Revision Carpal Tunnel Release Following Endoscopic Compared With Open Decompression.

Importance: Carpal tunnel release (CTR) technique may influence the likelihood of revision surgery. Prior studies of revision CTR following endoscopic CTR (ECTR) compared with open CTR (OCTR) have been limited by sample size and duration of follow-up. Objective: To estimate the incidence of revision CTR following ECTR compared with OCTR in a national cohort. Design, Setting, and Participants: This retrospective cohort study used data from the US Veterans Health Administration. Participants included all adults (age ≥18 years) undergoing at least 1 outpatient CTR from October 1, 1999, to May 20, 2021. Data were analyzed from May 21, 2021, to November 27, 2023. Exposure: Index CTR technique. Main Outcomes and Measures: The primary outcome was time to revision CTR, defined as repeat ipsilateral CTR during the study period. Secondary outcomes were indications for revision, findings during revision, and additional procedures performed during revision. Results: Among 134 851 wrists from 103 455 patients (92 510 [89.4%] male; median [IQR] age, 62 [53-70] years) undergoing at least 1 CTR, 1809 wrists underwent at least 1 revision at a median (IQR) of 2.5 (1.0-3.8) years. In competing-risks analysis, the cumulative incidence of revision was 1.06% (95% CI, 0.99%-1.12%) at 5 years and 1.59% (95% CI, 1.51%-1.67%) at 10 years. ECTR was associated with increased hazard of revision CTR compared with OCTR (adjusted hazard ratio [aHR], 1.56; 95% CI, 1.34-1.81; P < .001). The risk difference for revision CTR associated with ECTR compared with OCTR was 0.57% (95% CI, 0.31%-0.84%) at 5 years (number needed to harm, 176) and 0.72% (95% CI, 0.36%-1.07%) at 10 years (number needed to harm, 139). Regardless of index CTR technique, the most common indication for revision was symptom recurrence (1062 wrists [58.7%]). A reconstituted transverse carpal ligament (TCL) was more common after ECTR compared with OCTR, whereas scarring of the overlying tissues and of the median nerve itself were more common following OCTR. Incomplete transverse-carpal-ligament release was observed in 251 of the wrists undergoing revision CTR (13.94%) and was more common among revisions following ECTR (odds ratio, 1.62; 95% CI, 1.11-2.37; P = .01). Conclusions and Relevance: In this cohort study of revision CTR in the Veterans Health Administration, ECTR was associated with increased risk of revision compared with OCTR, but the absolute risk was low regardless of technique. Intraoperative findings at revision varied significantly according to index CTR technique.

Risk of Amyloidosis and Heart Failure Among Patients Undergoing Surgery for Trigger Digit or Carpal Tunnel Syndrome: A Nationwide Cohort Study With Implications for Screening.

PURPOSE: Tenosynovial biopsy during carpal tunnel release (CTR) leads to an earlier diagnosis of amyloidosis. Surgery for trigger digit-trigger release (TR)-may provide a similar opportunity. We sought to characterize the risk of amyloidosis diagnosis after TR and/or CTR. METHODS: We conducted a retrospective cohort study of adults without diagnosed amyloidosis undergoing TR and/or CTR in the Veterans Health Administration from 1999 to 2019, including matched controls. We used competing-risks methodology to estimate the cumulative incidence and adjusted subdistribution hazard ratios (sHRs) of amyloidosis, heart failure, and death after TR and/or CTR. RESULTS: Among the 126,788 patients undergoing TR and/or CTR, amyloidosis was diagnosed in 52 of 26,757 patients undergoing TR alone at a median of 4.7 years after surgery (10-year cumulative incidence: 0.26%, 95% CI: 0.18% to 0.34%), 396 of 91,384 patients undergoing CTR alone at a median of 5.1 years after surgery (10-year cumulative incidence: 0.60%, 95% CI: 0.53% to 0.67%), 50 of 8,647 patients undergoing both TR and CTR at a median of 3.1 years after surgery (10-year cumulative incidence: 0.80%, 95% CI: 0.54% to 1.1%), and 54 of 113,452 controls at a median of 5.0 years after the index date (10-year cumulative incidence 0.053%, 95% CI: 0.037% to 0.070%). In the adjusted analysis, patients who underwent TR and/or CTR had a higher risk of amyloidosis (TR: sHRadj 4.80, 95% CI: 3.33-6.92; CTR: sHRadj 10.2, 95% CI: 7.74-13.6; TR and CTR: sHRadj 14.9, 95% CI: 9.87-22.5) and heart failure (TR: sHRadj 1.91, 95% CI: 1.83-1.99; CTR: sHRadj 2.02, 95% CI: 1.97-2.07; TR and CTR: sHRadj 2.18, 95% CI: 2.04-2.33) but not death compared with the controls. Among the patients who underwent TR, age, Black race, prior CTR, heart failure, and the number of digits released were independent risk factors for amyloidosis. CONCLUSIONS: Patients undergoing TR and/or CTR are at increased risk of incident amyloidosis and heart failure compared to controls. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Syndactyly Release in the Hand: Surgical Technique.

SUMMARY: Syndactyly is one of the most common congenital differences treated by hand surgeons. Although dozens of techniques for syndactyly release have been described, a reliable method is based on a dorsal rectangular flap for commissure construction and a combination of interdigitating zigzag flaps and skin grafts for digital coverage. In this article, the authors present a detailed description of syndactyly release emphasizing principles integral to successful outcomes.

Diagnosing Systemic Amyloidosis Presenting as Carpal Tunnel Syndrome: A Risk Nomogram to Guide Biopsy at Time of Carpal Tunnel Release.

BACKGROUND: As carpal tunnel syndrome often precedes other signs of systemic amyloidosis, tenosynovial biopsy at the time of carpal tunnel release may facilitate early diagnosis and treatment. However, evidence-based guidelines for amyloidosis screening during carpal tunnel release have not been established. We sought to develop a predictive model for amyloidosis after carpal tunnel release to inform screening efforts. METHODS: We performed a retrospective cohort study of adults without known amyloidosis undergoing at least 1 carpal tunnel release from 2000 to 2019 with use of the national Veterans Health Administration database. After estimating the cumulative incidence of amyloidosis after carpal tunnel release, we identified risk factors, constructed a predictive nomogram based on a multivariable subdistribution-hazard competing-risks model, and performed cross-validation. RESULTS: Among 89,981 patients undergoing at least 1 carpal tunnel release, 310 were subsequently diagnosed with amyloidosis at a median interval of 4.5 years, corresponding to a cumulative incidence of 0.55% (95% confidence interval [CI]: 0.47% to 0.63%) at 10 years. Amyloidosis diagnosis following carpal tunnel release was associated with an increased hazard of heart failure (hazard ratio [HR], 4.68; 95% CI: 4.26 to 5.55) and death (HR, 1.27; 95% CI: 1.07 to 1.51) after adjustment for potential confounders. Age, male sex, Black race, monoclonal gammopathy of undetermined significance or multiple myeloma, rheumatoid arthritis, atrial fibrillation, spinal stenosis, and bilateral carpal tunnel syndrome were independently associated with increased risk of amyloidosis diagnosis and were included in the risk nomogram. CONCLUSIONS: Amyloidosis diagnosis after carpal tunnel release is rare but is associated with poor outcomes. We present an amyloidosis-risk nomogram to help guide tenosynovial biopsy at time of carpal tunnel release. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Index Finger Pollicization for Hypoplastic Thumb: Surgical Technique.

SUMMARY: Pollicization can be performed for secondary thumb reconstruction after traumatic injury or for primary thumb construction in cases of congenital thumb hypoplasia. Given the complexity of this operation, intimate familiarity with the involved anatomy and surgical principles is key to successful surgical outcomes. In this Video Plus article, the authors present a step-by-step approach to pollicization in case of Blauth type IIIB thumb hypoplasia.

Five Essential Principles for First Web Space Reconstruction in the Burned Hand.

BACKGROUND: Burn injuries commonly affect the hand, and the development of adduction contractures of the first web space is frequent and deleterious, both functionally and aesthetically. Many corrective techniques and algorithmic approaches have been described to treat this problem, but there is no consensus on the optimal management. METHODS: A retrospective review at a single high-volume pediatric burn center was undertaken to evaluate the clinical course of these patients. All pediatric patients undergoing initial release of burn scar contracture of the first web space from 2005 through 2015 were included in a retrospective cohort study. RESULTS: The authors identified 40 patients with 57 burned hands. The initial approach to management was variable. Z-plasty or other local flap was the first technique used in 28 hands (49 percent), split-thickness skin graft in 19 hands (33 percent), full-thickness skin graft in seven hands (12 percent), groin flaps in two hands (4 percent), and a reverse radial forearm flap in one hand (2 percent). The mean numbers of total reconstructive procedures per hand including the initial procedure were as follows: groin flap, 4.0; full-thickness skin graft, 3.1; split-thickness skin graft, 2.1; Z-plasty, 1.4; and reverse radial forearm flap, 1.0. CONCLUSIONS: Successful reconstruction of the first web space must be addressed in the context of the entire hand. It is the authors' preference to use split-thickness skin grafting whenever a skin deficiency is present-only then should leading edge contractures be addressed with Z-plasty. Based on their experience, the authors recommend five principles that are essential to successfully treat postburn contractures of the first web space. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Patient Transfer for Hand and Upper Extremity Injuries: Diagnostic Accuracy at the Time of Referral.

BACKGROUND: Local health care facilities are often unequipped to treat complex upper extremity injuries, and patients are therefore transferred to designated trauma centers. This study describes the characteristics of patients transferred to a Level I trauma center for hand and upper extremity injuries and to investigate the accuracy of the provided diagnosis at the time of referral. METHODS: Adult patients transferred from outside facilities to the authors' Level I trauma center by means of direct contract with the on-call fellow for the care of hand and upper extremity injuries were identified. Patient- and injury-related information was prospectively collected at the time of referral before patient transfer, and again following diagnostic evaluation by a hand surgeon at the authors' institution. RESULTS: Sixty-three patients were transferred to the authors' hand surgery service from outside facilities after direct contact with the on-call fellow. Most patients were referred by emergency medicine physicians [n = 47 (76 percent)], followed by midlevel emergency department providers (physician assistant or nurse practitioner) [n = 12 (19 percent)] or hand surgeons [n = 3 (5 percent)]. Six patients were transferred directly from a Level I trauma center. Twenty-one transferred patients (33 percent) had an inaccurate diagnosis at the time of referral. Factors associated with an inaccurate diagnosis included trauma level of the referring hospital and diagnoses of infection or dysvascularity. CONCLUSIONS: The diagnostic accuracy for hand injuries transferred from outside facilities by means of provider-to-provider communication is imperfect, and some injuries are misdiagnosed. Hand surgeons should continue to improve the triage and transfer process for patients with acute hand surgery injuries. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV.

Genetic Risk of Trigger Finger: Results of a Genomewide Association Study.

BACKGROUND: Trigger finger, or stenosing tenosynovitis, is one of the most common conditions affecting the hand, yet its pathophysiology remains poorly understood, and genetic association studies of trigger finger are lacking. The purpose of this study was to identify single-nucleotide polymorphisms associated with trigger finger through a genomewide approach. METHODS: The authors performed a case-control genomewide association study in the Partners HealthCare Biobank. Single-nucleotide polymorphism- and gene-based association analyses were carried out after quality control, imputation, and filtering. RESULTS: Among 942 trigger finger cases and 24,472 controls, the authors tested 7,846,471 single-nucleotide polymorphisms for association with trigger finger. In the single-nucleotide polymorphism-based analysis, a single locus on chromosome 13 corresponding to KLHL1 met the genomewide significance threshold (lead single-nucleotide polymorphism rs59988404; OR, 1.74; 95 percent CI, 1.47 to 2.07; p = 1.99 × 10). After mapping, gene-based analysis demonstrated a significant association with POLE2 (p = 7.53 × 10) on chromosome 14. Among trigger finger cases, rs59988404 genotype was significantly associated with the total number of trigger finger procedures performed (p = 0.026). CONCLUSIONS: In the first reported genomewide association study of trigger finger, the authors report significant associations of KLHL1 and POLE2 with risk of trigger finger. The authors' results may help to elucidate the pathophysiology of trigger finger and facilitate an individualized, precision-medicine treatment approach. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Surgery for lower extremity symptomatic neuroma: Long-term outcomes.

INTRODUCTION: Traumatic neuroma caused by injuries or surgery can result in neuropathic pain, functional impairment, and psychological distress, which has an impact on quality of life. The aim of this study was to identify the factors related to successful treatment of symptomatic lower extremity symptomatic neuromas using patient-reported outcome measures (PROMs). METHODS: Thirty-two patients with 48 symptomatic neuromas completed the PROMIS mobility, PROMIS pain interference (PI), Numeric Rating Scale (NRS) for pain (0-10) for both pre- and post-operative pain, and the PROMIS depression at a mean of 8.9±4.5 years following neuroma surgery. Neuromas were located around the foot and ankle (n=18, 38%), leg (n=14, 29%), around the knee (n=13, 27%), and in the thigh (n=3, 6.3%). Surgical treatment included neuroma excision and implantation (n=29, 60%) followed by neuroma excision alone or excision with placement in the subcutaneous tissue (n=12, 25%). We performed multivariable analysis to identify the factors influencing the PROMs. RESULTS: Patients reported significant reduction in mean NRS pain after surgery (7.3 vs 4.9, p=0.0013). Higher PROMIS depression scores were independently associated with inferior PROMIS mobility scores (ß=-0.38, p=0.001), higher PROMIS PI scores (ß=0.68, p<0.001), and higher NRS pain scores (ß=0.1, p=0.001). Additionally, smoking was independently associated with higher NRS pain scores (ß=1.59, p=0.049) CONCLUSION: Surgical treatment of symptomatic neuromas of the lower extremity provides a long-term improvement in 59% of patients, but 19% of patients still reported severe persistent pain despite surgical treatment. Smoking and negative mood have negative effects on patient-reported outcomes after neuroma surgery.

Patient-Reported Outcomes following Surgical Treatment of Symptomatic Digital Neuromas.

BACKGROUND: Many surgical techniques are used to treat symptomatic neuroma, but options are limited for digital neuromas because of a paucity of soft-tissue coverage and/or the absence of the terminal nerve end. The authors assessed factors that influence patient-reported outcomes after surgery for symptomatic digital neuroma. METHODS: The authors retrospectively identified 29 patients with 33 symptomatic digital neuromas that were treated surgically. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity and Pain Interference scales, a numeric rating scale for pain, and the PROMIS Depression scale at a median follow-up of 7.6 years postoperatively (range, 3.2 to 16.8 years). Surgical treatment for neuroma included excision with nerve repair/reconstruction (n =13; 39 percent), neuroma excision alone (n =10; 30 percent), and excision and implantation (n =10; 30 percent). Multivariable linear regression was performed to identify the factors that independently influenced patient-reported outcomes. RESULTS: The mean postoperative PROMIS Upper Extremity score was 45.2 ± 11.2, the mean Pain Interference score was 54.3 ± 10.7, and the mean numeric rating scale pain score was 3 (interquartile range, 1 to 5). Compared with other treatment techniques, neuroma excision with nerve repair/reconstruction was associated with lower numeric rating scale pain scores; lower Pain Interference scores, corresponding to less daily impact of pain; and higher Upper Extremity scores, reflecting better upper extremity function. Older age and higher Depression scores were associated with lower Upper Extremity scores and higher Pain Interference scores. Smoking was associated with higher Pain Interference and numeric rating scale pain scores. CONCLUSIONS: Neuroma excision followed by nerve repair/reconstruction resulted in better outcomes compared with neuroma excision alone with or without implantation. Patient age and psychosocial factors influenced patient-reported outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Fibroadipose Vascular Anomaly in the Upper Extremity: A Distinct Entity With Characteristic Clinical, Radiological, and Histopathological Findings.

PURPOSE: Fibroadipose vascular anomaly (FAVA) is an intramuscular vascular malformation that has been recently described as a distinct clinical entity. The clinical, radiological, and histopathological characteristics of FAVA in the upper extremity are reviewed. METHODS: This was a retrospective case series of upper-extremity FAVA lesions. RESULTS: We reviewed 19 patients with FAVA of the upper limb. Pain, stiffness, swelling, and flexion contractures were the most common presentations. Except for one lesion confined to the hand, all lesions either presented with or developed a contracture within 10 years. Ten patients underwent surgical debulking. Six required tendon transfer reconstruction and 3 necessitated a free functional muscle transfer. CONCLUSIONS: Fibroadipose vascular anomaly in the upper extremity requires an accurate diagnosis and may benefit from early referral to a multidisciplinary vascular anomaly center with experienced hand surgeons. Compression garments, propranolol, and sclerotherapy seem to be ineffective. Surgical resection focused on symptomatic regions with appropriate reconstruction may have benefit in salvage of limbs with compromised function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Longitudinal Microsurgery Laboratory Training during Hand Surgery Fellowship.

BACKGROUND: Laboratory training courses have traditionally offered an attractive method to learn microsurgery in a low-risk environment. However, courses are often limited by cost, accessibility, and their one-time, nonlongitudinal nature. Our aims were to (1) describe our institution's microsurgical training course for hand surgery fellows, which is longitudinal and integrated within our fellowship curriculum and (2) investigate how this course affects the microsurgical confidence and competence of trainees throughout their fellowship year. METHODS: All hand fellows who trained in our 1-year combined hand surgery fellowship from 2016 through 2018 participated in this study. Baseline data on the type and duration of residency training, previous microsurgery experience and self-reported confidence, knowledge, and interest in microsurgery were recorded. Self-reported scores were documented using a continuous scale ranging from 0 to 10. An initial 3-day laboratory course combining the use of didactic teaching, a nonliving synthetic model, and a live rat model was conducted. Repeat laboratory training occurred thereafter at 6 and 12 months. At the end of each session, fellows repeated the baseline questionnaire and faculty assessed their microsurgical competence using a standardized global rating scale (GRS). RESULTS: A total of six fellows (2 years) were enrolled. At the end of the initial course, there was a statistically significant increase in mean self-reported confidence in microsurgery from 4.3 to 6.2 and knowledge from 4.7 to 6.5. Mean scores in interest were unchanged, from 9.2 to 9.3. There was also an increase in mean GRS score from day 3 to months 6 and 12. CONCLUSION: A longitudinal microsurgical training course integrated within a hand surgery fellowship is associated with increased confidence and microsurgical skill. This study describes our approach and its feasibility.

Respiratory Failure following Abdominal Wall Reconstruction: An Analysis of the Nationwide Inpatient Sample.

BACKGROUND: Patients undergoing abdominal wall reconstruction are at increased risk of postoperative respiratory failure. Understanding the epidemiology of this complication may guide preventive efforts. METHODS: The authors performed a population-based retrospective cohort study of adults undergoing elective abdominal wall reconstruction (ventral hernia repair with component separation) in the United States from 2004 through 2011 using the Nationwide Inpatient Sample. RESULTS: Of 2283 patients undergoing elective abdominal wall reconstruction, 57 percent were women, with a median age of 57 years, median hospital stay of 5 days, and mean total cost of $23,730. Postoperative respiratory failure occurred in 212 patients (9.3 percent), 164 patients (7.2 percent) were discharged to a skilled nursing facility, and 18 patients (0.8 percent) died. On multivariate analysis, age, male sex, congestive heart failure, lung disease, obesity, and obstructive sleep apnea were independently associated with increased risk of respiratory failure. Respiratory failure was associated with significantly increased risk of death and discharge to a skilled nursing facility as well as significantly increased total cost and hospital length of stay. CONCLUSIONS: Respiratory failure is an uncommon but devastating complication of abdominal wall reconstruction. The authors report clinical risk factors that may facilitate perioperative risk-reduction strategies to improve outcomes of elective abdominal wall reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

MC1R gene polymorphisms are associated with dysfunctional immune responses and wound infection after burn injury.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is associated with organ failure and infectious complications after major burn injury. Recent evidence has linked melanocortin signaling to anti-inflammatory and wound-repair functions, with mutations in the melanocortin 1 receptor (MC1R) gene leading to increased inflammatory responses. Our group has previously demonstrated that MC1R gene polymorphisms are associated with postburn hypertrophic scarring. Thus, we hypothesized that MC1R single nucleotide polymorphisms (SNPs) would be associated with increased burn-induced SIRS and increased infectious complications. METHODS: We performed a retrospective cohort study of adults (>18 y of age) admitted to our burn center with >20% total body surface area (TBSA) partial/full thickness burns between 2006 and 2013. We screened for five MC1R SNPs (V60L, V92M, R151C, R163Q, T314T) by polymerase chain reaction from genomic DNA isolated from blood samples. We performed a detailed review of each patient chart to identify age, sex, race, ethnicity, %TBSA burned, burn wound infections (BWIs), and 72-hr intravenous fluid volume, the latter a surrogate for a dysfunctional inflammatory response to injury. Association testing was based on multivariable regression. RESULTS: Of 106 subjects enrolled, 82 had complete data for analysis. Of these, 64 (78%) were male, with a median age of 39 and median burn size of 30% TBSA. A total of 36 (44%) subjects developed BWIs. The median total administered IV crystalloid in first 72h was 24.6 L. In multivariate analysis, the R151C variant allele was a significant independent risk factor for BWI (adjusted prevalence ratio 2.03; 95% CI: 1.21-3.39; P = 0.007), and the V60L variant allele was independently associated with increased resuscitation fluid volume (P = 0.021). CONCLUSIONS: This is the first study to demonstrate a significant association between genetic polymorphisms and a nonfatal burn-induced SIRS complication. Our findings suggest that MC1R polymorphisms contribute to dysfunctional responses to burn injury that may predict infectious and inflammatory complications.

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.

Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients.

IMPORTANCE: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient. OBJECTIVE: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry. MAIN OUTCOMES AND MEASURES: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites. RESULTS: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress. CONCLUSIONS AND RELEVANCE: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients.

Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.

BACKGROUND: Hypertrophic scarring (HTS) is hypothesized to have a genetic mechanism, yet its genetic determinants are largely unknown. The mitogen-activated protein kinase (MAPK) pathways are important mediators of inflammatory signaling, and experimental evidence implicates MAPKs in HTS formation. We hypothesized that single-nucleotide polymorphisms (SNPs) in MAPK-pathway genes would be associated with severity of post-burn HTS. METHODS: We analyzed data from a prospective-cohort genome-wide association study of post-burn HTS. We included subjects with deep-partial-thickness burns admitted to our center who provided blood for genotyping and had at least one Vancouver Scar Scale (VSS) assessment. After adjusting for HTS risk factors and population stratification, we tested MAPK-pathway gene SNPs for association with the four VSS variables in a joint regression model. In addition to individual-SNP analysis, we performed gene-based association testing. RESULTS: Our study population consisted of 538 adults (median age 40 years) who were predominantly White (76%) males (71%) admitted to our center from 2007-2014 with small-to-moderate-sized burns (median burn size 6% total body surface area). Of 2,146 SNPs tested, a rare missense variant in the PTPN5 gene (rs56234898; minor allele frequency 1.5%) was significantly associated with decreased severity of post-burn HTS (P = 1.3×10-6). In gene-based analysis, PTPN5 (P = 1.2×10-5) showed a significant association and BDNF (P = 9.5×10-4) a borderline-significant association with HTS severity. CONCLUSIONS: We report PTPN5 as a novel genetic locus associated with HTS severity. PTPN5 is a MAPK inhibitor expressed in neurons, suggesting a potential role for neurotrophic factors and neuroinflammatory signaling in HTS pathophysiology.

Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults.

BACKGROUND: In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. METHODS: We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. RESULTS: After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. CONCLUSION: Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. LEVEL OF EVIDENCE: Epidemiologic study, level III.