RESUMO
BACKGROUND: Flumazenil is a competitive benzodiazepine (BZD) antagonist most used for treating delirium in BZD overdoses. Since its introduction, many have expressed concerns about its safety secondary to the risk of inducing BZD withdrawal and refractory seizures. STUDY QUESTION: What is the incidence of adverse drug events after the administration of flumazenil in patients with suspected iatrogenic BZD delirium? STUDY DESIGN: This is a retrospective cross-sectional study of patients from a single center from 2010 to 2013. Patients experiencing delirium after receiving BZDs in the hospital were included if they had a bedside toxicology consult and were administered flumazenil. Patients were excluded if they were given BZDs for ethanol withdrawal or if they did not have mental status documentation before and after flumazenil administration. Descriptive statistics were calculated. MEASURES AND OUTCOMES: The primary outcome was the incidence of adverse drug events after flumazenil administration. The secondary outcome was the efficacy of flumazenil determined by the patient's mental status. RESULTS: A total of 501 patient records were reviewed, and 206 patients were included in the final analysis. Of those patients, 172 (83.5%) experienced an objective improvement in their mental status within 1 hour after flumazenil administration. A total of 5 patients experienced adverse events (2.4%), 95% confidence interval (0.78, 5.54). Of these, 3 patients experienced minor agitation or restlessness without pharmacologic intervention. Two patients experienced moderate agitation or restlessness that resolved with haloperidol or physostigmine administration. No patients had a reported seizure, 95% confidence interval (0.0, 1.77). CONCLUSIONS: Flumazenil seems to be a safe and effective intervention for the reversal of delirium secondary to iatrogenic BZD administration.
Assuntos
Benzodiazepinas , Delírio , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Flumazenil , Benzodiazepinas/efeitos adversos , Benzodiazepinas/antagonistas & inibidores , Delírio/tratamento farmacológico , Delírio/etiologia , Estudos Retrospectivos , Estudos Transversais , Flumazenil/efeitos adversos , Flumazenil/uso terapêutico , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Incidência , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Doença IatrogênicaRESUMO
INTRODUCTION: Flumazenil is an antagonist of the GABA/benzodiazepines receptor complex that might play a role in the treatment of hepatic encephalopathy. However, its efficacy and safety are a matter of debate. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews including fourteen randomized trials. We concluded flumazenil does not reduce mortality in patients with hepatic encephalopathy and it is not clear whether it leads to any clinical improvement because the certainty of the evidence is very low.
INTRODUCCIÓN: El flumazenil es un antagonista del complejo receptor GABA/benzodiacepinas que podría tener un rol en el manejo de la encefalopatía hepática. Sin embargo, existe controversia sobre su eficacia y seguridad. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos dos revisiones sistemáticas que en conjunto incluyen catorce estudios aleatorizados. Concluimos que el uso de flumazenil no disminuye la mortalidad en pacientes con encefalopatía hepática, y no está claro si produce alguna mejoría clínica porque la certeza de la evidencia es muy baja.
Assuntos
Flumazenil/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Bases de Dados Factuais , Flumazenil/efeitos adversos , Flumazenil/farmacologia , Moduladores GABAérgicos/efeitos adversos , Moduladores GABAérgicos/farmacologia , Encefalopatia Hepática/mortalidade , Encefalopatia Hepática/fisiopatologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
GABA and glutamate are both affected by stress and are involved in nociception. Thus, we determined whether stress-induced enhancement of inflammatory hyperalgesia is mediated by an imbalance between glutamate and GABA neurotransmission. Male rats were subjected daily to 10 to 20 minutes per day of either forced swimming (FS) or sham swimming for 3 consecutive days; nonconditioned rats served as controls. Some rats were treated i.p. with ketamine (5 mg/kg), diazepam (2 mg/kg), flumazenil (0.1 mg/kg), or vehicle (0.9% NaCl), 30 to 60 minutes before each conditioning session or nociception assessment. Pain behavior, spinal nociceptive neuronal activation and GABA and glutamate release were respectively evaluated by the formalin test, the expression of c-Fos and in vivo microdialysis of superficial laminae of the lumbar spinal cord, 48 hours after the last conditioning session. Nitric oxide metabolites (NO(x)) were determined as markers of post-synaptic NMDA receptor activation. FS stress enhanced formalin-induced hyperalgesia, increased pain-elicited c-Fos expression, decreased basal and delayed pain-induced GABA release, and increased basal and induced glutamate release. Hyperalgesia and c-Fos overexpression were blocked only by prestress treatment with diazepam and post-stress treatment with ketamine, whereas changes in GABA and glutamate release were reversed by prestress treatment with diazepam. Diazepam effects were blocked by flumazenil. NO(x) increased in lumbar spinal cord of FS rats by a mechanism antagonized by ketamine. Thus, stress-induced hyperalgesia is initiated by a decreased and delayed GABA release and GABA-A receptor activation, whereas it is maintained by increased glutamate release and NMDA glutamate receptor activation at the spinal level.
Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Hiperalgesia/etiologia , Hiperalgesia/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Estresse Psicológico/complicações , Ácido gama-Aminobutírico/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Diazepam/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Flumazenil/farmacologia , Flumazenil/uso terapêutico , Formaldeído/efeitos adversos , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/uso terapêutico , Ácido Glutâmico/metabolismo , Hiperalgesia/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Masculino , Medição da Dor , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/tratamento farmacológico , Natação/psicologia , Fatores de TempoRESUMO
PURPOSE: To identify clinically significant drug interactions and potentially related adverse drug events associated with the use of midazolam. METHODS: Retrospective data analysis was performed at a single tertiary Brazilian Teaching Hospital from an electronic database derived from the Hospital's computerized physician order entry system over 1 year. Records from patients who received injectable midazolam within a period of 24 hours before flumazenil use were selected. Patients' orders were checked for the presence of clinically significant drug interactions and for the inclusion and discontinuation of potential trigger medications for adverse drug events related to midazolam. RESULTS: A total of 7431 patients were exposed to midazolam, representing 28% of all patients admitted to the hospital. Twenty-six (0.35%) patients received flumazenil within 24 hours after midazolam, corresponding to more than one third of the orders for flumazenil. Clinically significant drug interactions were observed in prescriptions of drugs preceding the use of flumazenil for 23 (88%) of these patients. The most prevalent group of drug interactions were related to the prescription of central nervous system depressants (22 cases), mainly opiate agonists. Analysis of inclusion and discontinuation of drugs demonstrated that the first order for opiates preceded the use of flumazenil in 31% of the cases and, except for tramadol, all opiates were discontinued after its administration, highlighting the potential of these drugs to act as triggers for adverse drug events. CONCLUSIONS: Midazolam-related drug interactions are not infrequent and may conduce to serious adverse drug events, including hypotension, respiratory depression, and arrest. Efforts directed toward monitoring interactions and preventing injuries from midazolam use are expected to have a substantial impact on patient safety concerning the use of midazolam.
Assuntos
Midazolam/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Depressores do Sistema Nervoso Central/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Flumazenil/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Humanos , Sistemas de Registro de Ordens Médicas , Midazolam/administração & dosagemRESUMO
Possible central nervous system effects of the gymnosperm lectin from Araucaria angustifolia seeds were studied in seizure and open field tests. Male Swiss mice were administered saline (control), lectin (0.1, 1, and 10 mg/kg), flumazenil (1 mg/kg), or diazepam (1 mg/kg) intraperitoneally. Lectin at the highest dose increased time to death in the pentylenetetrazole- and strychnine-induced seizure models as compared with control, but not in the pilocarpine model. In the open field test, lectin reduced locomotor activity at all doses tested, as did diazepam, when compared with control. These locomotor effects were reversed by flumazenil pretreatment. In conclusion, A. angustifolia lectin had a protective effect in the pentylenetetrazole- and strychnine-induced seizure models, suggestive of activity in the GABAergic and glycinergic systems, respectively, and also caused a reduction in animal movements, which was reversed by flumazenil, pointing to a depressant action mediated by a GABAergic mechanism.
Assuntos
Lectinas/farmacologia , Lectinas/uso terapêutico , Sementes/química , Convulsões/tratamento farmacológico , Análise de Variância , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Diazepam/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Flumazenil/farmacologia , Flumazenil/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Pentilenotetrazol , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Tempo de Reação/efeitos dos fármacos , Convulsões/induzido quimicamente , EstricninaRESUMO
The anticonvulsant effect of alpha,beta-epoxy-carvone (EC), a monoterpene monocyclic, was investigated in three animal models. EC at 300 or 400 mg/kg promoted protection of 75% and 87.5%, respectively, against convulsions induced chemically by pentylenetetrazole (PTZ) and it was efficient in prevents the tonic convulsions induced by maximal electroshock (MES) in doses of 200, 300 or 400 mg/kg, resulting in 25%, 25% and 100% of protection, respectively. This monoterpene was also capable to promote an increase of latency for development of convulsions induced by picrotoxin (PIC) at 300 or 400 mg/kg and presented a significant protection against convulsions at doses of 200, 300 or 400 mg/kg, resulting in 12.5%, 12.5% and 100% of protection, respectively. On the other hand, the anticonvulsant effect of EC, was not affected by pretreatment with flumazenil (FLU), a selective antagonist of benzodiazepine site of GABA(A) receptor. Additionally was observed that EC treatment reduced the levels of in vitro lipoperoxidation and decreased (21.2%) the amplitude of compound action potential after 30 min of incubation. The present results clearly indicate the ability of EC to modulate the anticonvulsant and antioxidant effects. However, our data suggests that the action mechanisms are not due a direct activation of the GABA(A) benzodiazepine receptors, but could be associated with the reduction of isolated nerve excitability, possibly involving a voltage-gated Na(+) channels blockade.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Monoterpenos/uso terapêutico , Potenciais de Ação/fisiologia , Animais , Convulsivantes/toxicidade , Monoterpenos Cicloexânicos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque/efeitos adversos , Epilepsia/etiologia , Flumazenil/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Técnicas In Vitro , Masculino , Camundongos , Pentilenotetrazol/toxicidade , Estimulação Física/métodos , Picrotoxina/toxicidade , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologiaRESUMO
OBJECTIVE: To determine the safety and efficacy of flumazenil when given for reversal of benzodiazepine-induced conscious sedation in children. DESIGN: Multicenter study conducted in emergency departments and pediatric endoscopy, bronchoscopy, or oncology suites. PATIENTS: One hundred seven children (median age, 6 years; range, 1 to 17 years) who received intravenous benzodiazepine for an invasive procedure. INTERVENTIONS: Flumazenil was given in increments of 0.01 mg/kg (0.2 mg maximum) at 1-minute intervals to a maximum total dose of 0.05 mg/kg (1.0 mg maximum). MEASUREMENTS: Clinical efficacy was assessed by the Clinical Global Impression Scale and Observer's Assessment of Alertness/Sedation Scale. The OAA/S, vital signs, lead II electrocardiogram, and clinical assessments were recorded at 0, 10, 30, 60, 90, and 120 minutes after flumazenil was given. RESULTS: All children received midazolam (mean total dose, 0.18 mg/kg) for sedation. One hundred (96%) patients achieved a complete or partial response to flumazenil by 10 minutes after its administration, on the basis of their CGIS scores (the mean dose of flumazenil administered at the time of the first complete response was 0.017 +/- 0.010 mg/kg). Seventy-one of 93 (76%) patients with a baseline OAA/S score < or = 3 (1 = deep sleep, 5 = alert) experienced an increase of > or = 2 points at 10 minutes after flumazenil administration, and 81 of 93 (87%) had a score of 4 or 5 after flumazenil administration. Seven patients, all within the 1- to 5-year age range, experienced resedation after initially responding to flumazenil. Thirty-seven of 107 patients (35%) experienced a total of 56 adverse events, most of which were considered to be unrelated to flumazenil administration. The most frequently occurring adverse events were abnormal crying, dizziness, nausea, fever, and headache. There were no clinically significant changes in vital signs or ECG tracings. No adverse events resulted in premature termination of drug administration. CONCLUSIONS: Flumazenil promptly and effectively reverses the central nervous system depressant effects of midazolam in children undergoing conscious sedation, with no significant adverse effects. Because of the potential for resedation, children who receive flumazenil should be monitored for 1 to 2 hours after its administration.
Assuntos
Antídotos/uso terapêutico , Benzodiazepinas , Sedação Consciente/efeitos adversos , Flumazenil/uso terapêutico , Midazolam , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Estudos RetrospectivosRESUMO
Los antídotos son sustancias cuya función es contrarrestar el efecto farmacológico y tóxico de otras sustancias, teniendo en cuenta la importancia de las medidas generales en el manejo del intoxicado (baño general, emesis, lavado gástrico, carbón activado, catárticos). Cada día aparecen sustancias nuevas con dichas características. En el presente artículo se pretende dar información breve y detallada sobre las propiedades farmacológicas, indicaciones, dosificación, efectos secundarios y contraindicaciones de algunos de uso general (carbón activado, soluciones electrolíticas con polietilenglycol) y principalmente de algunos específicos de uso reciente: flumazenil, fragmentos Fab-antidigoxina, glucagón, naloxona, clonidina, N-acetil-cisteína, azul de metileno, nitrito y tiosulfato de sodio, ácido-2-3-dimercaptosuccínico, penicilina benzatínica, glicopirrolato y S-adenosil-metionina.