Factores de riesgo de reacción paradójica asociados a sedación endovenosa con midazolam / Paradoxical reactions associated with midazolam conscious sedation

Background: Benzodiazepines are used for perioperative conscious sedation. However, its use may be associated with paradoxical reactions. The known risk factors for these reactions are age, alcohol and drug abuse and psychiatric disorders. Aim: To assess the incidence and impact of risk factors of paradoxical reactions to midazolam. Material and Methods: Cross sectional study of 218 patients aged 50 ± 16 years (51% women) scheduled for elective surgical procedures under regional anesthesia and midazolam sedation. The paradoxical reactions were classified according to their severity in three categories. Results: The incidence of paradoxical reactions to midazolam was 8.3% (95% confidence interval (CI) 5.0-12.7). All were mild and only 28% of the affected patients required pharmacological treatment, none of them flumazenil. A multivariable logistic regression model showed that the variables independently associated with a paradoxical reaction to midazolam were the use of psychoactive medications (Odds Ratio (OR) = 3.4 [1.1-11], p = 0.04, and the dose of midazolam (OR 1.35 [1.03-1.78], p = 0.03. Conclusions: The incidence of paradoxical reactions to midazolam was 8,3% and all were mild. Their risk factors are the use of psychoactive medications and the use of higher doses of midazolam.

Efecto antagonista del flumazenil sobre el isoflurano en la emersión de la anestesia general / Antagonist effect of flumazenil on isofluran in reversion of general anesthesia

INTRODUCTION AND OBJECTIVES: Isoflurane, an inhalational general anesthetic widely used in medical practice, belonging to the group of volatile liquids together with desflurane and sevoflurane, with various properties including sedation, hypnosis and anesthesia of patients undergoing treatment. surgical acts. Volatile inhalational anesthetics (halogenated) as mechanism of action, has the property of increasing inhibitory synaptic transmission at postsynaptic level by potentiating ion channels regulated by ligand activated by alpha-aminobutyric acid (GABA). Flumazenil is a benzodiazepine antagonist belonging to the group of imidazobenzodiazepine. It is currently known that there is no specific drug capable of antagonizing the effects of halogenates that allow the rapid and complete recovery of general anesthesia, for this reason this work focuses its efforts on demonstrating whether flumazenil has the ability to reverse the actions of the patient. isoflurane and allow an early restoration of the level of consciousness. MATERIAL AND METHODS: The study to be performed is a clinical type of longitudinal, prospective, unicentric and double blind. The sample will be formed by patients who are going to be subjected to a balanced general anesthesia. The sample will be divided into 2 large groups: group C (control) and group F (Flumazenil). At the end of the surgery, the mixture will be administered according to the selected group in a random manner (Flumazenil 0.25 mg or 0.9% solution in a 20 cc syringe) and the time of extubation, recovery time of the level of consciousness, time of discharge UCPA and hemodynamic state (FC, TAM and SO2). RESULTS: The flumazenil group showed a significantly shorter time from injection to extubation than the placebo group (p = 0.007). Differences in terms of shorter times needed to achieve Aldrete of 9 points in the flumazenil group (P = 0.04) were observed as were shorter anesthetic arousal times represented by a Ramsey 2. Heart rate, mean arterial pressure and saturation they had similar values between the 2 groups. CONCLUSION: The study showed that a single dose of 0.25 mg of flumazenil administered at the end of the surgical act, just after completing all surgical stimulation was beneficial (P = 0.007) in the context of extubation times and shorter anesthetic arousal times.

INTRODUCCIÓN Y OBJETIVOS: El isoflurano un anestésico general inhalatorio usado ampliamente en la práctica médica, perteneciente al grupo de los líquidos volátiles junto con el desflurano y sevoflurano, con variadas propiedades entre las que se encuentran la sedación, hipnosis y anestesia de los pacientes sometidos a actos quirúrgicos. Los anestésicos inhalatorios volátiles (halogenados) como mecanismo de acción, tiene la propiedad de aumentar la transmisión sináptica inhibidora a nivel postsináptico potenciando los canales iónicos regulados por ligando activados por ácido alfa-aminobutírico (GABA). El flumazenil es un antagonista benzodiazepínico perteneciente al grupo de los imidazobenzodiazepina. Se conoce actualmente que no existe un fármaco específico capaz de antagonizar los efectos de los halogenados que permitan la recuperación rápida y completa de la anestesia general, por tal motivo este trabajo centra sus esfuerzos en demostrar si el flumazenil tiene la capacidad para revertir las acciones del isoflurane y permitir un restablecimiento temprano del nivel de conciencia. MATERIALES Y MÉTODOS: El estudio a realizar es de tipo clínico de corte longitudinal, prospectivo, unicéntrico y doble ciego. La muestra se conformará por pacientes que vayan a ser sometidos a anestesia general balanceada. Se procederá a dividir la muestra en 2 grandes grupos: grupo C (control) y grupo F (flumazenil). Al final de la cirugía se administrará la mezcla según grupo seleccionado de manera al azar (flumazenil 0,25 mg o solución 0,9% en una jeringa de 20 cc) y se valorará el tiempo de extubación, tiempo de recuperación del nivel de conciencia, tiempo de alta de la UCPA y estado hemodinámico (FC, TAM y SO2). RESULTADOS: El grupo de flumazenil presentó un tiempo desde la inyección hasta la extubación significativamente más bajo que el grupo placebo (p = 0,007). Se observaron diferencias en términos de tiempos más bajos necesario para alcanzar Aldrete de 9 puntos en el grupo flumazenil (P = 0,04) al igual que tiempos de despertar anestésico más cortos representados por un Ramsey 2. La frecuencia cardíaca, presión arterial media y la saturación tuvieron valores similares entre los 2 grupos. CONCLUSIÓN: El estudio demostró que una única dosis de 0,25 mg de flumazenil administrado al final del acto quirúrgico, justo después de culminar toda estimulación quirúrgica fue beneficiosa (P = 0,007) en el contexto de tiempos de extubación y tiempos de despertar anestésico más cortos.

3-Carene, a Phytoncide from Pine Tree Has a Sleep-enhancing Effect by Targeting the GABA(A)-benzodiazepine Receptors

3-Carene, a bicyclic monoterpene, is one of the major components of the pine tree essential oils. It has been reported that, in addition to its known properties as a phytoncide, 3-carene has anti-inflammatory, antimicrobial, and anxiolytic effects. We have previously demonstrated that α-pinene, the major component of pine tree, has a hypnotic effect through GABA(A)-benzodiazepine (BZD) receptors. However, a hypnotic effect of 3-carene has not been studied yet. Here, we report that oral administration of 3-carene increases the sleep duration and reduces sleep latency in pentobarbital-induced sleep test. 3-Carene potentiates the GABA(A) receptor-mediated synaptic responses by prolonging the decay time constant of inhibitory synaptic responses. These enhancing effects of 3-carene are reproduced by zolpidem, a modulator for GABA(A)-BZD receptor, and fully inhibited by flumazenil, an antagonist for GABA(A)-BZD receptor. The molecular docking of 3-carene to the BZD site of GABA(A) protein structure, suggests that 3-carene binds to the BZD site of α1 and ϒ2 subunits of GABA(A)-BZD receptor. These results indicate that, similar to α-pinene, 3-carene shows a sleep-enhancing effect by acting as a positive modulator for GABA(A)-BZD receptor.

Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptor-benzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC₅₀ of 1.19, 0.84 μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes / O uso de flumazenil para depressão respiratória associada ao benzodiazepínico na recuperação pós-anestésica: riscos e resultados

Abstract Background and objectives The primary aim was to determine risk factors for flumazenil administration during postanesthesia recovery. A secondary aim was to describe outcomes among patients who received flumazenil. Methods Patients admitted to the postanesthesia recovery room at a large, academic, tertiary care facility after surgery under general anesthesia from January 1, 2010, to April 30, 2015, were identified and matched to 2 controls each, by age, sex, and surgical procedure. Flumazenil was administered in the recovery phase immediately after general anesthesia, according to the clinical judgment of the anesthesiologist. Demographic, procedural, and outcome data were extracted from the electronic health record. Conditional logistic regression, accounting for the 1:2 matched-set case-control study designs, was used to assess characteristics associated with flumazenil use. Results The incidence of flumazenil administration in the postanesthesia care unit was 9.9 per 10,000 (95% CI, 8.4-11.6) general anesthetics. History of obstructive sleep apnea (Odds Ratio [OR] = 2.27; 95% CI 1.02-5.09), longer anesthesia (OR = 1.13; 95% CI 1.03-1.24 per 30 minutes), use of total intravenous anesthesia (OR = 6.09; 95% CI 2.60-14.25), and use of benzodiazepines (OR = 8.17; 95% CI 3.71-17.99) were associated with risk for flumazenil administration. Among patients who received midazolam, cases treated with flumazenil received a higher median (interquartile range) dose than controls: 3.5 mg (2.0-4.0 mg) vs. 2.0 mg (2.0-2.0 mg), respectively (p < 0.001). Flumazenil use was correlated with a higher rate of unanticipated noninvasive positive pressure ventilation, longer postanesthesia care unit stay, and increased rate of intensive care unit admissions. Conclusions Patients who required flumazenil postoperatively had received a higher dosage of benzodiazepines and utilized more postoperative health care resources. More conservative perioperative use of benzodiazepines may improve postoperative recovery and use of health care resources.

Resumo Justificativa e objetivos Determinar os fatores de risco da administração de flumazenil durante a recuperação pós-anestésica e descrever os desfechos entre os pacientes que receberam flumazenil. Métodos Os pacientes admitidos em sala de recuperação pós-anestésica de um grande centro universitário em setor terciário de cuidados pós-cirurgia sob anestesia geral entre 1° de janeiro de 2010 e 30 de abril de 2015 foram identificados e pareados com dois controles cada por idade, sexo e procedimento cirúrgico. Flumazenil foi administrado na fase de recuperação imediatamente após a anestesia geral, de acordo com a avaliação clínica do anestesiologista. Os dados demográficos, dos procedimentos e dos desfechos foram extraídos do registro eletrônico de saúde. A regressão logística condicional para os desenhos do estudo de caso-controle pareado em 1:2 foi usada para avaliar as características associadas ao uso de flumazenil. Resultados A incidência da administração de flumazenil em sala de recuperação pós-anestésica foi de 9,9 por 10.000 (95% IC: 8,4-1,6) anestesias gerais. História da apneia obstrutiva do sono (razão de chances [OR] = 2,27; IC 95%: 1,02-5,09), anestesia de longa duração (OR = 1,13; IC 95%: 1,03-1,24 por 30 minutos), uso de anestesia intravenosa total (OR = 6,09; IC de 95%: 2,60-14,25) e uso de benzodiazepínicos (OR = 8,17; IC 95%: 3,71-17,99) foram associados a risco para a administração de flumazenil. Entre os pacientes que receberam midazolam, os casos tratados com flumazenil receberam uma dose mediana mais alta (intervalo interquartil) do que os controles: 3,5 mg (2,0-4,0 mg) vs. 2,0 mg (2,0-2,0 mg), respectivamente (p < 0,001). O uso de flumazenil foi correlacionado com uma taxa maior não prevista de ventilação não invasiva com pressão positiva, permanência mais longa em sala de recuperação pós-anestésica e aumento da taxa de admissões em unidade de terapia intensiva. Conclusão Os pacientes que precisaram de flumazenil no pós-operatório receberam uma dose maior de benzodiazepínicos e usaram mais recursos de cuidados da saúde no pós-operatório. O uso mais conservador de benzodiazepínicos no período perioperatório pode melhorar a recuperação e o uso de recursos de cuidados da saúde no pós-operatório.

Aphasic Status Epilepticus after Flumazenil Injection

No abstract available.

Sedation-related Adverse Events Associated with a Diagnostic Upper Endoscopy: A Single Center-observational Study

BACKGROUND/AIMS: Appropriate sedation during endoscopy can significantly reduce the discomfort experienced by a patient when the procedure is performed; however, it is associated with several potential risks. Very few reports describe sedation-related adverse events occurring during endoscopy. Our study evaluated the current status of sedation-related adverse events during a diagnostic upper endoscopy. MATERIALS AND METHODS: We reviewed medical records of 5,564 cases of diagnostic upper endoscopy performed using midazolam for sedation at the Ewha Womans University, Mokdong Hospital, between January 2015 and March 2016. RESULTS: Among the 5,564 cases, sedation-related adverse events were reported in 56 cases (1.0%). Among these 56 patients, 30 patients (53.6.%) were men and 26 patients (46.4%) were women. Mean age of the patients was 63.7±15.4 years. The most common adverse event reported was hypoxia, which was observed in 37 patients (0.7%). Other adverse events included sedation failure (18 patients, 0.3%) and delayed discharge from the recovery room due to delayed recovery of consciousness (one patient, 0.02%). Among patients presenting with hypoxia, 35 patients recovered after administration of intravenous flumazenil and oxygen via nasal prongs. Administration of oxygen alone helped recovery in 2 patients. All patients recovered uneventfully with no mortalities registered. CONCLUSIONS: Our study showed that the use of sedative midazolam is relatively safe during an upper endoscopy. The rate of occurrence of adverse events was very low, and no fatal adverse events were observed. However, close observation and continuous monitoring is an essential component of safe sedation during endoscopy.

Effect of (+)-dehydrofukinone on GABAA receptors and stress response in fish model

(+)-Dehydrofukinone (DHF) is a major component of the essential oil of Nectandra grandiflora (Lauraceae), and exerts a depressant effect on the central nervous system of fish. However, the neuronal mechanism underlying DHF action remains unknown. This study aimed to investigate the action of DHF on GABAA receptors using a silver catfish (Rhamdia quelen) model. Additionally, we investigated the effect of DHF exposure on stress-induced cortisol modulation. Chemical identification was performed using gas chromatography-mass spectrometry and purity was evaluated using gas chromatography with a flame ionization detector. To an aquarium, we applied between 2.5 and 50 mg/L DHF diluted in ethanol, in combination with 42.7 mg/L diazepam. DHF within the range of 10-20 mg/L acted collaboratively in combination with diazepam, but the sedative action of DHF was reversed by 3 mg/L flumazenil. Additionally, fish exposed for 24 h to 2.5-20 mg/L DHF showed no side effects and there was sustained sedation during the first 12 h of drug exposure with 10-20 mg/L DHF. DHF pretreatment did not increase plasma cortisol levels in fish subjected to a stress protocol. Moreover, the stress-induced cortisol peak was absent following pretreatment with 20 mg/L DHF. DHF proved to be a relatively safe sedative or anesthetic, which interacts with GABAergic and cortisol pathways in fish.

Flumazenil administration in suspected patients with acute hypnotics and sedatives poisoning: risk-benefit re-evaluation

PURPOSE: The use of flumazenil administration in the emergency department is still controversial because of concerns about adverse effects. The present study was conducted to re-evaluate the risk-benefit ratio associated with flumazenil administration to patients suspected of having acute hypnotics and sedatives poisoning in the emergency department. METHODS: A retrospective chart review study was conducted for patients whose final diagnoses were “poisoning” and “benzodiazepine” or “sedatives-hypnotics” from Mar. 2006 to Feb. 2015. The basal characteristics of the patients, including past medical history, ingredients and dose of ingested drug and co-ingested drugs were investigated. For patients administered flumazenil, responsiveness and time from admission to flumazenil administration were investigated with supplement. All collected data were analyzed in aspect terms of risk/benefit. RESULTS: A total of 678 patients were included in our study. Benzodiazepine was the most common sedative/hypnotic drug prescribed, and the frequency of prescription continuously increased. The proportion of TCA as co-ingestion decreased from 13.1% to 3.9% in patients with acute sedative/hypnotic poisoning. Flumazenil was administered to 55 patients (8.1%), of which 29 patients (52.7%) were applied to contraindications. Fifty-three patients (96.4%) showed positive responsiveness, including partial responsiveness after flumazenil administration. No severe adverse events were identified. CONCLUSION: Based on the current trends in prescription patterns for sedative/hypnotic drugs, increased use of non-TCA antidepressants, and responsiveness to administration of flumazenil, benefit seemed weighted more in this study, although the observed benefits were based on limited results. Further prospective multicenter studies will be needed to optimize benefit-risk ratio.

Clinical Analysis of Flumazenil Administration in the Single Emergency Department for Unconscious Patients, Suspected Benzodiazepine Overdose

PURPOSE: Flumazenil is an effective benzodiazepine antagonist. However, serious adverse effects, including seizures, cardiac arrhythmias, and even death, have been reported in patients treated with flumazenil. These adverse effects are commonly associated with co-ingested tricyclic antidepressants and benzodiazepine withdrawal. Herein, we examined the safety, effectiveness, and risk of using flumazenil to treat suspected benzodiazepine overdose in the emergency department (ED). METHODS: This is a retrospective observational study of adult patients administered with flumazenil for a known or suspected benzodiazepine overdose in the ED between July 2010 and January 2016. The outcomes included mental status improvement, incidence of seizures, and intubation rate after flumazenil administration. RESULTS: Seventy-six patients were included in the analysis. Thirty-eight (50%) patients experienced clinically significant mental status improvement. One patient had a seizure (1.3%), despite 17 reported proconvulsant coingestants. No patient required endotracheal intubation, and no patient had arrhythmias after flumazenil administration. Flumazenil was given intravenously bolus in all cases, and the average dose was 0.44mg. There were no significant changes in the vital signs after flumazenil administration. CONCLUSION: Flumazenil was effective and associated with a low frequency of seizure. However, patients with contraindications may develop seizures. The benefits with respect to risk of adverse effects should be considered carefully in all patients.

Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study

Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis.

Risperidone in a child with untractable emergency delirium: a case report / 대한마취과학회지

A 6-year-old boy was scheduled for thoracic magnetic resonance imaging under deep sedation with midazolam 1.8 mg and propofol 100 µg/kg/min via intravenous injection. He showed emergence delirium in the post-anesthesia care unit. The staff attempted to calm him by administering flumazenil as an antidote for midazolam, propofol for further sedation, and meperidine. However, this was not successful. A psychiatrist recommended the use of antipsychotics. Administration of risperidone led to immediate resolution of the boy's symptoms and relaxed him. The use of antipsychotic drugs is not common for anesthesiologists, but should be considered for treating uncontrolled emergence delirium after anesthesia.

Etifoxine for Pain Patients with Anxiety

Etifoxine (etafenoxine, Stresam(R)) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by GABA(A)alpha2 receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to beta2 or beta3 subunits of the GABA(A) receptor complex. It also modulates GABA(A) receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.

Fatores relacionados à utilização de flumazenil em pacientes hospitalizados / Factors related to use of flumazenil in hospitalized patients / Factores relacionados con el uso de flumazenil en pacientes hospitalizados

Interações medicamentosas (IM) exacerbam o risco de eventos adversos graves relacionados ao uso de benzodiazepínicos. Este estudo objetivou conhecer aspectos relacionados à utilização de flumazenil em pacientes hospitalizados. Através do método observacional, foram analisados prescrições e prontuários de 31 pacientes internados entre junho/2008 e junho/2010 quanto à indicação do flumazenil, aos fatores que podem ter contribuído para intoxicação por benzodiazepínicos e à frequência de IM potenciais (IMP). A frequência de indicação para reversão de sedação excessiva foi aproximadamente 1,3 prescrições por 1.000 pacientes. Foram identificadas IMP em 84% dessas prescrições. Para sete casos, não houve prescrição prévia de benzodiazepínicos. O exame permitiu a identificação dos eventos com necessidade do manejo da sedação excessiva relacionados à ocorrência de IMP entre benzodiazepínicos e outros medicamentos para um elevado percentual de pacientes. Observou-se que idade elevada, quadro clínico com muitas comorbidades e administração de medicamentos com interações bem definidas estiveram associados à hipersedação...

Drug interactions (DIs) heighten the risk of severe adverse events connected with use of benzodiazepines. This observational study aimed to ascertain aspects of use of flumazenil in hospital inpatients. The prescriptions and medicalrecords of 31 patients admitted between June 2008 and June 2010 were examined for indication of flumazenil, factors that could have contributed to benzodiazepine intoxication, and potential drug interaction (PDI) frequency. In 1.3 prescriptions per 1,000 patients the indication was for reversal of excessive sedation. PDIs were observed in 84% of these prescriptions. In 7 cases there was no prior prescription of benzodiazepines. The examination identified events requiring management of excessive sedation associated with occurrence of PDI between benzodiazepines and other drugs in a high percentage of patients. It was observed that more advanced age, clinical condition with many comorbidities, and administration of drugs with well-defined interactions were observed to associate with over-sedation...

Interacciones medicamentosas (IM) incrementan el riesgo de efectos adversos graves. Este estudio observacional investigó los aspectos relacionados con el uso de flumazenil en los pacientes hospitalizados. Se analizaron las prescripciones y prontuarios de 31 pacientes ingresados entre junio/2008 y junio/2010. La frecuencia de la indicación de reversión de la sedación excesiva fue de 1,3 prescripciones por 1.000 pacientes. Se identificaron IMP en 84% de estas prescripciones. En siete casos no hubo prescripción previa de benzodiazepínicos. Este estudio permitió la identificación de la sedación excesiva asociada con la aparición de IMP entre los benzodiazepínicos y otras drogas para un alto porcentaje de pacientes. Se ha observado que la edad avanzada, cuadro clínico con muchas comorbilidades y administración de fármacos con interacciones bien definidas se asociaron con excesiva sedación...

Isoliquiritigenin, a Chalcone Compound, Enhances Spontaneous Inhibitory Postsynaptic Response

Isoliquiritigenin (ILTG) is a chalcone compound and shows various pharmacological properties, including antioxidant and anti-inflammatory activities. In recent study, we have reported a novel role of ILTG in sleep through a positive allosteric modulation of gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. However, the effect of ILTG in GABA(A)R-mediated synaptic response in brain has not been tested yet. Here we report that ILTG significantly prolonged the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by GABA(A)R in mouse hippocampal CA1 pyramidal neurons without affecting amplitude and frequency of sIPSCs. This enhancement was fully inhibited by flumazenil (FLU), a specific GABA(A)-BZD receptor antagonist. These results suggest a potential role of ILTG as a modulator of GABAergic synaptic transmission.

Delayed Flumazenil Injection after Endoscopic Sedation Increases Patient Satisfaction Compared with Immediate Flumazenil Injection

BACKGROUND/AIMS: Flumazenil was administered after the completion of endoscopy under sedation to reduce recovery time and increase patient safety. We evaluated patient satisfaction after endoscopy under sedation according to the timing of a postprocedural flumazenil injection. METHODS: In total, 200 subjects undergoing concurrent colonoscopy and upper endoscopy while sedated with midazolam and meperidine were enrolled in our investigation. We randomly administered 0.3 mg of flumazenil either immediately or 15 minutes after the endoscopic procedure. A postprocedural questionnaire and next day telephone interview were conducted to assess patient satisfaction. RESULTS: Flumazenil injection timing did not affect the time spent in the recovery room when comparing the two groups of patients. However, the subjects in the 15 minutes injection group were more satisfied with undergoing endoscopy under sedation than the patients in the immediate injection group according to the postprocedural survey (p=0.019). However, no difference in overall satisfaction, memory, or willingness to undergo a future endoscopy was observed between the two groups when the telephone survey was conducted on the following day. CONCLUSIONS: This study demonstrated that a delayed flumazenil injection after endoscopic sedation increased patient satisfaction without prolonging recovery time, even though the benefit of the delayed flumazenil injection did not persist into the following day.

The Experiences of the Emergency Antidote Stock and Delivery Service by the Korean Poison Information Center

PURPOSE: Antidotes for toxicological emergencies can be life-saving. However, there is no nationwide stocking and delivery system for emergency antidotes in Korea. We report on a two-year experience of a nationwide stocking and delivery trial for emergency antidotes at emergency departments in Korea. METHODS: An expert panel of clinical toxicologists reviewed and made a list of 15 stocked antidote. These antidotes were purchased or imported from other countries and delivered from 14 antidote stocking hospitals nationwide 24 hours per day, seven days per week. RESULTS: From August 1, 2011 to April 30, 2013, 177 patients with acute poisoning, with a median age of 48.5 years, were administered emergency antidotes. The causes of poisoning were intentional in 52.0% and 88.0% were intentional as a suicide attempt. Regarding clinical severity, using the poisoning severity score, 40.7% of patients had severe to fatal poisoning and 39.0% had moderate poisoning according to clinical severity. The most frequent presenting symptom was neurologic deficit, such as altered mentality (62.7%). alerted mentality (62.7%). Emergency antidotes were administered as follows: methylene blue (49 cases), flumazenil (31), N-acetylcysteine (25), glucagon (17), 100% ethanol (15), cyanide antidote kit (12), anti-venin immunoglobulin (5), pyridoxine (4), hydroxocobalamine (2), and deferoxamine (1). The median time interval from antidote request to delivery at the patient's bedside was 95 minutes (interquartile range 58.8-125.8). CONCLUSION: Findings of this study demonstrated the possibility of successful operation of the nationwide system of emergency antidotes stocking and delivery in Korea.

A Case of Mental Change in a Patient Who Received a Zoletil Injection

Zoletil is a non-opioid, non-barbiturate animal anesthetic and proprietary combination of two drugs, a dissociative anesthetic drug, tiletamine, with the benzodiazepine anxiolytic drug, zolazepam. Zoletil has greater potency than ketamine. Zoletil is abused for recreational purposes, especially by people with easy access to medicine. However, in Korea, it is available over-the-counter. Here we report on a case of an 83-year-old woman who received injection of seven vials of "Zoletil 50" by her daughter and presented with an altered mental change. Her mental state was stupor and vital sign was hypotension, bradycardia. Her blood tests indicated metabolic and respiratory acidosis and hyperkalemia. She was treated with intravenous naloxone and flumazenil but was not responsive. She was admitted to the ICU and treated with supportive therapy. Her mental state showed transient recovery, however, her clinical manifestation worsened and she expired.

Participation of the GABAergic system in the anesthetic effect of Lippia alba (Mill.) N.E. Brown essential oil

The objective of this study was to identify the possible involvement of the GABAergic system in the anesthetic effect of Lippia alba essential oil (EO). We propose a new animal model using silver catfish (Rhamdia quelen) exposed to an anesthetic bath to study the mechanism of action of EO. To observe the induction and potentiation of the anesthetic effect of EO, juvenile silver catfish (9.30 ± 1.85 g; 10.15 ± 0.95 cm; N = 6) were exposed to various concentrations of L. alba EO in the presence or absence of diazepam [an agonist of high-affinity binding sites for benzodiazepinic (BDZ) sites coupled to the GABA A receptor complex]. In another experiment, fish (N = 6) were initially anesthetized with the EO and then transferred to an anesthetic-free aquarium containing flumazenil (a selective antagonist of binding sites for BDZ coupled to the GABA A receptor complex) or water to assess recovery time from the anesthesia. In this case, flumazenil was used to observe the involvement of the GABA-BDZ receptor in the EO mechanism of action. The results showed that diazepam potentiates the anesthetic effect of EO at all concentrations tested. Fish exposed to diazepam and EO showed faster recovery from anesthesia when flumazenil was added to the recovery bath (12.0 ± 0.3 and 7.2 ± 0.7, respectively) than those exposed to water (9.2 ± 0.2 and 3.5 ± 0.3, respectively). In conclusion, the results demonstrated the involvement of the GABAergic system in the anesthetic effect of L. alba EO on silver catfish.