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Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

ABSTRACT: CONTEXT:Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE:This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN:We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES:We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS:We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION:The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

SUBMITTER: Foster MA

PROVIDER: S-EPMC7043227 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

Foster Mark A MA Taylor Angela E AE Hill Neil E NE Bentley Conor C Bishop Jon J Gilligan Lorna C LC Shaheen Fozia F Bion Julian F JF Fallowfield Joanne L JL Woods David R DR Bancos Irina I Midwinter Mark M MM Lord Janet M JM Arlt Wiebke W

The Journal of clinical endocrinology and metabolism 20200301 3

<h4>Context</h4>Survival rates after severe injury are improving, but complication rates and outcomes are variable.<h4>Objective</h4>This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery.<h4>Design</h4>We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury ...[more]

PMID: 32101296

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Project description:Introduction: Brain plasticity, synaptic regeneration and neuroinflammation are crucial mechanisms that play important roles in the recovery from acute brain injuries, such as aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI). The p75 neurotrophic receptor (p75NTR) is a significant receptor that modulates brain plasticity, neuroinflammation and apoptosis, making it an interesting target for therapeutic interventions. However, despite the progress made in understanding the molecular mechanisms involved in brain plasticity and neuroinflammation, there are still significant knowledge gaps in identifying protein biomarkers and microRNAs (miRNAs) associated with different types of acute brain injuries. Addressing these gaps will be critical in advancing our understanding of the underlying mechanisms involved in brain injury and developing effective therapies or prognostic strategies for recovery. Hypotheses: We hypothesized that changes in serum levels of p75NTR and its linked neuroinflammatory signaling proteins could predict recovery from acute brain injuries, regardless of injury type. Differentially expressed (DE) circulating miRNAs following acute brain injuries may regulate studied protein targets and overall injury outcome. Methods: A prospective cohort of 74 patients with ischemic stroke (n=30), aneurysmal subarachnoid hemorrhage (n=31), and traumatic brain injury (n=13) was evaluated. Serum samples were collected at two time points after the injury (early at 1.9 ± 1.0 days and late at 5.9 ± 2.2 days) and outcome evaluation was performed after three months. Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1, TNF, and cyclophilin A. A 2-tailed 2-sample t-test, univariate, and multivariate linear discriminant analysis (LDA) was used to compare serum molecules between patients with favorable (modified Rankin Scale (mRS) 0-3) and unfavorable outcome (mRS 4-6). Additionally, circulating miRNAs were extracted from the samples (n=48, early and late) and DE miRNAs were identified using DESeq2. The miRNA putative target genes were predicted and LDA was performed using the normalized expression values of identified DE miRNAs. Results: In this study, p75NTR (p < 0.01) and IL1 (p < 0.05) were found to be independently associated with outcome among the six circulating protein biomarkers studied. Combinatory LDA analysis of all six biomarkers showed significant predictive value for favorable outcome (OR 2.95 (1.46-5.98); area under the curve (AUC)= 71.2%, 95% CI = (0.590-0.833), p = 0.003). Temporal alterations of miRNA expression were observed in the aSAH, TBI, and IS groups (p<0.05, FDR corrected). Twenty-three common miRNAs were identified that differentiated favorable and unfavorable outcome (p<0.05) in all three groups. LDA of four identified miRNAs with predicted targets to studied proteins showed high predictive accuracy (OR (95% CI) 11.7 (2.39-226)); AUC = 94.1%, 95% CI = (0.849 - 1.00), p = 0.016). Conclusions This study indicates that assessing serum levels of p75NTR and its mechanistically linked proteins can predict recovery outcome in patients with different types of acute brain injuries. The combined miRNA and protein biomarker models demonstrated accurate outcome prediction across diverse injury types, implying the presence of a common recovery mechanism. DE miRNAs were found to target the studied molecules, suggesting a potential mechanistical role in recovery. The identified common miRNAs may provide new targets for mechanistic validation in disease models. Further investigation is warranted to validate and explore the potential of these proteins and miRNAs in prognostication and as therapeutic targets for enhancing recovery from acute brain injuries.

Project description:BACKGROUND:Preoperative endothelial dysfunction is a predictor of myocardial injury and major adverse cardiac events. Non-cardiac surgery is known to induce acute endothelial changes. The aim of this explorative cohort study was to assess the extent of systemic endothelial dysfunction after major emergency abdominal surgery and the potential association with postoperative myocardial injury. METHODS:Patients undergoing major emergency abdominal surgery were included in this prospective cohort study. The primary outcome was the change in endothelial function expressed as the reactive hyperemia index from 4-24 h after surgery until postoperative day 3-5. The reactive hyperemia index was assessed by non-invasive digital pulse tonometry. Secondary outcomes included changes in biomarkers of nitric oxide metabolism and bioavailability. All assessments were performed at the two separate time points in the postoperative period. Clinical outcomes included myocardial injury within the third postoperative day and major adverse cardiovascular events within 30?days of surgery. RESULTS:Between October 2016 and June 2017, 83 patients were included. The first assessment of the endothelial function, 4-24?h, was performed 15.8 (SD 6.9) hours after surgery and the second assessment, postoperative day 3-5, was performed 83.7 (SD 19.8) hours after surgery. The reactive hyperemia index was suppressed early after surgery and did not increase significantly; 1.64 (95% CI 1.52-177) at 4-24?h after surgery vs. 1.75 (95% CI 1.63-1.89) at postoperative day 3-5, p =?0.34. The L-arginine/ADMA ratio, expressing the nitric oxide production, was reduced in the perioperative period and correlated significantly with the reactive hyperemia index. A total of 16 patients (19.3%) had a major adverse cardiovascular event, of which 11 patients (13.3%) had myocardial injury. The L-arginine/ADMA ratio was significantly decreased at 4-24?h after surgery in patients suffering myocardial injury. CONCLUSION:This explorative pathophysiological study showed that acute systemic endothelial dysfunction was present early after major emergency abdominal surgery and remained unchanged until day 3-5 after the procedure. Early postoperative disturbances in the nitric oxide bioavailability might add to the pathogenesis of myocardial injury. This pathophysiological link should be confirmed in larger studies. TRIAL REGISTRATION:clinicaltrials.gov no. NCT03010969.

Project description:BackgroundContinuous monitoring of central venous oxygen saturation (ScvO2) has been proposed as a prognostic indicator in several pathological conditions, including cardiac diseases, sepsis, trauma. To our knowledge, no studies have evaluated ScvO2 in polytraumatized patients with brain injury so far. Thus, the aim of the present study was to assess the prognostic role of ScvO2 monitoring during first 24 hours after trauma in this patients' population.MethodsThis prospective, non-controlled study, carried out between April 2006 and March 2008, was performed in a higher level Trauma Center in Florence (Italy). In the study period, 121 patients affected by major brain injury after major trauma were recruited. Inclusion criteria were: 1. Glasgow Coma Scale (GCS) score <or= 13; 2. an Injury Severity Score (ISS) >or= 15. Exclusion criteria included: 1. pregnancy; 2. age < 14 years; 3. isolated head trauma; 4. death within the first 24 hours from the event; 5. the lack of ScvO2 monitoring within 2 hours from the trauma. Demographic and clinical data were collected, including Abbreviated Injury Scale (AIS), Injury Severity Score (ISS), Simplified Acute Physiologic Score II (SAPS II), Marshall score. The worst values of lactate and ScvO2 within the first 24 hours from trauma, ICU length of stay (LOS), and 28-day mortality were recorded.ResultsPatients who deceased within 28 days showed higher age (53 +/- 16.6 vs 43.8 +/- 19.6, P = 0.043), ISS core (39.3 +/- 14 vs 30.3 +/- 10.1, P < 0.001), AIS score for head/neck (4.5 +/- 0.7 vs 3.4 +/- 1.2, P = 0.001), SAPS II score (51.3 +/- 14.1 vs 42.5 +/- 15, P = 0.014), Marshall Score (3.5 +/- 0.7 vs 2.3 +/- 0.7, P < 0.001) and arterial lactate concentration (3.3 +/- 1.8 vs 6.7 +/- 4.2, P < 0.001), than survived patients, whereas ScvO2 resulted significantly lower (66.7% +/- 11.9 vs 70.1% +/- 8.9 vs, respectively; P = 0.046). Patients with ScvO2 values <or= 65% also showed higher 28-days mortality rate (31.3% vs 13.5%, P = 0.034), ICU LOS (28.5 +/- 15.2 vs 16.6 +/- 13.8, P < 0.001), and total hospital LOS (45.1 +/- 20.8 vs 33.2 +/- 24, P = 0.046) than patients with ScvO2 > 65%.ConclusionScvO2 value less than 65%, measured in the first 24 hours after admission in patients with major trauma and head injury, was associated with higher mortality and prolonged hospitalization.

Dataset Information

Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

Publications

Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

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