Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

Local Anesthesia Thoracoscopy with versus without Midazolam: A Randomized Controlled Trial.

BACKGROUND: Medical thoracoscopy is the gold standard for the diagnosis of pleural diseases. To date, no consensus exists regarding the choice of sedative and analgesic agents in patients undergoing local anesthetic thoracoscopy (LAT), and questions are raised as to whether sedatives may add to respiratory side effects. OBJECTIVE: The aim of the study was to test the hypothesis that administration of midazolam associated with lidocaine versus lidocaine alone in patients with LAT adds to respiratory side effects. METHODS: We randomly assigned 80 patients to a 1:1 study to 2 groups: local anesthesia by lidocaine (n = 40) versus lidocaine and midazolam (n = 40), with the primary end point being the mean lowest oxygen saturation. The secondary end points were cardiovascular parameters, complications, days of drainage, hospital stay, and patients' quality of life (QoL) as assessed by a visual analog scale (VAS). RESULTS: The mean age of all patients was 66.6 ± 13.1 years. The study comprised 50 males (62.5%). No difference was observed in the demographics between the 2 groups. No significant difference was observed between the 2 groups in oxygen saturation (primary end point). A significant difference was observed in favor of the midazolam group regarding the QoL assessed by VAS. CONCLUSION: Midazolam does not add to respiratory side effects when it is used with lidocaine for LAT, while patients' QoL is actually improved in this group. Therefore, in our department, we changed our startegy in favor of the association of lidocaine and midazolam.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Application of sedation-agitation scale in conscious sedation before bronchoscopy in children.

This retrospective study investigated the application of the sedation-agitation scale (SAS) in pediatric bronchoscopy by observing its effects on sedative dosages and adverse reactions.Children who underwent sedation before bronchoscopy, during the period from January 2014 to June 2017, were divided into control and SAS groups. Patients in the control group were administered a single dose of 0.1 to 0.3 mg/kg midazolam, based on physicians' clinical experience. The initial dose of midazolam in the SAS group was 0.1 mg/kg, and was adjusted based on the SAS score, as evaluated by physicians. Between-group comparisons were made of midazolam dose; adverse reactions of midazolam, such as agitation, delirium, excessive sedation, and respiratory depression; operating time of bronchoscopy; and number of participants.No statistically significant differences in gender, age distribution, weight, or disease composition were observed between the groups. The midazolam dose, operating time, and number of participants at different ages were all lower in the SAS group than in the control group. Fewer adverse drug reactions, such as intraoperative agitation and delirium, were noted in the SAS group. Moreover, the overall number of participants was reduced, and the overall operating time was less than that in the control group.Application of SAS for assessment of sedation during pediatric bronchoscopy can guide individualized administration of midazolam, reduce midazolam dose while achieving an ideal sedative effect, reduce adverse reactions, and improve operator experience. Hence, its use should be promoted for pediatric patients undergoing bronchoscopy under local anesthesia and conscious sedation.

Serotonergic medications, herbal supplements, and perioperative serotonin syndrome.

PURPOSE: Perioperative use of serotonergic agents increases the risk of serotonin syndrome. We describe the occurrence of serotonin syndrome after fentanyl use in two patients taking multiple serotonergic agents. CLINICAL FEATURES: Two patients who had been taking multiple serotonergic medications or herbal supplements (one patient taking fluoxetine, turmeric supplement, and acyclovir; the other taking fluoxetine and trazodone) developed serotonin syndrome perioperatively when undergoing outpatient procedures. Both experienced acute loss of consciousness and generalized myoclonus after receiving fentanyl. In one patient, the serotonin syndrome promptly resolved after naloxone administration. In the other patient, the onset of serotonin syndrome was delayed and manifested after discharge, most likely attributed to the intraoperative use of midazolam for sedation. CONCLUSION: Even small doses of fentanyl administered to patients taking multiple serotonergic medications and herbal supplements may trigger serotonin syndrome. Prompt reversal of serotonin toxicity in one patient by naloxone illustrates the likely opioid-mediated pathogenesis of serotonin syndrome in this case. It also highlights that taking serotonergic agents concomitantly can produce the compounding effect that causes serotonin syndrome. The delayed presentation of serotonin syndrome in the patient who received a large dose of midazolam suggests that outpatients taking multiple serotonergic drugs who receive benzodiazepines may require longer postprocedural monitoring.

Changes in First Postoperative Night Bispectral Index After Daytime Sedation Induced by Dexmedetomidine or Midazolam Under Regional Anesthesia: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Supplementation of spinal anesthesia with various sedatives is a standard protocol to alleviate patient anxiety associated with the surgical procedure. We hypothesized that, compared with dexmedetomidine, midazolam might have a subtle influence on sleep quality after surgery following elective transurethral prostatic resection (TURP) in elderly male patients. METHODS: A randomized, double-blind, controlled trial was conducted at the First Hospital of China Medical University from July 2014 to January 2015. One hundred eleven patients undergoing TURP were enrolled and received intravenous saline infusion (control group), dexmedetomidine (dexmedetomidine group), or midazolam (midazolam group) for sedation during the spinal anesthesia procedure. The intraoperative sedative state and postoperative sleep quality were evaluated using a Bispectral Index (BIS)-Vista monitor. The primary outcome was postoperative sleep quality, as measured by the BIS-Vista monitor on the first night after surgery. RESULTS: The intraoperative BIS area under the curve value was significantly lower in the dexmedetomidine group (54.1%) compared with those in the other 2 groups (control group, 94.1%; midazolam group, 77.2%).The postoperative BIS area under the curve value was highest in the dexmedetomidine group at 88.7%. The BIS sleep efficiency index showed a significant 33.1% increase in the midazolam group compared with the dexmedetomidine group. The duration of sleep in the midazolam group was 237.8 minutes longer than that in the dexmedetomidine group. CONCLUSIONS: We conclude that midazolam combined with spinal anesthesia might preserve the sleep quality of elderly male patients immediately after TURP.

[Sedation with midazolam for ambulatory pediatric dentistry].

OBJECTIVE: To improve the quality of dental treatment in children by using combined anaesthesia technique including local anaesthesia and conscious sedation, and to assess the effectiveness of conscious sedation for younger children undergoing dental treatment. METHODS: The study included 208 children aged 14-88 months who received dental treatment for tooth decay and its complication under combined anaesthesia. Midazolam was used as sedative medication. Sedation level was assessed by visual scale and BIS-monitoring. ANI-monitoring was also used for pain sensitiveness evaluation. Results All 208 children were successfully treated under combined anaesthesia which showed satisfactory sedation rates both by visual scale and and BIS-monitoring values. While mean patient age was 39 months 20.6% were younger than 24 months. These data are extremely valuable as according to literature review conscious sedation in early infancy remains controversial. CONCLUSIONS: Our results proved conscious sedation to be effective in younger children undergoing dental treatment thus representing important alternative for general anaesthesia and providing a basis for later behavior management.

A reorientation strategy for reducing delirium in the critically ill. Results of an interventional study.

BACKGROUND: A wide variability in the approach towards delirium prevention and treatment in the critically ill results from the dearth of prospective randomised studies. METHODS: We launched a two-stage prospective observational study to assess delirium epidemiology, risk factors and impact on patient outcome, by enrolling all patients admitted to our Intensive Care Unit (ICU) over a year. The first step - from January to June 2008 was the observational phase, whereas the second one from July to December 2008 was interventional. All the patients admitted to our ICU were recruited but those with pre-existing cognitive disorders, dementia, psychosis and disability after stroke were excluded from the data analysis. Delirium assessment was performed according with Confusion Assessment Method for the ICU twice per day after sedation interruption. During phase 2, patients underwent both a re-orientation strategy and environmental, acoustic and visual stimulation. RESULTS: We admitted a total of respectively 170 (I-ph) and 144 patients (II-ph). The delirium occurrence was significantly lower in (II-ph) 22% vs. 35% in (I-ph) (P=0.020). A Cox's Proportional Hazard model found the applied reorientation strategy as the strongest protective predictors of delirium: (HR 0.504, 95% C.I. 0.313-0.890, P=0.034), whereas age (HR 1.034, 95% CI: 1.013-1.056, P=0.001) and sedation with midazolam plus opiate (HR 2.145, 95% CI: 2.247-4.032, P=0.018) were negative predictors. CONCLUSION: A timely reorientation strategy seems to be correlated with significantly lower occurrence of delirium.

Acute and chronic pretreatment with essential oil of peppermint (Mentha × piperita L., Lamiaceae) influences drug effects.

The appearance of common and self-initiative usage of various herbal preparations in everyday practice and life imposes the question of possible interactions with drugs. This survey examined the influence of acute and chronic peppermint oil (PO--Mentha × piperita L., Lamiaceae; prepared as emulsion for oral use) on pentobarbitone-induced sleeping time, analgesic effect of codeine and impairment of motor coordination caused by midazolam in mice. The chemical profile of essential oil was determined by GC-MS. Applied doses of PO were 0.1 and 0.2 mL/kg. Chronic PO intake (in both doses) led to significant decrease of analgesic effect of codeine, while acute intake of PO did not change this effect. Acute PO pretreatment in higher dose caused significant prolongation of pentobarbitone-induced sleeping time, while it was significantly shortened by chronic PO pretreatment at the same dose. Midazolam effect was enhanced and prolonged significantly by chronic PO intake at higher dose, while acute intake of PO did not change this effect. Gut motility was increased only by acute intake of higher PO dose. Regarding the fact that PO produces changes in tested drug effects, the interaction between drugs and phytopreparations containing PO should be additionally followed/confirmed in humans.

Perioperative effects of oral midazolam premedication in children undergoing skin laser treatment: a double-blinded randomized placebo-controlled trial / Efeitos peroperatórios da premedicação oral de midazolam em crianças submetidas a tratamento de pele por laser: estudo duplo-cego randomizado e controlado

PURPOSE: To investigate and compare the efficacy of oral midazolam with two different dosages in orange juice on perioperative hemodynamics and behavioral changes in children who underwent skin laser treatment in an academic educational Hospital. METHODS: Ninety children, candidates for skin laser treatment were randomly assigned to 1 of 3 groups of 30 each: the placebo group received 0.1 ml/kg orange flavored juice, group 2 and 3 receiving 0.5 and 1 mg/kg of injectable midazolam mixed with an equal volume of orange juice, respectively. The main outcome measures included the mask acceptance, patients' behavioral scales and postoperative events. RESULTS: There were no significant differences in heart rate, respiratory rate, and systolic blood pressure among the three groups. However, arterial oxygen saturation was significantly reduced in those given 1 mg.kg-1 midazolam. The median scores of anxiety, separation from parent, preparing an intravenous line, acceptance of the oxygen mask, good sedation, crying reduction and consciousness level were better in midazolam group. Postoperative agitation and re-crying were also more frequent in placebo receivers. Those given 1 mg.kg-1 midazolam were significantly more optimal for sedation, crying, consciousness, preparing an intravenous line, and postoperative re-crying compared with 0.5 mg.kg-1 midazolam receivers. CONCLUSION: As a preanaesthetic medication, the 1 mg.kg-1 dose of orally given midazolam especially in a volume of orange juice and can optimize the children's behavior during skin laser treatment with no serious adverse effects, enhancing their parents' satisfactions about the sedative protocol.

OBJETIVO:Investigar e comparar a eficácia do uso oral de midazolam com duas diferentes doses de suco de laranja na hemodinâmica peropeatória e mudanças de desempenho em crianças submetidas tratamento de pele por laser em Hospital educacional e acadêmico. MÉTODOS:Noventa crianças candidatas a tratamento de pele por laser foram distribuídas aleatóriamente em três grupos de 30 cada: o grupo placebo recebeu 0.1mg/kg de suco de laranja, grupos dois e três receberam 0.5 e 1mg/kg de midazolam injetável misturado em igual volume de suco de laranja respectivamente. Os principais registros incluíam a aceitação da máscara, escalas de comportamento e eventos pós-operatórios. RESULTADOS:Não houve diferenças significantes cardíacas, respiratórias e pressão sanguinea sistólica nos três grupos. Contudo, o nível de saturação de oxigênio foi reduzido significantemente nos que receberam 1mg.kg-1 de midazolam. Os níveis médios de ansiedade, separação dos pais, preparo intravenoso, aceitação da máscara de oxigênio, boa sedação, redução do choro e nível de consciência, foram melhores no grupo midazolam. Agitação pós-operatória e retorno do chora foi mais freqüente nos que receberam placebo. Observou-se que o grupo que recebeu 1mg.kg-1 foi melhor comparado ao que recebeu 0.5mg.kg-1. CONCLUSÃO:Como medicação pré-anestésica na dose de 1mg.kg-1 de midazolam, fornecida em igual volume de suco de laranja, é satisfatória no comportamento de crianças durante tratamento de pele por laser, proporcionando satisfação dos pais.

Potential interactions with herbal medications and midazolam.

UNLABELLED: In the management of patients who require intravenous sedation with midazolam care must be taken if the patient is taking herbal drugs. There is a potential for harmful drug interactions between herbal drugs and midazolam.Assessment of which herbal drugs a patient is taking should be part of the treatment planning stage so interactions can be avoided or anticipated. CLINICAL RELEVANCE: Growing numbers of patients are taking herbal or Chinese medication and may not disclose this to the sedation team. Such drugs have the potential for interactions and can affect induction and recovery from sedation.

Factors affecting outcomes in colonoscopy.

There are many factors that influence successful outcomes in colonoscopy. The aims of this study were to evaluate these factors and determine ways to improve outcomes. All participants (N=229) who underwent planned colonoscopy between July and September 2004 were retrospectively included. Participants included 118 men and 111 women with a mean age of 59 years. Completion rate was 92%. Reasons of failure included poor bowel preparation (2.2%, p< .025), bowel looping (2.2%, p< .025), participant discomfort (1.3%), and obstructing lesion (1.3%). Mean midazolam dose was 3.8 mg. Three participants (1.3%) had midazolam alone, and all had complete colonoscopy. One hundred thirty-three participants (60.7%) had additional meperidine, with a completion rate of 94%. Eighty three participants (37.9%) had additional meperidine and Buscopan, with a completion rate reduced to 89.2%. There was no correlation between sedatives used and completion rate. Completion rate of colonoscopy in our unit was acceptable at 92%. A combination of midazolam and meperidine gave the best completion rates (94%). The two main reasons for incompletion were poor bowel preparation and excessive bowel looping.

Detection of hypoventilation during thoracoscopy: combined cutaneous carbon dioxide tension and oximetry monitoring with a new digital sensor.

BACKGROUND: Changes in Paco(2) have not been described during thoracoscopy under sedation-assisted local anesthesia. We hypothesized that hypoventilation might occur secondary to administration of sedatives and decreased ventilation in one lung. AIM: Prospectively measure cutaneous carbon dioxide tension (Pcco(2)) in addition to pulse oximetric saturation (Spo(2)) using a new combined digital sensor to examine the occurrence of hypoventilation during thoracoscopy under sedation-assisted local anesthesia. SETTING: University hospital. METHODS: Following validation studies, Pcco(2) was prospectively measured in 16 consecutive patients undergoing thoracoscopy under sedation-assisted local anesthesia using a combined digital earlobe sensor measuring Spo(2) (percentage) and Pcco(2) (millimeters of mercury). All patients received supplemental oxygen. Routine BP monitoring and Spo(2) was continued. Patients received IV hydrocodone, 5 mg, and intermittent boluses or IV midazolam and pethidine. RESULTS: Mean baseline Pcco(2) measurement was 39.1 +/- 7.2 mm Hg (+/- SD) [range, 27.5 to 50.5 mm Hg], and peak measurement during the procedure was 52.3 +/- 10.3 mm Hg (range, 37.2 to 77 mm Hg) [p < 0.001]. Median and mean changes in Pcco(2) measurement from baseline were 13.0 mm Hg and 13.2 +/- 5.3 mm Hg (range, 5.5 to 27.8 mm Hg), respectively. Mean fall in Spo(2) during the procedure was 4.6 +/- 3.2% (range, 1 to 14%). CONCLUSIONS: Thoracoscopy performed under sedation-assisted local anesthesia is associated with significant hypoventilation. Combined measurement of Spo(2) and Pcco(2) during thoracoscopy is a novel approach in the monitoring of ventilation, enhancing patient safety, and might allow to guide the administration of sedation in a better way.

The use of intrathecal midazolam in humans: a case study of process.

UNLABELLED: Early preclinical work demonstrated the potential role of spinal benzodiazepine pharmacology in regulating spinal nociceptive transmission. We review this preclinical activity and the evolving implementation of intrathecal midazolam in humans for pain management. Important elements in this development for use in humans are issues pertinent to safety and the preclinical reports that have increased our understanding of intrathecal midazolam toxicity. We seek to emphasize the time course of these studies and how they merged to provide enabling data that drove the clinical implementation. In the case of midazolam, we point to the potential issues that arose when preclinical safety data were unreasonably ignored and how consideration of preclinical safety data can serve to facilitate drug development by demonstrating reasonable safety profiles that document the minimal degree of potential risk to the patient. Issues that are of continuing relevance to the use of intrathecal midazolam, including issues of formulation and kinetics, are considered. IMPLICATIONS: The intrathecal use of midazolam has evolved over 20 years though a combination of preclinical and clinical investigations. We review the time course of this development to define critical elements that should be pursued in reducing the risk associated with the clinical use of a novel spinal drug.

Local anesthesia and midazolam versus spinal anesthesia in ambulatory pilonidal surgery.

STUDY OBJECTIVE: To evaluate two anesthetic techniques, namely, local anesthesia with sedation, and spinal anesthesia, with respect to recovery times, postoperative side effects, pain scores, patient satisfaction, and hospital costs for ambulatory pilonidal disease surgery. DESIGN: Prospective, randomized study. SETTING: University Hospital of Pamukkale. PATIENTS: 60 consenting patients scheduled for pilonidal disease operation with Limberg flap technique. INTERVENTION: Patients were randomly allocated into two groups: Group 1 (n = 30) received spinal anesthesia with hyperbaric bupivacaine 1.5 mL 0.5%, and Group 2 (n = 30) received local infiltration with a 50-mL mixture containing 10 mL bupivacaine 0.5%, 10 mL prilocaine HCl 2%, and 30 mL isotonic solution with 1:200,000 epinephrine in combination with intravenous (i.v.) midazolam sedation. MEASUREMENTS: Perioperative and postoperative side effects, patient satisfaction, preoperative visual analog scale (VAS) pain scores, and VAS scores from the fourth hour postoperatively until the seventh day were assessed. Anesthesia, operation, surgery, and total hospital time, and costs (drug, resources, and labor) were recorded. MAIN RESULTS: No difference was found between groups in the frequency of side effects. Urinary retention was diagnosed in two patients in the spinal anesthesia group. There was no statistical significant difference seen in satisfaction scores between groups. No statistical significance in VAS pain scores between groups was noted except for the fourth postoperative hour values. The average time spent in the operating room (OR) was greater in the spinal anesthesia group. All Group 2 patients achieved fast-tracking criteria in the OR and were able to bypass the postanesthesia care unit (PACU). Total hospital time and total cost were significantly higher in the spinal anesthesia group than local anesthesia-sedation group (p < 0.05). CONCLUSION: The use of local anesthesia-sedation for ambulatory anorectal surgery resulted in a shorter hospital time, lower hospital costs, and no side effects compared with spinal anesthesia.