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BACKGROUND: In major trauma patients, hypocalcemia is associated with increased mortality. Despite the absence of strong evidence on causality, early calcium supplementation has been recommended. This study investigates whether calcium supplementation during trauma resuscitation provides a survival benefit. METHODS: We conducted a retrospective analysis using data from the TraumaRegister DGU® (2015-2019), applying propensity score matching to balance demographics, injury severity, and management between major trauma patients with and without calcium supplementation. 6 h mortality, 24 h mortality, and in-hospital mortality were considered as primary outcome parameters. RESULTS: Within a cohort of 28,323 directly admitted adult major trauma patients at a European trauma center, 1593 (5.6%) received calcium supplementation. Using multivariable logistic regression to generate propensity scores, two comparable groups of 1447 patients could be matched. No significant difference in early mortality (6 h and 24 h) was observed, while in-hospital mortality appeared higher in those with calcium supplementation (28.3% vs. 24.5%, P = 0.020), although this was not significant when adjusted for predicted mortality (P = 0.244). CONCLUSION: In this matched cohort, no evidence was found for or against a survival benefit from calcium supplementation during trauma resuscitation. Further research should focus on understanding the dynamics and kinetics of ionized calcium levels in major trauma patients and identify if specific conditions or subgroups could benefit from calcium supplementation.
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Calcio , Puntaje de Propensión , Sistema de Registros , Resucitación , Heridas y Lesiones , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Calcio/uso terapéutico , Calcio/sangre , Calcio/análisis , Resucitación/métodos , Resucitación/estadística & datos numéricos , Sistema de Registros/estadística & datos numéricos , Heridas y Lesiones/terapia , Heridas y Lesiones/mortalidad , Anciano , Suplementos Dietéticos , Estudios de Cohortes , Mortalidad Hospitalaria , Modelos LogísticosRESUMEN
Objectives: Protection of the cervical spine is recommended following multisystem injury. In 2021, Ambulance Victoria changed clinical practice guidelines to apply soft collars instead of semi-rigid collars for suspected cervical spine injury. The aim of this study was to describe associated changes in imaging practices and diagnoses of pressure sores, hospital acquired pneumonia, and spinal cord injury. Methods: A retrospective pre- and postintervention study was conducted including all consecutive patients that presented to an adult major trauma center in Melbourne, Australia with a cervical collar placed by emergency medical services over two 3-month periods. Results: There were 1762 patients included. A computed tomography (CT) of the cervical spine was performed in 795 (88.4%) patients in the semi-rigid collar period and 810 (93.8%) in the soft collar period (p = 0.001). Soft collars were associated with higher rates of clearance of the cervical spine in the emergency department (ED) (odds ratio [OR] 4.14; 95% confidence interval [CI]: 3.36-5.09). There were no differences in diagnosis of pressure sores (0.11% vs. 0.23%, p = 0.97) or hospital acquired pneumonia (2.0% vs. 2.7%; p = 0.44) or cervical spinal cord injury (0.45% vs. 0.81%; p = 0.50). Conclusions: Following a change from prehospital semi-rigid collars to soft collars, more patients were investigated with a CT scan and more frequent clearance of the cervical spine occurred in the ED. There were no differences in the rates of spinal cord injuries, pressure sores or hospital acquired pneumonia, but the study was underpowered to detect significant differences. The practice of soft collars for prehospital care of patients with suspected neck injury requires ongoing surveillance.
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OBJECTIVES: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders. METHODS: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified-Delphi process. Twenty-eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified-Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%-79% fully or partially agree, <10% disagree. RESULTS: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non-seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep-related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. SIGNIFICANCE: Significant comorbidities are present in most phenotypes of SCN8A-related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long-term management for patients with these comorbidities and provide the basis for future evidence-based studies on optimal treatments of SCN8A-related disorders. Identifying the prognosis of patients with SCN8A-related disorders will also improve care and quality-of-life for patients and their caregivers.
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Comorbilidad , Consenso , Epilepsia , Canal de Sodio Activado por Voltaje NAV1.6 , Trastornos del Neurodesarrollo , Humanos , Técnica Delphi , Epilepsia/epidemiología , Epilepsia/genética , Epilepsia/diagnóstico , Canal de Sodio Activado por Voltaje NAV1.6/genética , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/genética , PronósticoRESUMEN
OBJECTIVE: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. METHODS: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. RESULTS: Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. SIGNIFICANCE: This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.
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Consenso , Epilepsia , Canal de Sodio Activado por Voltaje NAV1.6 , Trastornos del Neurodesarrollo , Humanos , Anticonvulsivantes/uso terapéutico , Técnica Delphi , Epilepsia/diagnóstico , Epilepsia/terapia , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/terapia , FenotipoRESUMEN
BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is characterized by severe colonic distension without mechanical obstruction. It has an uncertain pathogenesis and poses diagnostic challenges. This study aims to explore risk factors and clinical outcomes of ACPO in polytrauma patients, and contributing information to the limited literature on this condition. METHODS: This retrospective study, conducted at a Level 1 Trauma Centre, analysed data from trauma patients with ACPO admitted between July 2009 and June 2018. A control cohort of major trauma patients was utilized. Data review encompassed patient demographics, abdominal imaging, injury characteristics, analgesic usage, interventions, complications, and mortality. Statistical analyses, including logistic regression and correlation coefficients, were employed to identify risk factors. RESULTS: There were 57 cases of ACPO, with an incidence of 1.7 / 1000 patients, rising to 4.86 in major trauma. Predominantly affecting those over 50 years of age (75%) and males (75%), with motor vehicle accidents (50.8%) and falls from height (36.8%) being the commonest mechanisms. Noteworthy associated injuries included retroperitoneal bleeds (RPB) (37%), spinal fractures (37%), and pelvic fractures (37%). Analysis revealed significant associations between ACPO and Shock Index >0.9, Injury Severity Score > 18, opioid use, RPB, and pelvic fractures. A caecal diameter of ≥12 cm had a significant association with caecal ischemia or perforation. CONCLUSION: This study underscores the significance of ACPO in polytrauma patients, demonstrating associations with risk factors and clinical outcomes. Clinicians should maintain a high index of suspicion, particularly in older patients with RPB, pelvic fractures, and opioid use. Early supportive therapy, vigilant monitoring, and timely interventions are crucial for a favourable outcome. Further research and prospective trials are warranted to validate these findings and enhance understanding of ACPO in trauma patients. LEVEL OF EVIDENCE: Prognostic and Epidemiological, Level IV.
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BACKGROUND: Analgesia is an important component for patient well-being, but commonly delayed during trauma resuscitation. The Pharmacists in Trauma trial assessed the effects of integrating pharmacists into trauma response teams to improve analgesia delivery and medication management. METHODS: This unblinded randomised trial compared emergency medicine (EM) pharmacist involvement in trauma callouts versus standard care at an Australian level 1 trauma centre. Randomisation was performed via an online single sequence randomisation service. Eligible patients included those managed with a trauma callout during working hours of an EM pharmacist. Pharmacists were able to prescribe medications using a Partnered Pharmacist Medication Charting model. The primary outcome was the proportion of patients who had first dose analgesia within 30 min compared using the χ2 test. RESULTS: From 15 July 2021 until 31 January 2022, there were 119 patients randomised with 37 patients excluded as no analgesia was required. There were 82 patients included for analysis, 39 in the control arm and 43 in the intervention arm. The primary outcome was achieved in 25 (64.1%) patients in the control arm and 36 (83.7%) patients in the pharmacist arm (relative risk 1.31; 95% CI 1.0 to 1.71; p=0.042). Time to analgesia in the control arm was 28 (22-35) mins and 20 (15-26 mins) with pharmacist involvement; p=0.025. In the pharmacist arm, the initial dose of analgesia was prescribed by the pharmacist for 38 (88.4%) patients. There were 27 other medications prescribed by the pharmacist for the management of these patients. There were no differences in emergency and trauma centre or hospital length of stay. CONCLUSION: Addition of the EM pharmacist in trauma response teams improved time to analgesia. Involvement of an EM pharmacist in trauma reception and resuscitation may assist by optimising medication management, with members of the team more available to focus on other life-saving interventions. TRIAL REGISTRATION NUMBER: ACTRN12621000338864.
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Farmacéuticos , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Centros Traumatológicos/organización & administración , Heridas y Lesiones/terapia , Australia , Grupo de Atención al Paciente , Rol Profesional , Medicina de Emergencia/métodos , Manejo del Dolor/métodosRESUMEN
PURPOSE: Electrographic seizures (ES) are common in critically ill children undergoing continuous EEG (CEEG) monitoring, and previous studies have aimed to target limited CEEG resources to children at highest risk of ES. However, previous studies have relied on observational data in which the duration of CEEG was clinically determined. Thus, the incidence of late occurring ES is unknown. The authors aimed to assess the incidence of ES for 24 hours after discontinuation of clinically indicated CEEG. METHODS: This was a single-center prospective study of nonconsecutive children with acute encephalopathy in the pediatric intensive care unit who underwent 24 hours of extended research EEG after the end of clinical CEEG. The authors assessed whether there were new findings that affected clinical management during the extended research EEG, including new-onset ES. RESULTS: Sixty-three subjects underwent extended research EEG. The median duration of the extended research EEG was 24.3 hours (interquartile range 24.0-25.3). Three subjects (5%) had an EEG change during the extended research EEG that resulted in a change in clinical management, including an increase in ES frequency, differential diagnosis of an event, and new interictal epileptiform discharges. No subjects had new-onset ES during the extended research EEG. CONCLUSIONS: No subjects experienced new-onset ES during the 24-hour extended research EEG period. This finding supports observational data that patients with late-onset ES are rare and suggests that ES prediction models derived from observational data are likely not substantially underrepresenting the incidence of late-onset ES after discontinuation of clinically indicated CEEG.
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BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).
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Hemorragia Cerebral , Humanos , Hemorragia de los Ganglios Basales/mortalidad , Hemorragia de los Ganglios Basales/cirugía , Hemorragia de los Ganglios Basales/terapia , Teorema de Bayes , Hemorragia Cerebral/mortalidad , Hemorragia Cerebral/cirugía , Hemorragia Cerebral/terapia , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Resultado del Tratamiento , NeuroendoscopíaRESUMEN
In the last several decades, advances in genetic testing have transformed the diagnostic and therapeutic approach to pediatric epilepsy. However, the interpretation of these genetic tests often requires expert analysis and counseling. For this reason, as our molecular understanding of the linkages between abnormal cerebral physiology and genetics has grown, so too has the field of clinical epilepsy genetics. Here we explore recent advances in genetic testing, describe the benefits of genetic testing in epilepsy, and provide a practice guideline for testing and referrals to specialized epilepsy genetics centers, highlighting the Epilepsy NeuroGenetics Initiative (ENGIN) Clinic and the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at the Children's Hospital of Philadelphia as an illustration of such a specialized center.
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Epilepsia , Pruebas Genéticas , Derivación y Consulta , Humanos , Epilepsia/diagnóstico , Epilepsia/genética , Niño , Algoritmos , Asesoramiento Genético , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. OBJECTIVE: This post hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). METHODS: Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at week 52 were performed as a function of the fold change in FeNO at week 52 and the maximum fold change in Eos over weeks 0-12 (also change from baseline in pre-BD FEV1 at week 12). RESULTS: The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by week 2 and then gradually to week 52 in patients treated with dupilumab versus placebo; Eos, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with the change in biomarkers in either treatment group. The change from baseline in pre-BD FEV1 at week 52 was inversely associated with the fold change in FeNO in both groups, with a significant difference between the dupilumab and placebo curves (P = .014), and was positively associated with the fold change in Eos in both groups (P = .022). CONCLUSIONS: Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed a predictive value for lung function improvement; for FeNO, this was specific to the dupilumab treatment arm.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Biomarcadores , Eosinófilos , Óxido Nítrico , Humanos , Asma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Antiasmáticos/uso terapéutico , Volumen Espiratorio Forzado , Índice de Severidad de la Enfermedad , Método Doble Ciego , Resultado del Tratamiento , Progresión de la Enfermedad , Recuento de LeucocitosRESUMEN
BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).
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COVID-19 , Adulto , Humanos , Adolescente , SARS-CoV-2 , Ivermectina/uso terapéutico , Teorema de Bayes , Resultado del TratamientoRESUMEN
The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement.
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Epilepsia , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Encéfalo/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Lípidos , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Proteínas de Unión al GTP rab/metabolismoRESUMEN
OBJECTIVES: A 2021 safety alert restricted endovascular gelfoam use in Australia and resulted in an embargo on gelfoam sales to Interventional Radiology departments. This study aimed to show that gelfoam is safe in a population of trauma patients with pelvic injury, and discuss the basis of the recent controversies. METHODS: Retrospective cohort study was conducted between 1 January 2010 and 21 May 2021 for the patients who underwent gelfoam embolization for pelvic arterial haemorrhage. Primary outcome was the rate of adverse events related to intravascular gelfoam administration. RESULTS: Inclusion criteria met in 50 patients, comprising 58% males median age 59.9 years, and median injury severity score 31. There were 0 complications related to gelfoam use and 100% technical success. Thirty-five patients (70%) received a non-targeted embolization approach. All-cause mortality was observed in 5 patients (10%), unrelated to gelfoam. CONCLUSIONS: Gelfoam is a safe and effective embolic agent in pelvic trauma. Patients are in urgent need of universal on-label registration of endovascular gelfoam products, as it is life-saving in major haemorrhage after trauma. ADVANCES IN KNOWLEDGE: Endovascular gelfoam is mandatory for a high-quality trauma service, and this study shows that it is safe to use intentionally in the endovascular space. Companies should work with interventional radiologists, sharing and collaborating to ensure positive outcomes for patients.
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Embolización Terapéutica , Esponja de Gelatina Absorbible , Hemorragia , Humanos , Persona de Mediana Edad , Masculino , Esponja de Gelatina Absorbible/uso terapéutico , Estudios Retrospectivos , Femenino , Embolización Terapéutica/métodos , Anciano , Adulto , Pelvis/irrigación sanguínea , Hemostáticos/uso terapéutico , Resultado del Tratamiento , Puntaje de Gravedad del Traumatismo , Australia , Anciano de 80 o más AñosRESUMEN
Introduction: Transfusion of blood components is vital for the resuscitation of injured patients in hemorrhagic shock. Delays in initiating transfusion have been associated with harm, as has excess transfusion. The aim of this study was to evaluate variables associated with hospital mortality, with a focus on the two modifiable risk factors- time to initiate transfusion and volume of blood components-with hospital mortality. Methods: This was a registry-based cohort study, including all consecutive adult patients presenting with hemorrhagic shock (systolic blood pressure (SBP) ≤90 mm Hg and transfusion of blood components) to a level 1 adult trauma center during a 5-year period (January 1, 2017-December 31, 2021). Associations with hospital mortality were assessed using multivariable logistic regression analysis, with final models developed using backward elimination. Results: There were 195 patients included and there were 49 (25.1%) in-hospital deaths. The median time to first transfusion was 10 (IQR 6-16) minutes. Age (adjusted OR (aOR) 1.06; 95% CI: 1.03 to 1.08), initial SBP (aOR 0.96; 95% CI: 0.3 to 0.98), intracranial bleeding or diffuse axonal injury (aOR 2.63; 95% CI: 1.11 to 6.23), and the volume of blood components in the first 4 hours (aOR 1.08; 95% CI: 1.03 to 1.13) were associated with mortality. Time to transfusion was not associated with in-hospital mortality (aOR 0.99; 95% CI: 0.95 to 1.03). Among the 90 patients who underwent urgent transfer to the operating room or angiography suite, the median time to transfer was 2.38 hours (IQR 1.5-3.7). In this subgroup, age (aOR 1.11; 95% CI: 1.05 to 1.18) and volume of blood components (aOR 1.20; 95% CI: 1.08 to 1.34) were associated with mortality. Discussion: In this setting where times to transfusion are short, further reductions in the time to transfusion are unlikely to improve outcome. In our population, for every unit of blood component transfused, the adjusted odds of death increased by 8%. These findings suggest investigation into strategies to achieve earlier control of hemorrhage. Level of evidence: III.
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The market approval of Tazemetostat (TAZVERIK) for the treatment of follicular lymphoma and epithelioid sarcoma has established "enhancer of zeste homolog 2" (EZH2) as therapeutic target in oncology. Despite their structural similarities and common mode of inhibition, Tazemetostat and other EZH2 inhibitors display differentiated pharmacological profiles based on their target residence time. Here we established high throughput screening methods based on time-resolved fluorescence energy transfer, scintillation proximity and high content analysis microscopy to quantify the biochemical and cellular binding of a chemically diverse collection of EZH2 inhibitors. These assays allowed to further characterize the interplay between EZH2 allosteric modulation by methylated histone tails (H3K27me3) and inhibitor binding, and to evaluate the impact of EZH2's clinically relevant mutant Y641N on drug target residence times. While all compounds in this study exhibited slower off-rates, those with clinical candidate status display significantly slower target residence times in wild type EZH2 and disease-related mutants. These inhibitors interact in a more entropy-driven fashion and show the most persistent effects in cellular washout and antiproliferative efficacy experiments. Our work provides mechanistic insights for the largest cohort of EZH2 inhibitors reported to date, demonstrating that-among several other binding parameters-target residence time is the best predictor of cellular efficacy.
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Proteína Potenciadora del Homólogo Zeste 2 , Piridonas , Humanos , Benzamidas , Compuestos de Bifenilo , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Morfolinas , Piridonas/uso terapéuticoRESUMEN
INTRODUCTION: Trauma to the pelvic ring and associated haemorrhage represent a management challenge for the multidisciplinary trauma team. In up to 10% of patients, bleeding can be the result of an arterial injury and mortality is reported as high as 89% in this cohort. We aimed to assess the mortality rate after pelvic trauma embolisation and whether earlier embolisation improved mortality. METHODS: Retrospective study at single tertiary trauma and referral centre, between 1 January 2009 and 30 June 2022. All adult patients who received embolisation following pelvic trauma were included. Patients were excluded if angiography was performed but no embolisation performed. RESULTS: During the 13.5-year time period, 175 patients underwent angiography and 28 were excluded, leaving 147 patients in the study. The all-cause mortality rate at 30-days was 11.6% (17 patients). The median time from injury to embolisation was 6.3 h (range 2.8-418.4). On regression analysis, time from injury to embolisation was not associated with mortality (OR 1.01, 95% CI 0.952-1.061). Increasing age (OR 1.20, 95% CI 1.084-1.333) and increasing injury severity score (OR 1.14, 95% CI 1.049-1.247) were positively associated with all-cause 30-day mortality, while non-selective embolisation (OR 0.11, 95% CI 0.013-0.893) was negatively associated. CONCLUSION: The all-cause mortality rate at 30-days in or cohort was very low. In addition, earlier time from injury to embolisation was not positively associated with all-cause 30-day mortality. Nevertheless, minimising this remains a fundamental principle of the management of bleeding in pelvic trauma.
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Embolización Terapéutica , Fracturas Óseas , Huesos Pélvicos , Adulto , Humanos , Estudios Retrospectivos , Fracturas Óseas/terapia , Pelvis/diagnóstico por imagen , Pelvis/lesiones , Hemorragia/diagnóstico por imagen , Hemorragia/terapia , Huesos Pélvicos/diagnóstico por imagen , Huesos Pélvicos/lesionesRESUMEN
INTRODUCTION: The Glasgow Coma Scale (GCS) and pupil response to light are commonly used to assess brain injury severity and predict outcomes. The aim of this study was to investigate whether the GCS combined with pupil response (GCS-P), compared to the GCS alone, could be a better predictor of hospital mortality for patients with traumatic brain injury (TBI). METHODS: A retrospective cohort study was undertaken at an adult level one trauma centre including patients with isolated TBI of Abbreviated Injury Scale above three. The GCS and pupil response were combined to an arithmetic score (GCS score (range 3-15) minus the number of nonreacting pupils (0, 1, or 2)), or by treating each factor as separate categorical variables. The association of in-hospital mortality with GCS-P as a categorical variable was evaluated using Nagelkerke's R2 and compared using areas under the receiver operating characteristic (AUROC) curve. RESULTS: There were 392 patients included over the study period of 1 July 2014 and 30 September 2017, with an overall mortality rate of 15.2%. Mortality was highest at GCS-P of 1 (79%), with lowest mortality at a GCS-P 15 (1.6%). Nagelkerke's R2 was 0.427 for GCS alone and 0.486 for GCS-P. The AUROC for GCS-P to predict mortality was 0.87 (95%CI: 0.82-0.72), higher than for GCS alone (0.85; 95%CI: 0.80-0.90; p < .001). DISCUSSION: GCS-P provided a better predictor of mortality compared to the GCS. As both the GCS and pupillary response are routinely recorded on all patients, combination of these pieces of information into a single score can further simplify assessment of patients with TBI, with some improvement in performance.
RESUMEN
Venous access is a key component of managing haemorrhagic shock. Obtaining intravenous access in trauma patients is challenging due to circulatory collapse in shock. This literature review examines the feasibility of direct puncture and cannulation of the brachiocephalic veins (BCVs) for intravenous access in shocked adult trauma patients. Three literature searches were conducted. OVID Medline was searched for articles on the use of the BCVs for venous access in adults and on the BCVs in shock. A third systematic search of OVID Medline, OVID Embase and Cochrane Library was conducted on the use of the BCVs for access in shocked trauma patients. After full-text review, 18 studies were selected for inclusion for the search on the use of the BCVs for access in adults. No studies met the inclusion criteria for the search on the BCVs in shock and BCV access in shocked trauma patients. The BCVs are currently used for central venous access, haemodialysis and totally implantable venous access devices (TIVADs) in adults. There is a preference for the right BCV (RBCV) over the left as the RBCV is more superficial, straighter, larger, has less anatomical variation and avoids the risk of thoracic duct puncture. The BCVs appear to be stabilised in shock by surrounding bony structures. The BCVs may provide a site for initial, rapid access in trauma resuscitation. Further research is required to determine if the BCVs collapse in shock and if venous access using the BCVs is feasible in a trauma resuscitation setting.
Asunto(s)
Venas Braquiocefálicas , Cateterismo Venoso Central , Choque , Humanos , Estudios de Factibilidad , ResucitaciónRESUMEN
OBJECTIVES: We aimed to identify clinical and EEG monitoring characteristics associated with generalized, lateralized, and bilateral-independent periodic discharges (GPDs, LPDs, and BIPDs) and to determine which patterns were associated with outcomes in critically ill children. METHODS: We performed a prospective observational study of consecutive critically ill children undergoing continuous EEG monitoring, including standardized scoring of GPDs, LPDs, and BIPDs. We identified variables associated with GPDs, LPDs, and BIPDs and assessed whether each pattern was associated with hospital discharge outcomes including the Glasgow Outcome Scale-Extended Pediatric version (GOS-E-Peds), Pediatric Cerebral Performance Category (PCPC), and mortality. RESULTS: PDs occurred in 7% (91/1,399) of subjects. Multivariable logistic regression indicated that patients with coma (odds ratio [OR], 3.45; 95% confidence interval [CI]: 1.55, 7.68) and abnormal EEG background category (OR, 6.85; 95% CI: 3.37, 13.94) were at increased risk for GPDs. GPDs were associated with mortality (OR, 3.34; 95% CI: 1.24, 9.02) but not unfavorable GOS-E-Peds (OR, 1.93; 95% CI: 0.88, 4.23) or PCPC (OR, 1.64; 95% CI: 0.75, 3.58). Patients with acute nonstructural encephalopathy did not experience LPDs, and LPDs were not associated with mortality or unfavorable outcomes. BIPDs were associated with mortality (OR, 3.68; 95% CI: 1.14, 11.92), unfavorable GOS-E-Peds (OR, 5.00; 95% CI: 1.39, 18.00), and unfavorable PCPC (OR, 5.96; 95% CI: 1.65, 21.46). SIGNIFICANCE: Patients with coma or more abnormal EEG background category had an increased risk for GPDs and BIPDs, and no patients with an acute nonstructural encephalopathy experienced LPDs. GPDs were associated with mortality and BIPDs were associated with mortality and unfavorable outcomes, but LPDs were not associated with unfavorable outcomes.