) and assault (>60% of this population). With an estimated 25 million transgender individuals worldwide and increased access to care for the transgender population, trauma surgeons are more likely to care for patients who completed or are in the process of medical gender transition. As transgender health is rarely taught in medical education, knowledge of the unique health care needs and possible alterations in anatomy is critical to appropriately and optimally treat transgender trauma victims. Considerations of cross-gender hormones and alterations of the craniofacial, laryngeal, chest, and genital systems are offered in this review. Further research on the optimal treatment mechanisms for transgender patients is needed.

Duration of Respiratory Failure After Trauma Is Not Associated With Increased Long-Term Mortality.

OBJECTIVES: Although 1-year survival in medically critically ill patients with prolonged mechanical ventilation is less than 50%, the relationship between respiratory failure after trauma and 1-year mortality is unknown. We hypothesize that respiratory failure duration in trauma patients is associated with decreased 1-year survival. DESIGN: Retrospective cohort of trauma patients. SETTING: Single center, level 1 trauma center. PATIENTS: Trauma patients admitted from 2011 to 2014; respiratory failure is defined as mechanical ventilation greater than or equal to 48 hours, excluded head Abbreviated Injury Score greater than or equal to 4. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality was calculated from the Washington state death registry. Cohort was divided into short (≤ 14 d) and long (> 14 d) ventilation groups. We compared survival with a Cox proportional hazard model and generated a receiver operator characteristic to describe the respiratory failure and mortality relationship. Data are presented as medians with interquartile ranges and hazard ratios with 95% CIs. We identified 1,503 patients with respiratory failure; median age was 51 years (33-65 yr) and Injury Severity Score was 19 (11-29). Median respiratory failure duration was 3 days (2-6 d) with 10% of patients in the long respiratory failure group. Cohort mortality at 1 year was 16%, and there was no difference in mortality between short and long duration of respiratory failure. Predictions for 1-year mortality based on respiratory failure duration demonstrated an area under the receiver operator characteristic curve of 0.57. We determined that respiratory failure patients greater than or equal to 75 years had an increased hazard of death at 1 year, hazard ratio, 6.7 (4.9-9.1), but that within age cohorts, respiratory failure duration did not influence 1-year mortality. CONCLUSIONS: Duration of mechanical ventilation in the critically injured is not associated with 1-year mortality. Duration of ventilation following injury should not be used to predict long-term survival.

A Potential Mechanism for Immune Suppression by Beta-Adrenergic Receptor Stimulation following Traumatic Injury.

BACKGROUND: ß-Adrenergic agents suppress inflammation and may play an important role in posttraumatic infections. Mechanisms may include inhibition of MAP kinase signaling. We sought to determine whether MKP-1 contributed to catecholamine suppression of innate immunity and also wanted to know whether early catecholamine treatment after traumatic injury increases the risk of later nosocomial infection. METHODS: We performed experiments using THP-1 cells and peripheral blood mononuclear cells from healthy individuals. We exposed cells to epinephrine and/or LPS and measured inflammatory gene transcription and MAP kinase activation. We inhibited MKP-1 activity to determine its role in catecholamine-induced immune suppression. Finally, we studied injured subjects to determine whether early catecholamine treatment was associated with nosocomial infection. RESULTS: Epinephrine increases MKP-1 transcripts and protein and decreases LPS-induced p38 and JNK phosphorylation and TNF-α gene transcription. RNAi inhibition of MKP-1 at least partially restores LPS-induced TNF-α gene expression (p = 0.024). In the clinical cohort, subjects treated with ß-adrenergic agents had an increased risk of ventilator-associated pneumonia (aOR = 1.9; 95% CI = 1.3-2.6) and bacteremia (aOR = 1.5; 95% CI = 1.1-2.3). CONCLUSIONS: MKP-1 may have a role in catecholamine-induced suppression of innate immunity, and exogenous catecholamines might contribute to nosocomial infection risk.

Biochemical Markers of Nutrition Support in Critically Ill Trauma Victims.

BACKGROUND: In critically ill patients, plasma serum albumin and transthyretin concentrations are thought to reflect the effects of acute illness, including resuscitation and inflammation. Their use as markers for preexisting nutrition status is, therefore, not recommended. Whether they can be used to assess subsequent effectiveness of artificial nutrition support is unclear. We sought to determine if these biomarkers are associated with enteral caloric intake in critically ill trauma patients. MATERIALS AND METHODS: We analyzed data from adult trauma victims who required ≥2 days of mechanical ventilation and ≥7 days of intensive care. We categorized patients into low, middle, or high enteral calorie delivery groups (2, 9, or 17 kcal/kg/d during the first week). We compared serial concentrations of serum albumin, transthyretin, and C-reactive protein. Multiple linear and Poisson regression were used to determine relationships between calorie intake and nutrition biomarkers. RESULTS: In total, 1056 patients were analyzed. Their median age was 44 (interquartile range [IQR], 28-57) years, and median injury severity score was 34 (IQR, 26-41). Calorie intake during the first week was not related to biomarkers during the first or second week. However, by the beginning of the third week, the highest calorie group showed greater changes in concentrations of transthyretin (+3.0 mg/dL relative to initial concentration, P = .01) and serum albumin (+0.17 g/dL, P = .05) compared with the lowest calorie group. CONCLUSIONS: In trauma patients requiring 1 or more weeks of intensive care, changes in transthyretin were associated with enteral caloric intake. Our data suggest that transthyretin could be used to monitor nutrition support after 2 weeks in intensive care.

Protein Delivery in the Intensive Care Unit: Optimal or Suboptimal?

Emerging evidence suggests that exogenous protein/amino acid supplementation has the potential to improve the recovery of critically ill patients. After a careful review of the published evidence, experts have concluded that critically ill patients should receive up to 2.0-2.5 g/kg/d of protein. Despite this, however, recent review of current International Nutrition Survey data suggests that protein in critically ill patients is underprescribed and grossly underdelivered. Furthermore, the survey suggests that most of protein administration comes from enteral nutrition (EN) despite the availability of products and protocols that enhance the delivery of protein/amino acids in the intensive care unit (ICU) setting. While future research clarifies the dose, timing, and composition for exogenous protein administration, as well as identification of patients who will benefit the most, ongoing process improvement initiatives should target a concerted effort to increase protein intake in the critically ill. This assertion follows from the notion that current patients are possibly being harmed while we wait for confirmatory evidence. Further research should also develop better tools to enable bedside practitioners to monitor optimal or adequate protein intake for individual patients. Finally, exploring the effect of combining adequate protein delivery with early mobility and/or resistance exercise in the ICU setting has the greatest potential for improving the functional outcomes of survivors of critical illness and warrants further study.

Outcomes in necrotizing soft tissue infections treated with therapeutic plasma exchange.

BACKGROUND: Treatment of necrotizing soft tissue infections (NSTIs) includes prompt surgical debridement and antibiotics, but despite standard care, the morbidity and mortality remain high. Since therapeutic plasma exchange (TPE) has been considered for treatment of severe sepsis, this study evaluates the efficacy of TPE for patients with NSTI. STUDY DESIGN AND METHODS: This is a retrospective study of patients with diagnosis of NSTI who received treatment with and without TPE over an 11-year period. The primary outcome was in-hospital mortality. RESULTS: Fifty-two patients with NSTI treated with TPE (TPE group) and 125 patients with NSTI not treated with TPE (non-TPE group) were assessed. Nineteen (36.5%) patients died in the TPE group, and 35 (28%) patients died in the non-TPE group. Within the TPE group, there was significant improvement in white blood cell (WBC) count and sodium levels 7 days after TPE treatment, but no improvement in creatinine. Inverse probability weighting based on propensity scores was used to compare survival in the TPE and non-TPE groups and demonstrated that TPE was associated with an increased odds of death (odds ratio, 2.8). A second analysis matched for six variables yielded 31 pairs and demonstrated no significant difference in mortality or length of stay. CONCLUSIONS: This study describes the largest series of patients with NSTIs treated with TPE and showed no evidence of clinical benefit. Further carefully designed studies with meaningful clinical endpoints would prove useful in assessing reproducibility and determining if there is a role for TPE in other forms of severe sepsis.

Parenteral and enteral nutrition in surgical critical care: Plasma metabolomics demonstrates divergent effects on nitrogen, fatty-acid, ribonucleotide, and oxidative metabolism.

BACKGROUND: Artificial nutrition support is central to the care of critically ill patients and is primarily provided enterally (EN). There are circumstances when parenteral nutrition (PN) is considered necessary. We are uncertain how each of these approaches confer clinical benefits beyond simply providing calories. We sought to better understand how each of these techniques influence metabolism in critically ill patients using a broad-based metabolomics approach. Metabolic responses to EN and PN may differ in ways that could help us understand how to optimize use of these therapies. METHODS: We prospectively enrolled subjects over 7 months in 2015 at an urban, Level I trauma center. Subjects were included before starting either EN or PN during their inpatient admission. Plasma samples were obtained between 1 and 12 hours before initiation of artificial nutrition, and 3 and 7 days later. All samples were analyzed with liquid chromatography/mass spectrometry-based metabolomics. Differences in metabolite concentrations were assessed via principal component analyses and multiple linear regression. RESULTS: We enrolled 30 subjects. Among the critically ill subjects, 10 received EN and 10 received PN. In subjects receiving EN, amino acid and urea cycle metabolites (citrulline, p = 0.04; ornithine, p = 0.05) increased, as did ribonucleic acid metabolites (uridine, p = 0.04; cysteine, 0 = 0.05; oxypurinol, p = 0.04). Oxidative stress decreased over time (increased betaine, p = 0.05; decreased 4-pyridoxic acid, p = 0.04). In subjects receiving PN, amino acid concentrations increased over time (taurine, p = 0.04; phenylalanine, p = 0.05); omega 6 and omega 3 fatty acid concentrations decreased over time (p = 0.05 and 0.03, respectively). CONCLUSION: EN was associated with amino acid repletion, urea cycle upregulation, restoration of antioxidants, and increasing ribonucleic acid synthesis. Parenteral nutrition was associated with increased amino acid concentrations, but did not influence protein metabolism or antioxidant repletion. This suggests that parenteral amino acids are used less effectively than those given enterally. The biomarkers reported in this study may be useful in guiding nutrition therapy for critically ill patients. LEVEL OF EVIDENCE: Therapeutic study, level III; prognostic study, level II.

Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study.

OBJECTIVE: The aim of the study was to determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma. BACKGROUND: Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma. PATIENTS AND METHODS: We genotyped eight common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the intensive care unit at a Level 1 trauma center (2003-2005). RESULTS: A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (adjusted odds ratio [ORadj] = 0.48, 95% confidence interval [CI]: 0.28-0.81, P = 0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj = 0.30, 95% CI: 0.13-0.70, P = 0.005). CONCLUSIONS: MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis.