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AIMS/HYPOTHESIS: Regulators worldwide are reviewing safety data on glucagon-like peptide-1 receptor agonists (GLP-1RA), following reports by the Icelandic Medicines Agency in July 2023 of suicidal ideation and self-injury (SIS) in individuals taking liraglutide and semaglutide. We aimed to assess the risk of SIS in new users of GLP-1RA when compared with sodium-glucose cotransporter 2 inhibitors (SGLT-2i) users, prescribed to treat type 2 diabetes in individuals with obesity. METHODS: This is a cohort study combining several population-wide databases and covering a Spanish population of five million inhabitants, including all adults with obesity who initiated treatment with either GLP-1RA or SGLT-2i for type 2 diabetes from 2015 to 2021. To estimate the comparative effect of GLP-1RA on the risk of SIS, we employed a new user, active comparator design and we carried out multivariable Cox regression modelling with inverse probability of treatment weighting (IPTW) based on propensity scores. We performed several stratified and sensitivity analyses. RESULTS: We included 3040 patients initiating treatment with GLP-1RA and 11,627 with SGLT-2i. When compared with patients treated with SGLT-2i, those in the GLP-1RA group were younger (55 vs 60 years old, p<0.001), had more anxiety (49.4% vs 41.5%, p<0.001), sleep disorders (43.2% vs 34.1%, p<0.001) and depression (24.4% vs 19.0%, p<0.001), and were more obese (35.1% of individuals with BMI ≥40 vs 15.1%, p<0.001). After propensity score weighting, standardised mean differences between groups were <0.1 for all covariates, showing adequate balance between groups at baseline after adjustment. In the main per-protocol analyses we found no evidence that GLP-1RA increased the incidence of SIS (HR 1.04; 95% CI 0.35, 3.14). Intention-to-treat analyses resulted in an HR of 1.36 (95% CI 0.51, 3.61). In analyses excluding individuals with no BMI information and using imputation for BMI missing values, respective HRs were 0.89 (95% CI 0.26, 3.14) and 1.29 (95% CI 0.42, 3.92). Stratified analyses showed no differences between subgroups. CONCLUSIONS/INTERPRETATION: Our findings do not support an increased risk of SIS when taking GLP-1RA in individuals with type 2 diabetes and obesity; however, the rarity of SIS events and the wide uncertainty of effect size (although null, effect may be compatible with a risk as high as threefold) calls for a cautious interpretation of our results. Further studies, including final evaluations from regulatory bodies, are called for to discard a causal link between GLP-1RA and suicidality.
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OBJECTIVE: To identify individual and initial prescription-related factors associated with an increased risk for opioid-related misuse, poisoning and dependence (MPD) in patients with non-cancer pain. METHODS: Cohort study linking several databases covering 5 million inhabitants of the region of Valencia, Spain, including all adults initiating prescription opioids in the period 2012-2018. To ascertain the association between the characteristics of the initial prescription choice and the risk of opioid MPD, we used shared frailty Cox regression models. We additionally considered death as a competing risk in sensitivity analyses. RESULTS: 958 019 patients initiated opioid prescription from 2012 to 2018, of which 0.13% experienced MPD. Most patients were prescribed tramadol as initial opioid (76.7%) followed by codeine (16.3%), long-acting opioids (6.7%), short-acting opioids (0.2%) and ultrafast opioids (0.1%). Initiation with ultrafast (HR 7.2; 95% CI 4.1 to 12.6), short-acting (HR 4.8; 95% CI 2.3 to 10.2) and long-acting opioids (HR 1.5; 95% CI 1.2 to 1.9) were associated with a higher risk of MPD when compared with tramadol. Initial prescriptions covering 4-7 days (HR 1.3; 95% CI 1.0 to 1.8), 8-14 days (HR 1.4; 95% CI 1.0 to 1.9), 15-30 days (HR 1.7; 95% CI 1.2 to 2.3) and more than one a month (HR 1.8; 95% CI 1.3 to 2.5) were associated with more MPD risk than initial prescriptions for 1-3 days. Treatments with >120 daily morphine milligram equivalents (MME) increased MPD risk (vs <50 MME, HR 1.6; 95% CI 1.1 to 2.2). Main individual factors associated with increased risk of MPD risk were male sex (HR 2.4; 95% CI 2.1 to 2.7), younger age (when compared with patients aged 18-44 years, patients aged 45-64 years, HR 0.4; 95% CI 0.4 to 0.5; patients aged 65-74 years, HR 0.4; 95% CI 0.3 to 0.5 and patients aged 75 years old and over, HR 0.7; 95% CI 0.6 to 0.8), lack of economic resources (2.1; 95% CI 1.8 to 2.5) and registered misuse of alcohol (2.9; 95% CI 2.4 to 3.5). Sensitivity analyses yielded overall comparable results. CONCLUSIONS: Our study identifies riskier patterns of opioid prescription initiation for non-cancer indications, as well as patient subgroups with higher risk of misuse, poisoning and dependence.
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Transtornos Relacionados ao Uso de Opioides , Tramadol , Adulto , Humanos , Masculino , Idoso , Feminino , Analgésicos Opioides/uso terapêutico , Estudos de Coortes , Estudos Retrospectivos , Tramadol/uso terapêutico , Padrões de Prática Médica , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , PrescriçõesRESUMO
After the publication of the recommendations, agreed by all the scientific societies through the ILCOR, at the end of 2020, the GRN-SENeo began a process of analysis and review of the main changes since the last guidelines, to which a specific consensus positioning on controversial issues, trying to avoid ambiguities and trying to adapt the evidence to our environment. This text summarizes the main conclusions of this work and reflects the positioning of that group.
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Ressuscitação , ConsensoRESUMO
Introduction: Europe has seen a steady increase in the use of prescription opioids, especially in non-cancer indications. Epidemiological data on the patterns of use of opioids is required to optimize prescription. We aim to describe the patterns of opioid therapy initiation for non-cancer pain and characteristics of patients treated in a region with five million inhabitants in the period 2012 to 2018. Methods: Population-based retrospective cohort study of all adult patients initiating opioid therapy for non-cancer pain in the region of Valencia. We described patient characteristics at baseline and the characteristics of baseline and subsequent treatment initiation. We used multinominal regression models to identify individual factors associated with initiation. Results: A total of 957,080 patients initiated 1,509,488 opioid treatments (957,080 baseline initiations, 552,408 subsequent initiations). For baseline initiations, 738,749 were with tramadol (77.19%), 157,098 with codeine (16.41%) 58,436 (6.11%) with long-acting opioids, 1,518 (0.16%) with short-acting opioids and 1,279 (0.13%) with ultrafast drugs. When compared to tramadol, patients initiating with short-acting, long-acting and ultrafast opioids were more likely to be older and had more comorbidities, whereas initiators with codeine were more prone to be healthier and younger. Treatments lasting less than 7 days accounted for 41.82% of initiations, and 11.89% lasted more than 30 days. 19.55% of initiators with ultrafast fentanyl received more than 120 daily Morphine Milligram Equivalents (MME), and 16.12% of patients initiating with long-acting opioids were prescribed more than 90 daily MME (p < 0.001). Musculoskeletal indications accounted for 65.05% of opioid use. Overlap with benzodiazepines was observed in 24.73% of initiations, overlap with gabapentinoids was present in 11.04% of initiations with long-acting opioids and 28.39% of initiators with short-acting opioids used antipsychotics concomitantly. In subsequent initiations, 55.48% of treatments included three or more prescriptions (vs. 17.60% in baseline initiations) and risk of overlap was also increased. Conclusion: Opioids are initiated for a vast array of non-oncological indications, and, despite clinical guidelines, short-acting opioids are used marginally, and a significant number of patients is exposed to potentially high-risk patterns of initiation, such as treatments lasting more than 14 days, treatments surpassing 50 daily MMEs, initiating with long-acting opioids, or hazardous overlapping with other therapies.
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After the publication of the recommendations, agreed by all the scientific societies through the ILCOR, at the end of 2020, the GRN-SENeo began a process of analysis and review of the main changes since the last guidelines, to which a specific consensus positioning on controversial issues, trying to avoid ambiguities and trying to adapt the evidence to our environment. This text summarizes the main conclusions of this work and reflects the positioning of that group.
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BACKGROUND: A complete course of prenatal corticosteroids reduces the possibility of morbimortality and neonatal respiratory distress syndrome (RDS). Occasionally, it is not possible to initiate or complete the maturation regimen, and the preterm neonate is born in a non-tertiary hospital. This study aimed to assess the effects of a single dose of betamethasone within 3 h before delivery on serious outcomes (mortality and serious sequelae) and RDS in preterm neonates born in tertiary vs. non-tertiary hospitals. MATERIALS AND METHODS: Preterm neonates who were <35 weeks and ≤1500 g, treated during a period of five years in a level IIIC NICU, were included in this retrospective cohort study. Participants were divided into groups as follows: NM, non-matured; PM, partial maturation (one dose of betamethasone up to 3 h antepartum). They were further divided based on their place of birth (NICU-IIIC vs. non-tertiary hospitals). The morbimortality rates and the severity of neonatal RDS were evaluated. RESULTS: A total of 76 preterm neonates were included. A decrease in serious outcomes was found in the PM group in comparison to the NM group (OR = 0.2; 95%CI (0.07-0.9)), as well as reduced need for mechanical ventilation (54% vs. 68%). The mean time between maternal admission and birth was similar in both cohorts. The mean time from the administration of betamethasone to delivery was 1 h in the PM cohort. With regard to births in NICU-IIIC, the PM group performed better in terms of serious outcomes (32% vs. 45%) and the duration of mechanical ventilation (117.75 vs. 132.18 h) compared to the NM group. In neonates born in non-tertiary hospitals with PM in comparison to the NM group, a trend towards a reduced serious outcome (28.5% vs. 62.2%) and a decreased need for mechanical ventilation (OR = 0.09; 95%CI (0.01-0.8)) and maximum FiO2 (p = 0.01) was observed. CONCLUSIONS: A single dose of betamethasone up to 3 h antepartum may reduce the rate of serious outcomes and the severity of neonatal RDS, especially in non-tertiary hospitals.
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The International Liaison Committee on Resuscitation (ILCOR) recommendations provide a universal guide of measures to support the transition and resuscitation of newborn after their birth. This guide is expected to be adapted by local groups or committees on resuscitation, according to their own circumstances. The objective of this review is to analyse the main changes, to discuss several of the controversies that have appeared since 2010, and contrasting with other national and international organisations, such as European Resuscitation Council (ERC), American Heart Association (AHA), or the Australian-New Zealand Committee on Resuscitation (ANZCOR). Thus, the Neonatal Resuscitation Group of the Spanish Society of Neonatology (GRN-SENeo) aims to give clear answers to many of the questions when different options are available, generating the forthcoming recommendations of our country to support the transition and/or resuscitation of a newborn after birth, safely and effectively.
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Ressuscitação/normas , Algoritmos , Humanos , Recém-Nascido , InternacionalidadeRESUMO
Resumen Introducción: La pandemia por SARS-CoV-2 ha inspirado intriga sobre la respuesta inmune a dicho virus, especialmente en pacientes graves con síndrome de dificultad respiratoria aguda (SDRA). Este estudio describe el comportamiento de la respuesta inmune, la inmunosupresión y sus desenlaces en los pacientes con ventilación mecánica (VM). Material y métodos: Cohorte prospectiva. Del 23 de marzo al 31 de diciembre de 2020 se recolectó información basal, parámetros ventilatorios, gasométricos y estudios de laboratorio de todos los pacientes mayores de 18 años que recibieron VM por COVID-19 con registros hasta el día 15 de VM. Se dividieron los grupos en pacientes vivos a los 90 días y defunciones. Resultados: Registramos 218 pacientes, con mortalidad de 23%. En el día 1 de VM, los pacientes no presentaron diferencias en conteos celulares o reactantes de fase aguda, excepto dímero D de 1,020 (705-1,711) vs 1,328 (940-2,340) ng/dL p = 0.035. En el análisis de regresión lineal de efectos mixtos se observaron diferencias cronológicas estadísticamente significativas en leucocitos y proteína C reactiva (PCR) concordante con la elevación de la presión de distensión alveolar (PDalv). No se encontró asociación con mortalidad en el uso de tocilizumab 2.20 (0.279-17.358) y corticosteroides 0.54 (0.229-1.273) en riesgos proporcionales de Cox al día 1 de VM. Durante los 15 días de VM los pacientes que fallecieron recibieron dosis más altas de corticosteroides, dosis mayores de 150 mg/día equivalente a prednisona se asocian a mortalidad. Conclusiones: Existe evolución cronológica similar en elevación de PCR, leucocitos y elevación de la PDalv, las cuales se explican por la disminución de la distensibilidad pulmonar estática (Cstat) y la presión positiva al final de la espiración total (PEEP total). El uso de tocilizumab no tuvo asociación con la mortalidad y dosis equivalentes a prednisona entre 100-150 mg/día se asocian a mejores resultados.
Abstract Introduction: The SARS-CoV-2 pandemic has inspired interest in the immune response to the virus, especially in severe patients with acute respiratory distress syndrome (ARDS). The study describes the behaviour of the immune response, immune suppression, and their results in patients under mechanical ventilation (MV). Material and methods: Prospective cohort. From March 23rd to December 31st, 2020, we recollected basal information, MV parameters, blood gas analysis and laboratory studies of all the patients over 18 years who received MV secondary to COVID-19. We registered 15 continuous days of MV. We divided the groups in patients alive at day 60 and deaths. Results: We included 218 patients with a mortality of 23%. In day 1 of MV, the patients didn't have any differences in cell counts or acute phase reactants, except for D Dimer (705-1,711) vs 1,328 (940-2,340) ng/dL p = 0.035. In mixed effects linear regressions, we found statistically significant chronological differences in C reactive protein (CPR) and leucocyte count, concordant with the elevation of the driving pressure (DP). In the Cox regression we found no association with tocilizumab and corticosteroids with mortality on day 1 of MV. Patients who died received higher doses of corticosteroids throughout the 15 days of MV, with doses equivalent to prednisone over 150 mg/day are associated with mortality. Conclusions: There is a similar chronological behaviour in the elevation of acute phase reactants and the elevation con DP with no elevation of Vt, which can be explained by the drop of total PEEP and Cstat. There was no association with the use of tocilizumab and mortality, and a dose of 100-150 mg/día of equivalent of prednisone was associated with better results.
Resumo Introdução: A pandemia de SARS-CoV-2 inspirou intrigas sobre a resposta imune ao referido vírus, especialmente em pacientes gravemente doentes com síndrome do desconforto respiratório do adulto (SDRA). Este estudo descreve o comportamento da resposta imune, imunossupressão e seus desfechos em pacientes em ventilação mecânica (VM). Material e métodos: Coorte prospectiva. De 23 de março a 31 de dezembro de 2020, foram coletadas informações basais, parâmetros ventilatórios e gasométricos e estudos laboratoriais de todos os pacientes maiores de 18 anos que receberam VM para COVID-19 com registros até o dia 15 de VM. Os grupos foram divididos em pacientes vivos em 90 dias e óbitos. Resultados: Registramos 218 pacientes, com mortalidade de 23%. No dia 1 de VM, os pacientes não apresentaram diferenças na contagem de células ou reagentes de fase aguda, exceto dimero D 1020 (705-1711) vs 1328 (940-2340) ng/dL p = 0.035. Na análise de regressão linear dos efeitos mistos, observam-se diferenças cronológicas estatisticamente significativas nos leucócitos e na proteína C reativa (PCR), consistentes com o aumento da pressão de distensão alveolar (PDalv). Não foi encontrada associação com mortalidade no uso de tocilizumab 2.20 (0.279-17.358) e corticoide 0.54 (0.229-1.273) nos riscos proporcionais de COX no 1o dia de VM. Durante os 15 dias de VM, os pacientes que foram a óbito receberam doses maiores de corticosteróides, doses a partir de 150 mg/dia equivalentes a prednisona estão associadas à mortalidade. Conclusões: Há evolução cronológica semelhante em PCR e leucócitos elevados e PDalv elevados, explicados pela diminuição da complacência pulmonar estática (Cstat) e da pressão positiva ao final da expiração total (PEEPtotal). O uso de tocilizumab não foi associado à mortalidade e doses equivalentes à prednisona entre 100-150 mg/dia estão associadas a melhores resultados.
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Resumen: Introducción: La prevalencia del síndrome eutiroideo enfermo en pacientes con sepsis es aproximadamente de 60%; existe poca información sobre su correlación con falla multiorgánica. Objetivo: Estimar la prevalencia del síndrome eutiroideo enfermo (SEE) y correlacionar con la presencia de fallas orgánicas específicas y puntajes de gravedad y desenlaces clínicos. Métodos: Se incluyeron pacientes con diagnóstico de sepsis en una unidad de cuidados críticos durante el periodo comprendido de marzo de 2014 a febrero de 2016; se tomaron variables clínicas y estudios de laboratorio que incluían perfil tiroideo en todos los pacientes. Análisis estadístico: Estadística descriptiva con medidas de frecuencia, tendencia central y dispersión. Se realizaron análisis de supervivencia con modelos de regresión de Cox y curvas de Kaplan-Meier para mortalidad; razones de riesgo e intervalos de confianza de 95%. Un error alfa ajustado menor de 5% a dos colas fue considerado significativo. Se usó la paquetería estadística STATA SE versión 11.1. Resultados: Se incluyó un total de 90 pacientes, 51.1% de sexo femenino, con edad de 71 ± 14.15 años, IMC al ingreso a la UCI de 24.94 ± 5.07 kg/m2. La prevalencia global de SEE es de 61.1%. Los pacientes con SEE presentaron en mayor proporción falla hemodinámica, renal y hematológica, sin alcanzar significancia estadística. En la fases combinadas 2 y 3 de SEE, sí se observó mayor proporción de falla renal: 88 versus 63.3%, RR = 1.8 (IC 95% 1.1-2.6, p = 0.037), así como altas dosis de vasopresores (norepinefrina > 0.1 µg/kg/min) RR = 2.3 (IC 95% 1.063-5.18, p = 0.024) y menor supervivencia, con una mediana en días de 28 (RIQ 19-39) versus 26 (RIQ 13-36), p = 0.7; PCT igual o mayor a 6 en un 65.5 versus 40%, RR = 1.87 (IC 95% 1.1-3.1, p = 0.18), mayor puntaje de SOFA con mediana de 12 (RIQ 8-4) versus 9 (RIQ 7-13) puntos, p = 0.09. Además, peores desenlaces durante la estancia hospitalaria, evaluados por un índice compuesto que incluye mortalidad, necesidad de ventilación mecánica invasiva (VMI), SOFA ≥ 9 con un RR = 1.713 (IC 95% 1.036-2.83, p = 0.05). El análisis de curva ROC detectó el mejor punto de corte de SOFA como predictor de SEE ≥ 11 con sensibilidad 60.0, especificidad 62 LR + 1.6, LR - 0.63, AUC = 0.6. RR = 1.7 (IC 95% 1.024-3.05, p = 0.034). Conclusiones: Los pacientes con SEE presentan mayor elevación de marcadores de inflamación, requerimiento de vasopresores y soporte ventilatorio, compromiso multiorgánico y mortalidad.
Abstract: Introduction: The prevalence of euthyroid sick syndrome in patients with sepsis is approximately 60%; there is little information on its correlation with multiorgan failure. Objective: To estimate the prevalence of euthyroid sick syndrome (ESS) and correlate it with the presence of specific organ failures, severity scores and clinical outcomes. Methods: Patients with diagnosis of sepsis in a critical care unit during the period from March 2014 to February 2016; we registered the clinical variables and laboratory studies, including thyroid function, in all patients. Statistical analysis: Descriptive statistics with frequency measures of central tendency and dispersion. Mortality-survival analysis with Cox regression models and Kaplan-Meier were made, as well as risk ratios and confidence intervals of 95%. A two-tailed adjusted alpha error of less than 5% was considered significant. The statistical package STATA SE version 11.1 was used. Results: Ninety patients were included, 51.1% female, aged 71 ± 14.15 years; the BMI at admission to the ICU was 24.94 ± 5.07 kg/m2. The overall prevalence of ESS was 61.1%. ESS patients presented in greater proportion with hemodynamic, renal and hematologic failure, without reaching statistical significance. In the combined phases 2 and 3 of SEE, a higher proportion of renal failure was observed: 88 vs. 63.3 %, RR = 1.8 (95% CI 1.1-2.6, p = 0.037). High doses of vasopressors (norepinephrine > 0.1 µg/kg/min) RR = 2.3 (95% CI 1.063-5.18, p = 0.024). Lower survival with a median of 28 days (IQR 19-39) versus 26 (IQR 13-36), p = 0.7. PCT greater than or equal to 6 in 65.5 versus 40%, RR = 1.87 (95% CI 1.1-3.1, p = 0.18); higher SOFA score with a median of 12 (IQR 8-4) versus 9 (IQR 7-13) points, p = 0.09. In addition to worse outcomes during hospital stay evaluated by a composite index that included mortality, need for invasive mechanical ventilation (IMV), SOFA ≥ 9 with a RR = 1.713 (95% CI 1.036-2.83, p = 0.05). ROC curve analysis detected the best cut of SOFA as a predictor of ESS ≥11, sensitivity 60.0, specificity 62 LR + 1.6, LR-0.63, AUC = 0.6. RR = 1.7 (95% CI 1.024-3.05, p = 0.034). Conclusions: Patients with ESS have higher markers of inflammation, increased requirement for vasopressors and ventilatory support, as well as elevated multiorgan failure and mortality.
Resumo: Introdução: A prevalência da síndrome do doente eutireoidiano em pacientes com sepse é de aproximadamente 60%, além disso há pouca informação sobre sua correlação com a insuficiência de múltiplos órgãos. Objetivo: Estimar a prevalência da síndrome do doente eutireoidiano (ESS) e correlacionar com a presença de insuficiência orgânica específica, pontuações de gravidade e desenlaces clínicos. Foram incluídos pacientes diagnosticados com sepse em uma unidade de terapia intensiva durante o período de março de 2014 a fevereiro de 2016, se tomaram variáveis clínicas e estudos laboratoriais que incluiam perfil tireoidiano em todos os pacientes. Análise estatística: Estatística descritiva com medidas de frequência, tendência central e dispersão. Realizaram-se análises de sobrevivência com modelos de regressão de Cox e curvas de Kaplan-Meier para mortalidade. Taxas de risco e intervalos de confiança de 95%. O erro alfa ajustado menor a 5% bicaudal, serão considerados significativos. O programa estatístico STATA versão 11.1. Resultados: Incluiram-se um total de 90 pacientes, 51.1% do sexo feminino, com idades entre 71 ± 14.15 anos, IMC na admissão na UTI foi de 24.94 ± 5.07 kg/m2. A prevalência global de ESS foi de 61.1%. Os pacientes com ESS apresentaram maior proporção de alteração hemodinâmica, renal e hematológica sem alcançar significância estatística. Nas fases 2 e 3 combinadas de ESS se observou maior proporção de insuficiência renal 88 versus 63.3%, RR = 1.8 (IC 95%1.1-2.6, p = 0.037). Altas doses de vasopressores (norepinefrina > 0.1 µg/kg/min) RR = 2.3 (IC 95% 1.063-5.18, p = 0.024). Menor sobrevida com uma média em dias de 28 (IQR 19-39) vs 26 (RIQ 13-36), p = 0.7. PCT igual ou maior a 6 em um 65.5 vs 40%, RR = 1.87 (IC de 95% 1.1-3.1, p = 0.18) maior pontuação SOFA com uma média de 12 (RIQ 8-4) vs 9 (RIQ 7-13) pontos, p = 0.09. Ademais com piores desenlaces durante a estadia hospitalar avaliada por um índice de composto que inclui a mortalidade, a necessidade de VMI, SOFA ≥ 9 com um RR = 1.713 (IC 95% 1.036-2.83, p = 0.05). A análise da curva ROC detectou o melhor ponto de corte de SOFA como um preditor de ESS ≥ 11 sensibilidade 60.0, especificidade 62 LR + 1.6, LR-0.63, AUC = 0.6. RR = 1.7 (IC de 95% 1.024-3.05, p = 0.034). Conclusões: Os pacientes com ESS apresentam maior elevação dos marcadores inflamatórios, maior necessidade de vasopressores, suporte ventilatório, compromisso múltiplo de órgãos e mortalidade.