Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. Objective: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. Design, Setting, and Participants: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. Interventions: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). Main Outcomes and Measures: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. Results: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). Conclusions and Relevance: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. Trial Registration: ClinicalTrials.gov Identifier: NCT01990768.

Substantia nigra hyperechogenicity correlates with subtle motor dysfunction in tap dancers.

Hyperechogenicity of the substantia nigra (SN) detected by transcranial sonography is a typical finding in more than 90% of patients with Parkinson's disease (PD) but may also be visible in about 9% of healthy adults. In this study, we found a correlation between SN hyperechogenicity and subtle motor dysfunction in otherwise healthy young tap dancers. In accordance with former findings, results of the present study confirm the hypothesis that SN hyperechogenicity is a marker for a possible functional impairment of the nigrostriatal system, that may become evident under challenging conditions.

Continuous transesophageal echo-Doppler assessment of hemodynamic function during laparoscopic cholecystectomy.

STUDY OBJECTIVE: The objective of this study was to examine the utility of the transesophageal echo-Doppler device in evaluating hemodynamic changes during laparoscopic cholecystectomy. DESIGN: This was a prospective, controlled, observational open study. SETTING: The study took place in a university hospital. PATIENTS: Twenty patients with ASA physical statuses II and III undergoing laparoscopic cholecystectomy were enrolled into the study. INTERVENTIONS AND MEASUREMENTS: A standardized general anesthetic and surgical technique was used for all patients. Similar depth of hypnosis (using bispectral index monitoring) was maintained in all patients. Hemodynamic parameters including mean arterial pressure (MAP), cardiac index (CI), left ventricular (LV) ejection time interval indexed to the heart rate, maximum acceleration, peak velocity, and systemic vascular resistance (SVR) were recorded at predetermined intervals: before incision, after peritoneal CO(2) insufflation and head-up tilt, every 10 minutes thereafter, and after deflation of the abdomen and return to supine position. MAIN RESULTS: The transesophageal echo-Doppler probe placement was achieved in 3 to 5 minutes in all patients, and the probe position was maintained after creation of pneumoperitoneum and change in positioning. Induction of pneumoperitoneum and head-up tilt resulted in a significant increase in MAP and SVR (P < .05) that remained higher until deflation. The CI, LV ejection time interval indexed to the heart rate (a measure of LV filling), and maximum acceleration (a measure of contractility and global ventricular function) remained stable. CONCLUSIONS: The transesophageal echo-Doppler device can be used during laparoscopic cholecystectomy. The LV function, as determined by measurement of CI and maximum acceleration, was preserved during laparoscopic cholecystectomy despite significant increases in afterload (ie, MAP and SVR).

Collider bias in trauma comparative effectiveness research: the stratification blues for systematic reviews.

BACKGROUND: Collider bias, or stratifying data by a covariate consequence rather than cause (confounder) of treatment and outcome, plagues randomised and observational trauma research. Of the seven trials of prehospital hypertonic saline in dextran (HSD) that have been evaluated in systematic reviews, none found an overall between-group difference in survival, but four reported significant subgroup effects. We hypothesised that an avoidable type of collider bias often introduced inadvertently into trauma comparative effectiveness research could explain the incongruous findings. METHODS: The two most recent HSD trials, a single-site pilot and a multi-site pivotal study, provided data for a secondary analysis to more closely examine the potential for collider bias. The two trials had followed the a priori statistical analysis plan to subgroup patients by a post-randomisation covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥ 10 unit of red blood cells within 24h of admission. Despite favourable HSD effects in the MT subgroup, opposite effects in the non-transfused subgroup halted the pivotal trial early. In addition to analyzing the data from the two trials, we constructed causal diagrams and performed a meta-analysis of the results from all seven trials to assess the extent to which collider bias could explain null overall effects with subgroup heterogeneity. RESULTS: As in previous trials, HSD induced significantly greater increases in systolic blood pressure (SBP) from prehospital to admission than control crystalloid (p=0.003). Proportionately more HSD than control decedents accrued in the non-transfused subgroup, but with paradoxically longer survival. Despite different study populations and a span of over 20 years across the seven trials, the reported mortality effects were consistently null, summary RR=0.99 (p=0.864, homogeneity p=0.709). CONCLUSIONS: HSD delayed blood transfusion by modifying standard triggers like SBP with no detectable effect on survival. The reported heterogeneous HSD effects in subgroups can be explained by collider bias that trauma researchers can avoid by improved covariate selection and data capture strategies.

Epidural analgesia improves outcome after multiple rib fractures.

BACKGROUND: Rib fractures are common and associated with significant pulmonary morbidity. We hypothesized that epidural analgesia would provide superior pain relief, and reduce the risk of subsequent pneumonia. METHODS: A prospective, randomized trial of epidural analgesia versus IV opioids for the management of chest wall pain after rib fractures was carried out. Entry criteria included patients older than 18 years with more than 3 rib fractures and no contraindications to epidural catheter placement. RESULTS: From March 2000 to December 2003, 408 patients were admitted with more than 3 rib fractures; 282 met exclusion criteria, 80 could not be consented, and 46 were enrolled (epidural n = 22, opioids n = 24). The groups were comparable for mean age, injury severity score, gender, chest Abbreviated Injury Scale, and mean number of rib fractures. The epidural group tended to have more flail segments (38% vs 21%, P = .20) and pulmonary contusions (59% vs 38%, P = .14), and required more chest tubes (95% vs 71%, P = .03) Despite the greater direct pulmonary injury in the epidural group, their rate of pneumonia was 18% versus 38% for the intravenous opioid group. When adjusted for direct pulmonary injury, there was a greater risk of pneumonia in the opioid group: OR, 6.0; 95% CI, 1.0-35; P = .05. When stratified for the presence of pulmonary contusion there was a 2.0-fold increase in the number of ventilator days for the opioid group: incident rate ratio, 2.0; 95% CI, 1.6-2.6; P < .001. CONCLUSIONS: The use of epidural analgesia is limited in the trauma population due to numerous exclusion criteria. However, when feasible, epidural analgesia is associated with a decrease in the rate of nosocomial pneumonia and a shorter duration of mechanical ventilation after rib fractures.

Waiver of consent in noninterventional, observational emergency research: the PROMMTT experience.

BACKGROUND: In the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, waiver of consent was used because previous literature reported low response rates and subsequent bias. The goal of this article was to examine the rationale and tradeoffs of using waiver of consent in PROMMTT. METHODS: PROMMTT enrolled trauma patients receiving at least 1 U of red blood cells within 6 hours after admission at 10 US Level 1 trauma centers. Local institutional review boards (IRBs) from all sites approved the study. Site 8 was required by their IRB to attempt consent but was allowed to retain data on patients unable to be consented. RESULTS: Of 121 subjects enrolled at Site 8, 55 consents were obtained (46%), and no patient or legally authorized representative refused to give consent. Of the patients, 36 (30%) died, and 6 (5%) were discharged before consent could be attempted. Consent was attempted but not possible among 24 patients (20%). Of the 10 clinical sites, 6 of the local IRBs approved collection of residual blood samples, 1 had previous approval to collect timed blood samples under a separate protocol, and 3 reported that their local IRBs would not approve collection of residual blood under a waiver of consent. CONCLUSION: Waiver of consent was used in PROMMTT because of the potential adverse impact of consent refusals; however, there were no refusals. If the IRB for Site 8 had required withdrawal of patients unable to consent and destruction of their data, a serious bias would likely have been introduced. Other tradeoffs included a reduction in sites participating in residual blood collection and a smaller than expected amount of residual blood collected among sites operating under a waiver of consent. Noninterventional emergency research studies should consider these potential tradeoffs carefully before deciding whether waiver of consent would best achieve the goals of a study.

The health-related quality of life of children with an extremity fracture: a one-year follow-up study.

PURPOSE: To document the health-related quality of life (HRQOL) of children with an extremity fracture at 3 and 12 months postinjury and to determine whether it varies significantly by fracture region and site. METHODS: Children hospitalized for an extremity fracture at 4 pediatric trauma centers were studied. A baseline, 3-month, and 12-month telephone interview were completed by a primary caregiver to measure the child's HRQOL using the Pediatric Quality of Life Inventory (PedsQL). HRQOL was modeled as a function of injury, patient, and family characteristics using a longitudinal regression model. RESULT: Of the 100 children enrolled, 52 sustained a lower extremity fracture (LEF) and 48 an upper extremity fracture (UEF). Postinjury HRQOL scores were significantly poorer than preinjury scores for all subjects (P = 0.05). In addition, a significant proportion of subjects reported impaired physical and psychosocial HRQOL at 3 (44% and 46%, respectively) and 12 months (23% and 33%, respectively) postinjury. At 3 months postinjury, children with an LEF had significantly poorer HRQOL outcomes compared to children with a UEF. By 12 months postinjury, the physical function of children with a tibia and/or fibula fracture remained significantly lower than children with a UEF (P < or = 0.05). CONCLUSIONS: Children hospitalized for an extremity fracture suffered dramatic declines in physical and psychosocial well-being during the first 3 months postinjury. By 1 year postinjury, most children recovered; however, children with a tibia and/or fibula fracture still reported significantly poorer physical functioning.

Oxandrolone does not improve outcome of ventilator dependent surgical patients.

BACKGROUND: Multisystem injury and major surgical stress result in a hypermetabolic state with accelerated breakdown of protein stores. Loss of lean muscle mass impairs wound healing, increases infection rates, and weakens respiratory musculature. Oxandrolone is an anabolic steroid that attenuates loss of lean body mass and improves wound healing in burn patients. We hypothesized that oxandrolone would improve outcome for ventilator-dependent surgical patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of oxandrolone therapy for surgical/trauma patients requiring >7 days of ventilation. The primary end point was time on the ventilator. RESULTS: Forty-one patients were enrolled between January 1, 2001, and June 15, 2003, 18 received oxandrolone (10 mg po BID) and 23 received a placebo. Groups were comparable for age, gender, injury severity score, and APACHE II score. The majority were trauma patients (83%), and 90% received enteral feeding. The oxandrolone group received higher caloric and protein intake before enrollment, but these differences were not significant. Contrary to our hypothesis, patients receiving oxandrolone spent significantly longer time on the ventilator than the placebo group (mean 21.7 days vs. 16.4 days, P = 0.03). There was no difference in infectious complications, acute respiratory distress syndrome, or multiple organ failure scores. Patients receiving oxandrolone had a longer intensive care unit stay but no difference in total hospital stay. CONCLUSION: Ventilator-dependent surgical patients receiving oxandrolone had a more prolonged course of mechanical ventilation, suggesting that oxandrolone may be detrimental in this circumstance. Oxandrolone may enhance collagen deposition and fibrosis in the later stages of acute respiratory distress syndrome and thus prolong recovery.

Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.

OBJECTIVE: To determine the effectiveness of early, routine antioxidant supplementation using alpha-tocopherol and ascorbic acid in reducing the rate of pulmonary morbidity and organ dysfunction in critically ill surgical patients. SUMMARY BACKGROUND DATA: Oxidative stress has been associated with the development of the acute respiratory distress syndrome (ARDS) and organ failure through direct tissue injury and activation of genes integral to the inflammatory response. In addition, depletion of endogenous antioxidants has been associated with an increased risk of nosocomial infections. The authors postulated that antioxidant supplementation in critically ill surgical patients may reduce the incidence of ARDS, pneumonia, and organ dysfunction. METHODS: This randomized, prospective study was conducted to compare outcomes in patients receiving antioxidant supplementation (alpha-tocopherol and ascorbate) versus those receiving standard care. The primary endpoint for analysis was pulmonary morbidity (a composite measure of ARDS and nosocomial pneumonia). Secondary endpoints included the development of multiple organ failure, duration of mechanical ventilation, length of ICU stay, and mortality. RESULTS: Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60-1.1) in patients receiving antioxidant supplementation. Multiple organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19-0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay. CONCLUSIONS: The early administration of antioxidant supplementation using alpha-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients.