Brief Consent Methods Enable Rapid Enrollment in Acute Stroke Trial: Results From the TICH-2 Randomized Controlled Trial.

BACKGROUND: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. METHODS: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. RESULTS: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up. CONCLUSIONS: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.

BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

Relation of RhoA in Peripheral Blood Mononuclear Cells With Severity of Aneurysmal Subarachnoid Hemorrhage and Vasospasm.

BACKGROUND AND PURPOSE: Rho-kinase, an effector of RhoA, is associated with various cardiovascular diseases in circulating blood cells. However, the role of RhoA/Rho-kinase in peripheral blood mononuclear cells from patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) has not yet been studied in relation to the severity of this disease. Therefore, we analyzed the expression and activity of RhoA as a possible biomarker in aSAH. METHODS: Twenty-four patients with aSAH and 15 healthy subjects were examined. Peripheral blood mononuclear cells were collected, and RhoA activity and expression were determined by RhoA activation assay kit (G-LISA) and enzyme-linked immunosorbent assay tests, respectively. The severity of aSAH was determined from the World Federation of Neurological Surgeon scale, and vasospasm was evaluated using clinical symptoms, arteriography, and sonography. RESULTS: RhoA expression was significantly increased in peripheral blood mononuclear cells from patients on days 0, 2, and 4 after aSAH versus healthy subjects (P=0.036, 0.010, and 0.018, respectively, by U Mann-Whitney analysis). There was a significant correlation between RhoA expression and injury severity on days 2 and 4 (Spearman test, day 2: r=0.682, n=14, P=0.007; day 4: r=0.721, n=14, P=0.004). No significant correlation was observed on day 0 (day 0: r=0.131, n=6, P=0.805). Active RhoA was not significantly different in patients and healthy subjects on days 0, 2, and 4 (P=0.243, 0.222, and 0.600, respectively) nor did it increase significantly on days 0 and 2 in patients with vasospasm versus patients without vasospasm (P=0.064 and 0.519, respectively). In contrast, active RhoA was significantly higher on day 4 in patients who developed vasospasm versus patients without vasospasm (P=0.028). CONCLUSIONS: Our preliminary results indicate that RhoA expression and activity in peripheral blood mononuclear cells might be related with aSAH severity and cerebral vasospasm. RhoA is a potential biomarker of the risks associated with aSAH.

IMPACT Score for Traumatic Brain Injury: Validation of the Prognostic Tool in a Spanish Cohort.

BACKGROUND: The aim of this work was to validate the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) model in a Spanish cohort of patients with moderate-severe TBI (traumatic brain injury). SETTING: Two level I neurotrauma centers. PARTICIPANTS: Patients admitted to these hospitals between 2011 and 2014 with a diagnosis of TBI and a Glasgow Coma Scale score of 12 or less. DESIGN: Prospective observational study. MAIN MEASURES: We collected prospectively the clinical variables included in the IMPACT models. Outcome evaluation was prospectively done at 6-month follow-up according to the Glasgow Outcome Scale. RESULTS: A total of 290 patients were included in the study. Forty-seven patients (16.2%) died within 6 months post-TBI, and 74 patients (25.5%) had an unfavorable outcome. The Hosmer-Lemeshow test revealed that there was no difference between observed and predicted outcomes; hence, the 3 models displayed adequate calibration for predicting 6-month mortality or unfavorable outcome. The receiver operating characteristic curve indicated that the 3 models (Core, Extended, and Lab) could accurately discriminate between favorable and unfavorable outcomes, as well as between survival and mortality (P < .001). CONCLUSION: The IMPACT model validates prediction of 6-month outcomes in a Spanish population of moderate-severe TBI. IMPACT Lab model is the one that presents a higher discriminative capacity. These results encourage the implementation of the IMPACT model as a prognostic tool in the management of patients with TBI.

Validation of S100B use in a cohort of Spanish patients with mild traumatic brain injury: a multicentre study.

INTRODUCTION: The aim of this study was to validate the S100B protein as a diagnostic tool for ruling out the presence of intracranial lesion (IL) after mild traumatic brain injury (mTBI). Subjects with a Glasgow Coma Scale (GCS) score of 15 and at least one neurological symptom post-trauma were selected from a large Spanish cohort. METHODS: A number of 260 patients with mTBI were enrolled. Blood samples were extracted within 6 h and CT scan performed within 24 h post-injury. Blood samples were also drawn from 18 healthy subjects. RESULTS: CT scan revealed the presence of IL in 22 patients (8.5%). Patients with mTBI had higher S100B serum levels (p = 0.008) than the healthy subjects (p < 0.001). The ROC analysis of S100B discriminated between patients with and without IL (AUC: 0.671; 95%CI: 0.574-0.769; p = 0.008). The multivariate analysis identified male gender (OR: 5.39; 95%CI: 1.45-20.10; p = 0.012), age > 65 (OR: 2.97; 95%CI: 1.04-8.44; p = 0.041) and S100B level >0.10 µg/L (OR: 7.93; 95%CI: 1.03-60.76; p = 0.046) as independent risk factors for IL in patients with mTBI. CONCLUSION: Measurement of S100B within 6 h of mTBI accurately predicts risk of IL in patients with a GCS score of 15 and at least one neurological symptom.

Comparison of two competitive enzyme immunoassay kits for quantification of plasma Urotensin-II in rats.

Changes in Urotensin-II (U-II) concentration, a potent vasoconstrictor peptide, have been detected in various pathologies, but it has been impossible to define a normality range. We aimed to analyze the concordance and interchangeability between two enzyme immunoassay methods developed by Phoenix Pharmaceuticals, Inc. to measure U-II plasma concentration in rats: ELISA and fluorescent EIA. Assays resulted positively correlated (r = 0.850; p < 0.01). There was a significant difference between assays values (p < 0.001). The analysis of agreement (Bland and Altman plot) stated that the mean of the differences was 2.055 (SD ± 0.588). Hence, we concluded that the two U-II assays were correlated but not interchangeable.

The Effect of Tranexamic Acid on Neurosurgical Intervention in Spontaneous Intracerebral Hematoma: Data From 121 Surgically Treated Participants From the Tranexamic Acid in IntraCerebral Hemorrhage-2 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: An important proportion of patients with spontaneous intracerebral hemorrhage (ICH) undergo neurosurgical intervention to reduce mass effect from large hematomas and control the complications of bleeding, including hematoma expansion and hydrocephalus. The Tranexamic acid (TXA) for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial demonstrated that tranexamic acid (TXA) reduces the risk of hematoma expansion. We hypothesized that TXA would reduce the frequency of surgery (primary outcome) and improve functional outcome at 90 days in surgically treated patients in the TICH-2 data set. METHODS: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not. RESULTS: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P-value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P-value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P-value = .45). CONCLUSION: TXA was not associated with less neurosurgical intervention, reduced HV, or improved outcomes after surgery.

Deep Learning Applied to Intracranial Hemorrhage Detection.

Intracranial hemorrhage is a serious medical problem that requires rapid and often intensive medical care. Identifying the location and type of any hemorrhage present is a critical step in the treatment of the patient. Detection of, and diagnosis of, a hemorrhage that requires an urgent procedure is a difficult and time-consuming process for human experts. In this paper, we propose methods based on EfficientDet's deep-learning technology that can be applied to the diagnosis of hemorrhages at a patient level and which could, thus, become a decision-support system. Our proposal is two-fold. On the one hand, the proposed technique classifies slices of computed tomography scans for the presence of hemorrhage or its lack of, and evaluates whether the patient is positive in terms of hemorrhage, and achieving, in this regard, 92.7% accuracy and 0.978 ROC AUC. On the other hand, our methodology provides visual explanations of the chosen classification using the Grad-CAM methodology.

Prognosis Factors of Patients Undergoing Renal Replacement Therapy.

BACKGROUND: Survival in patients with end-stage kidney disease (ESKD) on renal replacement therapy (RRT) is less than that of the general population of the same age, and depends on patient factors, the medical care received, and the type of RRT used. The objective of this study is to analyze the factors associated with survival in patients undergoing RRT. METHODS: We conducted a retrospective observational study of adult patients with an incident of ESKD on RRT in Andalusia from 1 January 2008 to 31 December 2018. Patient characteristics, nephrological care received, and survival from the beginning of RRT were evaluated. A survival model for the patient was developed according to the variables studied. RESULTS: A total of 11,551 patients were included. Median survival was 6.8 years (95% CI (6.6; 7.0)). After starting RRT, survival at one year and five years was 88.7% (95% CI (88.1; 89.3)) and 59.4% (95% CI (58.4; 60.4)), respectively. Age, initial comorbidity, diabetic nephropathy, and a venous catheter were independent risk factors. However, non-urgent initiation of RRT and follow-up in consultations for more than six months had a protective effect. It was identified that renal transplantation (RT) was the most influential independent factor in patient survival, with a risk ratio of 0.13 (95% CI (0.11; 0.14)). CONCLUSIONS: The receiving of a kidney transplant was the most beneficial modifiable factor in the survival of incident patients on RRT. We consider that the mortality of the renal replacement treatment should be adjusted, taking into account both modifiable and nonmodifiable factors to achieve a more precise and comparable interpretation.

Effectiveness Factors of Organ Donation in Andalusia.

OBJECTIVES: Donation effectiveness is one of the most important factors for the sustainability of the donation transplant process. The aim of this study was to characterize and identify hypothetical factors associated with effective donation (at least one organ transplanted) in the Andalusian population. METHOD: Cross-sectional descriptive observational study of a sample of 4144 potential organ donors registered in the Andalusian Information System of Transplant from January 2006 to December 2018. Donors were categorized according to the result of the donation and analyzed depending their effectiveness. RESULTS: The Andalusian donors were mainly men (60%) and were between 55 and 75 years of age (47.6%). The majority died of brain death (87.45%) caused by a cerebrovascular accident (63.5%). They had cardiovascular risk factors such as hypertension (38.3%), diabetes mellitus (14.8%), dyslipidemia (11.1%), smoking (20.4%), and overweight with a median body mass index of 27.1 kg/m2 (IQR, 24.6-29.4). Effective donor rate was 84.5%. Increasing age, diabetes mellitus, increasing body mass index, and the presence of antibodies against hepatitis C virus were hypothetical predictors of an ineffective donation. CONCLUSIONS: In view of our results, we can say that the Andalusian donor population has a high effectiveness rate, presenting hypothetical factors that could allow one to predict the outcome of an effective donation.

Immunomodulation of Oxidative Stress during Organ Donation Process: Preliminary Results.

The objective was to quantify oxidative stress resulting from ischemia during the donation process, using malondialdehyde (MDA) measurement, and its modulation by the administration of melatonin. We designed a triple-blind clinical trial with donors randomized to melatonin or placebo. We collected donors by donation after brain death (DBD) and controlled donation after circulatory death (DCD), the latter maintained by normothermic regional perfusion (NRP). Melatonin or placebo was administered prior to donation or following limitation of therapeutic effort (LTE). Demographic variables and medical history were collected. We also collected serial measurements of MDA, at 60 and 90 min after melatonin or placebo administration. A total of 53 donors were included (32 from DBD and 21 from DCD). In the DBD group, 17 donors received melatonin, and 15 placebo. Eight DCD donors were randomized to melatonin and 13 to placebo. Medical history and cause for LTE were similar between groups. Although MDA values did not differ in the DBD group, statistical differences were observed in DCD donors during the 0-60 min interval: -4.296 (-6.752; -2.336) in the melatonin group and -1.612 (-2.886; -0.7445) in controls. Given the antioxidant effect of melatonin, its use could reduce the production of oxidative stress in controlled DCD.

Outcomes in Antiplatelet-Associated Intracerebral Hemorrhage in the TICH-2 Randomized Controlled Trial.

Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH-2 (Tranexamic Acid in Intracerebral Hemorrhage-2) double-blind, randomized, placebo-controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre-ICH antiplatelet therapy, and 24-hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre-ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no-antiplatelet group. Pre-ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01-1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32-1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25-2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62-0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41-0.91) with no significant interaction between pre-ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

Transplant of Tissue-Engineered Artificial Autologous Human Skin in Andalusia: An Example of Coordination and Institutional Collaboration.

A new model of tissue-engineered artificial autologous human skin developed in Andalusia is currently being transplanted into patients suffering from large burns within the Andalusian Public Healthcare System. This product is considered an advanced therapy medicinal product (ATMP) in Europe, and its clinical use implies meeting transplant and medicinal product legal requirements, being the Guidelines of Good Manufacturing Practice for ATMPs of particular importance. The preclinical research and clinical translation of the product have represented a technical, regulatory, and organizational challenge, which has taken 10 years since the first preclinical experiments were designed. Twelve patients with large burns, including 3 pediatric patients, have hitherto received artificial autologous skin grafts with an overall survival rate of 75% and positive clinical, homeostatic, and histologic results. Achieving such a milestone within our Healthcare System was possible through a multidisciplinary approach and the joint efforts of multiple publicly funded institutions and units under the coordination of the Andalusian Initiative for Advanced Therapies. In this article, we present the organizational model set up to facilitate collaboration and logistics among the professionals involved, totaling more than 80 people. The similarities between the tissue-engineered artificial autologous human skin transplant and other organ and tissue transplants, in terms of logistic requirements, reveal how regional and hospital transplant coordination have played a crucial role.

Brain Injury Biomarker Behavior in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: S100B and neuron-specific enolase (NSE) have been widely studied in diverse neurocritical pathologies, being recognized as the most promising biomarkers for brain injury assessment. However, their role in intracerebral hemorrhage (ICH) has not been widely analyzed. METHODS: This was an observational prospective cohort study of patients with ICH admitted to a neurocritical care unit. Blood samples were collected on admission and at 24 hours, 48 hours, and 72 hours. Patient outcomes were assessed at 6 months after the event. RESULTS: Thirty-six patients with ICH were included in the study. The mortality rate was 36%. Nonsurvivors had higher S100B values than survivors at admission, 24 hours, and 48 hours (P < 0.05). Likewise, S100B levels were higher in patients with poor outcomes (modified Rankin Scale [mRS] score >4) compared with those with good outcome (mRS score ≤3) in the 24-hour, 48-hour, and 72-hour samples. Receiver operating characteristic (ROC) curve analysis showed that S100B at admission, 24 hours, and 48 hours can discriminate between patients who survive and those who die as a consequence of ICH. The 48-hour sample (area under the ROC curve, 0.817; P = 0.003) reached the best values for sensitivity (75%) and specificity (80%); cutoff, 0.250 µg/L. For 6-month functional outcome, S100B protein could differentiate between groups at 24, 48, and 72 hours. The S100B 24-hour sample had the best values for sensitivity (82.6%) and specificity (72.7%), with a cutoff of 0.202 µg/L. We found no clear relationship between NSE values and clinical characteristics. CONCLUSIONS: S100B protein acts as early predictor of mortality and functional outcome in patients with ICH. This biomarker measurement can provide additional information beyond clinical and radiologic findings to guide physicians in the management of these patients.

Geographic Information System Analysis: Promoting the Organ Donation Process in Andalusia.

OBJECTIVE: The objective is to study the geographic distribution of public awareness and acceptance of organ donation in Andalusian municipalities and determine its relationship with each population and the rate of aging. METHODS: Data on organ donors from the Information System for Autonomous Regional Transplant Coordination in Andalusia were analyzed from 2006 to 2017. The geographic analysis was performed using free software from the Generalitat Valenciana Geographic Information System (gvGIS, Valencia, Spain). Data from the Spanish National Statistics Institute for the year 2017 were used as a reference for population estimates and calculating the rate of aging. RESULTS: From 2006 to 2017, a total of 3698 donors were registered in Andalusia, 28 of whom were residing in another autonomous community and 120 who were not censored as residents of their municipality, leaving a final total of 3550 donors. The rate of aging in 2017 was 1.02. Choropleth mapping was used to identify donors in each municipality. Population and aging rate in 2017 for these areas were also analyzed. CONCLUSION: Georeferenced data on organ donation not only reveals spatial differences in the distribution of public acceptance; it also provides insight into the relationship between this distribution and the sociodemographic characteristics of each community. In this study, areas with the least number of donors seem to coincide with difficult accessibility, higher aging index, and low population rates. These maps can assist transplant coordinators in targeting areas for public education and information campaigns to heighten awareness of the positive results of organ donation and potentiate its acceptance.