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BackgroundDespite frequent benzodiazepine use in anxiety disorders, the trajectory and magnitude of benzodiazepine response and the effects of benzodiazepine potency, lipophilicity, and dose on improvement are unknown.MethodsWe performed a meta-analysis using weekly symptom severity data from randomized, parallel group, placebo-controlled trials of benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in anxiety was evaluated as a function of medication, disorder, time, potency, lipophilicity, and standardized dose and compared among benzodiazepines.ResultsData from 65 trials (73 arms, 7 medications, 7110 patients) were included. In the logarithmic model of response, treatment effects emerged within 1 week of beginning treatment (standardized benzodiazepine-placebo difference = −0.235 ± 0.024, CrI: −0.283 to −0.186, P < .001) and placebo response plateaued at week 4. Doses P = .039 for low vs medium dose and P = .005 for high vs medium dose) and less lipophilic benzodiazepines (beta = 0.028 ± 0.013, P = .030) produced a greater response over time. Relative to the reference benzodiazepine (lorazepam), clonazepam (beta = −0.217 ± 0.95, P = .021) had a greater trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam).ConclusionsIn adults with anxiety disorders, benzodiazepine-related improvement emerges early, and the trajectory and magnitude of improvement is related to dose and lipophilicity. Lower doses and less lipophilic benzodiazepines produce greater improvement.

Background Methamphetamine (M) is a widely used, powerful sympathomimetic drug that produces significant CNS stimulation. Its use is associated with psychiatric disorders, abnormal brain chemistry, and cardiovascular disease. Pre-hospital M use is associated with increased intubation, intensive care unit admission, and hospital length of stay. The purpose of this study was to determine the influence of acute M use on analgesia and sedation requirements in mechanically ventilated trauma patients. Methods This single center retrospective cohort study included injured adult patients (≥16 years) admitted to the trauma intensive care unit (TICU) between 2016 and 2018 who were mechanically ventilated and had a urine drug screen (UDS) completed. The primary outcome was the median sedation and total analgesia administered during the first 48 hours of TICU admission, expressed as propofol, dexmedetomidine, lorazepam, and morphine equivalents. Secondary endpoints included the median Richmond Agitation Sedation Scale (RASS) score, median Critical Pain Observation Tool (CPOT) score, ventilator days, length of stay, in-hospital mortality, and discharge disposition. Results A total of 245 patients were included in the final analysis (53 M+ and 192 M-). The patients were mostly men (78%) and sustained blunt trauma (89%) with a median age of 35 (IQR 26-52) years and median ISS of 11 (IQR 4-24). A M+ UDS was associated with increased morphine requirements, defined as greater than the cohort median of 1.91 mg/kg, during the first 12 hours of admission on the univariable analysis (OR 2.03; 95% CI, 1.07-3.82). There was no difference in median propofol (M+ 30 mcg/kg/min vs. M- 30 mcg/kg/min, p=0.58) or total morphine equivalents (M+ 5.42 mg/kg s. M- 3.89 mg/kg, p=0.30) over 48 hours between M+ and M- groups to achieve similar RASS and CPOT scores. Conclusion To achieve the same level of pain control and depth of sedation, intubated TICU patients with a M+ UDS do not require more analgesia and sedation than patients with a M- UDS during the first 48 hours of admission.

Introduction Phenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital. Methods This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter. Results Of 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007]. Conclusions Patients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.

Clinicians often encounter agitated patients, and current treatment options include benzodiazepines and antipsychotics. Ketamine rapidly induces dissociation, maintains cardiovascular stability, spontaneous respirations, and airway reflexes. There are no prospective, randomized studies comparing ketamine to other agents in the initial management of acute agitation in the Emergency Department (ED).Determine the efficacy and safety of ketamine compared to parenteral haloperidol plus lorazepam for initial control of acute agitation.This study was a prospective, single-institution, randomized, open-label, real world, standard of care pilot study. Adult patients with combative agitation were randomized to ketamine (4 mg/kg IM or 1 mg/kg IV) or haloperidol/lorazepam (haloperidol 5-10 mg IM or IV + lorazepam 1-2 mg IM or IV). The primary outcome was sedation within 5 min, and secondary outcomes included sedation within 15 min, time to sedation, and safety.Ninety three patients were enrolled from January 15, 2018 to October 10, 2018. Significantly more patients who received ketamine compared to haloperidol/lorazepam were sedated within 5 min (22% vs 0%, p = 0.001) and 15 min (66% vs 7%, p 0.001). The median time to sedation in patients who received ketamine compared to haloperidol/lorazepam was 15 vs 36 min respectively (p 0.001). Patients who received ketamine experienced a significant, but transient tachycardia (p = 0.01) and hypertension (p = 0.01).In patients with combative agitation, ketamine was significantly more effective than haloperidol/lorazepam for initial control of acute agitation, and was not associated with any significant adverse effects.

Scopolamine is an alkaloid which acts as competitive antagonists to acetylcholine at central and peripheral muscarinic receptors. We report the case of a 41-year-old male convict with a 27-year history of cannabis abuse who suddenly died in the bed of his cell after having smoked buscopan® tablets. Since both abuse of substances and recent physical assaults had been reported, we opted for a comprehensive approach (post-mortem computed tomography CT (PMCT), full forensic autopsy, and toxicology testing) to determine which was the cause of the death. Virtopsy found significant cerebral edema and lungs edema that were confirmed at the autopsy and at the histopathological examination. Scopolamine was detected in peripheral blood at the toxic concentration of 14 ng/mL in blood and at 263 ng/mL in urine, and scopolamine butyl bromide at 17 ng/mL in blood and 90 ng/mL in urine. Quetiapine, mirtazapine, lorazepam, diazepam, and metabolites and valproate were also detected (at therapeutic concentrations). Inmates, especially when they have a history of drug abuse, are at risk to use any substance they can find for recreational purposes. In prisons, active surveillance on the management and assumption of prescribed drugs could avoid fatal acute intoxication.

Purpose: To describe the use of ketamine in an adult patient in aborting a cyclic vomiting syndrome (CVS) episode. Summary: A 40-year-old man with a history of CVS was admitted after several days of nausea and vomiting. He was given parenteral doses of lorazepam and ondansetron but was unable to remain emesis-free. Ketamine was recommended by Gastroenterology as a therapeutic option after exhausting all first- and second-line agents. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that is widely used for its analgesic and sedative effects. While there is some data to support its use in CVS, most of the published literature has been limited to the Emergency Department setting and no specific therapeutic dose has been established. We will review our institution’s experience with low dose ketamine in an adult patient with a CVS episode that is refractory to first-line agents. Conclusion: In the case described, ketamine at a low sub-anesthetic dose successfully aborted a CVS episode with no appreciable side effects. As much of ketamine’s full effects remain relatively unknown, additional studies are needed to determine optimal strategies for ketamine use in patients with a CVS episode.

Background Lithium can cause not only acute neurotoxicity but also chronic and persistent neurotoxicity known as syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The combined use of lithium and antipsychotics increases the possibility of SILENT. Neuroleptic malignant syndrome (NMS) is a reversible, idiosyncratic, and potentially life-threatening reaction, which is usually caused by antipsychotics and other agents, such as mood stabilizers (eg, lithium and metoclopramide). Neuroleptic malignant syndrome is characterized by hyperpyrexia, muscle rigidity, and altered mental status. We describe a case of SILENT combined with NMS in this case report. Case report A 46-year-old man who had been treated with lithium for bipolar II disorder since 2008 was prescribed lorazepam, lithium, and aripiprazole at his last outpatient visit. The patient experienced financial difficulties (bankruptcy) and suffered severe emotional stress. Subsequently, he overused lorazepam, lithium, and aripiprazole. Two days after the overdose, he experienced a high fever, confused mental status, and rhabdomyolysis and was diagnosed with NMS. However, even after resolution of NMS-related symptoms, quadriplegia, visual field defects, ataxia, and severe dysarthria persisted. A positron emission tomography-computed tomography brain scan showed decreased 15F-fludeoxyglucose uptake in bilateral primary motor cortices and in the thalamus, midbrain, and cerebellum. Brain magnetic resonance imaging diffusion tensor imaging and diffusion tensor tractography of the subcortical tracts revealed structural disruptions, especially in the corticospinal tract, dentatorubrothalamic tract, and optic radiation, which seemed to be correlated with the clinical symptoms of the patient. Conclusion This case suggests that the clinical use of diffusion tensor tractography could be helpful to explain the clinical features in the case of SILENT combined with NMS.

Background: Granisetron is a popular antiemetic medication used in the emergency department to control nausea and vomiting with an excellent side effect profile among adults and pediatric, in both healthy and oncology patients. Case Presentation: Our patient received granisetron for nausea and vomiting then developed torsional nystagmus, asymmetrical abnormal muscle contractions, and electrocardiography showed QTc prolongation 487 ms. The patient did improve after IV lorazepam and magnesium sulphate administration. Conclusion: QTc prolongation increases the risk of developing Torsades de Pointes and sudden death. Extrapyramidal syndrome caused by granisetron is rare and should not be confused with seizure. Both are significant effects associated with 5-HT3 antagonists administration to be aware of and if they occurred, should be managed in a timely fashion.

Background: Status epileptics are classically defined as seizures that are continuous for 30 minutes or longer or repetitive seizures between which the patient does not regain consciousness. This study reports a case of a boy with a 2-hour seizure. Case Presentation: We present the case of a 7-year-old boy, who is known to have tuberous sclerosis (TSC2 gene mutation). On the day of presentation, the seizure had started with aura (epigastric pain with weakness in the face), then started to seize in a form left focal jerky movement with generalization associated with rolling up of the eyes, and lasted for 5 minutes; it was aborted clinically by lorazepam 0.1 mg/kg IV. However, the electroencephalography (EEG) showed subclinical seizure. The patient received a loading dose of phenytoin, 20 mg/kg IV, with no changes in the EEG; then Keppra (three doses) with a total of 40 mg/kg IV was given, but subclinical seizure still persisted. The patient was given one dose of Ketamine IV of 1 mg/kg, which resulted in complete cessation of the seizure activity within 3 minutes after injection, which was confirmed by prolonged EEG monitoring. The total duration of the seizure was 2 hours. Conclusion: Ketamine can be considered as a third-line drug in refractory status epilepticus.

Electroconvulsive therapy (ECT) may be considered for treatment of severe, treatment-resistant, and emergent depression associated with MDD or bipolar disorder. Patients with epilepsy usually take medications that raise the seizure threshold, which poses challenges during ECT. We report a 66-year-old male with epilepsy taking levetiracetam extended-release (XR), lorazepam, and zonisamide requiring ECT for severe MDD. After literature review, the XR form of levetiracetam was changed to higher doses of the immediate-release (IR) formulation, and zonisamide was discontinued 2 days prior to ECT in the hospital and was resumed when the patient underwent outpatient continuation ECT. The patient was treated to remission after receiving 8 acute bilateral ECT treatments before being transitioned to continuation ECT. We provide a brief review of medication management of antiepileptic drugs and other medications that increase the seizure threshold during ECT. To our knowledge, this is the first reported case describing the management of levetiracetam, lorazepam, and zonisamide concomitantly during ECT. Our case suggests that utilizing the IR formulation of levetiracetam, administering the evening dose early the day prior to the procedure, and temporarily discontinuing zonisamide prior to bilateral ECT is effective for the treatment of severe MDD while maintaining seizure prophylaxis.

Since the 1960s, benzodiazepines have been a clinical mainstay, utilized for sedation, anxiety, and withdrawal states. Between 1996 and 2013 alone, benzodiazepine prescriptions increased annually by 2.5%. Rather than risk symptoms of withdrawal such as muscle pain and severe cardiomyopathy, patients must be properly informed about how to taper their medications. A 75-year-old female with a history of anxiety, hypertension, lupus, and degenerative disc disease presented with palpitations, mid-sternal chest pain, diaphoresis, and progressive shortness of breath. The patient was found to have elevated troponins (peak troponin of 1.45) and EKG showed sinus rhythm and ST segment abnormalities. The patient stated that her chest pain started 24 hours ago, 48 hours after she had stopped taking lorazepam which she had been taking for the past 50 years for anxiety. Her PCP gave her a plan to taper down the dose of lorazepam safely, but the patient opted to stop “cold turkey.” Due to the patient’s typical chest pain and elevating troponin level, ACS protocol was initiated. Initial echocardiogram showed an ejection fraction of 35-40% with hypokinesis of the anterioseptal wall with impaired left ventricular diastolic filling. The cardiology team performed a catheterization which showed minimal coronary artery disease and no significant stenosis in the left anterior descending artery. Within the next few days, the patient’s chest pain resolved and her troponins were negative. The medical team concluded that the physical stress from withdrawing from benzodiazepine caused the patient to go into Takotsubo Cardiomyopathy. This case illustrates the risks involved with benzodiazepine in an era of polypharmacy. More importantly, this case illustrates the strong need to taper benzodiazepines properly. Because this patient had taken a benzodiazepine for 50 years, the tapering should have been as slow as possible. The result was Takotsubo cardiomyopathy.

Pharmacological agents are analyzed, in respect of which it is advisable to develop dosage forms for inhalation use as medical means of protection at the prehospital stage of medical evacuation in case of damage by emergency-hazardous chemicals. It was found that the inhalation intake of hazardous chemicals, especially with a pronounced pulmonotoxic, irritating and generally poisonous effect, is highly likely to develop post-intoxication complications associated with damage to the lung parenchyma, and death. For the therapy of such intoxications, it is advisable to administrate drugs in a dosage form for inhalation administration, which have several advantages: high bioavailability, rapid onset of effect, and severity of local action in various parts of tracheobronchial tree. The data of experimental and clinical studies of the effectiveness of drugs belonging to various pharmacological groups allow us to recommend for the further development of inhaled forms of means of prevention and treatment of toxic pulmonary edema (fluticasone, roflumilast, rolipram). Bronchodilators and donors of sulfhydryl groups (ipratropium bromide, tiotropium bromide, atropine sulfate, fenoterol, salbutamol, formoterol, unitiol dimercaprol) are referred to means of correction of respiratory disorders of various etiologies. Diazepam, midazolam, clonazepam, lorazepam are considered to be the most likely anticonvulsants from the enzodiazepine-class suitable for inhalation. Acetylcysteine, hydroxycobalamin can be used to combat hypoxia. The principal possibility of inhalation application of bioscavengers (acetylcholinesterase, butyrylcholinesterase) for the treatment of cholinopositive symptoms of toxic genesis is shown. Existing methods and means of delivery allow the use of these drugs at the prehospital stage of medical evacuation as part of single dose metered powder inhalers.

Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation.This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion.Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%,Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

BACKGROUND The rapidity with which a medication can be delivered to the systemic circulation and then into the brain always play a significant role in reducing the mortality and morbidity. We wanted to determine and compare the efficacy of intranasal midazolam with that of intravenous lorazepam in the control of acute onset seizures and side effects. METHODS This is an open labelled randomized control trial conducted in the Emergency Department of KIMS Hospital, which is a multi-specialty tertiary care centre in south Kerala, India, among children with acute seizure between 6 months and 15 years of age. They received intranasal midazolam or intravenous lorazepam. RESULTS 65.2 % (15) of the children in whom intranasal midazolam was given, seizures were controlled within 5 minutes from ER presentation, whereas in lorazepam group, only 34.8 % (8) children ceased to seizure within 5 minutes. P value was 0.039. CONCLUSIONS The overall time to cessation of seizure after arrival at hospital was faster with intranasal midazolam than intravenous lorazepam. No untoward side effects were noticed. KEYWORDS Acute Seizure in Children, Intranasal Midazolam, Lorazepam, Randomized Trial

BACKGROUND The optimal agent to treat acute agitation in the emergency department (ED) has not been determined. The objective of this study was to compare the effectiveness and safety of intramuscular droperidol, ziprasidone, and lorazepam for acute agitation in the ED. METHODS This was a randomized, double-blind trial of ED patients with acute agitation requiring parenteral sedation. The study was conducted under exception from informed consent (21 CFR 50.24) from July 2004 to March 2005. Patients were randomized to receive 5 mg of droperidol, 10 mg of ziprasidone, 20 mg of ziprasidone, or 2 mg of lorazepam intramuscularly. We recorded Altered Mental Status Scale (AMSS) scores, nasal end-tidal carbon dioxide (ETCO2 ), and pulse oximetry (SpO2 ) at 0, 15, 30, 45, 60, 90, and 120 minutes as well as QTc durations and dysrhythmias. Respiratory depression was defined as a change in ETCO2 consistent with respiratory depression or SpO2

Background Redotex™ is a Mexican weight-loss supplement that is not U.S. Food and Drug Administration–approved. It consists of the following five ingredients: tri-iodothyronine 75 μg, atropine 0.36 mg, diazepam 8 mg, aloin 16 mg, and d-norpseudoephedrine 50 mg per tablet. There are few case reports with clinically severe ingestions. We report two cases of clinical thyrotoxicosis due to use of Redotex. Case Reports A 29-year-old woman presented to the emergency department (ED) with anxiety and palpitations. She reported taking Redotex daily for 1 week. Her temperature was 37.1°C, blood pressure (BP) was 166/104 mm Hg, and heart rate (HR) was 140 beats/min. Laboratory analysis was significant for a bicarbonate level of 20 mmol/L (reference 22–29 mmol/L), free T4 0.75 ng/dL (reference 0.93–1.70 ng/dL), and thyroid-stimulating hormone (TSH) 0.05 uIU/mL (reference 0.27–4.20 uIU/mL). She was treated with 2 mg i.v. lorazepam and 20 mg oral propranolol. A 37-year-old woman presented with chest pain, palpitations, and nausea after taking Redotex 1 to 2 tablets daily for 6 weeks. Her HR was 134 beats/min and BP was 130/66 mm Hg. Thyroid function tests on initial presentation showed a TSH of 0.013 uU/mL, free T4 of 0.24 ng/dL, and free T3 of >30 pg/mL. She was treated with propranolol 1 mg i.v. twice per day and 2 doses of lorazepam 1 mg. Both patients had resolution of their symptoms. Why Should an Emergency Physician Be Aware of This? When taken chronically and at recommended doses, Redotex can present with clinically significant T3 thyrotoxicosis. This has not been seen in prior reports.

Aim: The aim was to evaluate the “effect size (ES),” tolerability, and acceptability of lithium, carbamazepine, and sodium valproate in the acute phase treatment of pediatric Bipolar 1 disorder patients during manic phase. Materials and Methods: This hospital-based, prospective, open-label study included 67 patients in manic phase of bipolar I disorder, aged 6–17 years, after informed consent by the caregivers. The patients were randomly assigned to the lithium group (n = 30), carbamazepine group (n = 20), and sodium valproate group (n = 17). They were assessed with the Schedule for Affective Disorders for School Age Children's-Present and Life time version administered to the parent and child separately, Conner's Abbreviated Rating Scale, and Cassidy Scale for Manic States (CSMS). Lithium was started in the dose of 30 mg per kg of body weight, carbamazepine in the dose of 10–20 mg/kg/day, and sodium valproate in the dose of 10–20 mg/kg body weight. Antipsychotic (chlorpromazine [CPZ] 100–500 mg per day or haloperidol up to 750 mg of CPZ equivalent) was allowed in the study. Injection haloperidol 10 mg and injection promethazine 50 mg intramuscular were allowed for initial 3–5 days to combat acute agitation. Rescue medication such as injection lorazepam 2–4 mg intramuscular was allowed throughout the study duration. The patients were rated weekly on CSMS, Bipolar Clinical Global Impression, Udvalg for kliniske Undersogelser Side Effect Rating Scale, and side effect checklist for lithium, sodium valproate, and carbamazepine, respectively. The serum level of concerned drug was obtained at weekly intervals and dose hiked, if needed to get target serum level. Results: The response rate was 90% in lithium group, 70% in carbamazepine group, and 88% in sodium valproate group on the basis of ≥33% reduction from baseline CSMS. The effects of change of CSMS over the 6 weeks across the three treatment group were found to be highly statistically significant. Conclusions: In the acute phase treatment of pediatric bipolar 1 disorder patients during manic phase, the ES for lithium was 0.85, for carbamazepine 0.71, and for sodium valproate 0.84. These agents are well tolerated in treating bipolar disorder in children.

Rationale: Benzodiazepines are useful and commonly prescribed. Unfortunately, they are associated with subtle but functionally significant neurocognitive side effects that increase the risk of motor vehicle accidents and falls. Objective: The objective of this study was to determine whether clinically feasible measures of simple reaction time and reaction accuracy are sensitive to a single dose of lorazepam. Methods: Using a randomized, double-blind, crossover design, 26 healthy adults (13 women; age = 26.9 ± 8.2 yr) were given 1.0 mg lorazepam or placebo 90 minutes prior to two data collection sessions. Participants completed simple and reaction accuracy tasks using a standardized “ruler drop” testing paradigm during each session. Outcomes were mean and variability of simple reaction time and reaction accuracy, which evaluates a participant’s ability to catch the device solely on the random 50% of trials that lights affixed to it illuminate on release. Reaction accuracy requires a go/no-go decision within 420 ms before the falling device strikes the floor. Results: As compared with placebo, lorazepam increased simple reaction time variability (range = 43 ± 18 vs. 60 ± 23 ms, respectively; p = 0.004 and standard deviation = 14.6 ± 5.7 vs. 19.7 ± 7.3 ms, respectively; = 0.006) and decreased reaction accuracy (90 ± 7% vs. 84 ± 11%, respectively; p = 0.010). Conclusion: Given prior work demonstrating associations between simple reaction time and reaction accuracy and functional outcomes such as self-protection, response to perturbations, and fall risk, these clinically available measures may have a role in identifying subtle, functionally significant cognitive changes related to short-term benzodiazepine use.

Organophosphates (OPs) are widely used as pesticides and have been employed as warfare agents. OPs inhibit acetylcholinesterase, leading to over-stimulation of cholinergic synapses and can cause status epilepticus (SE). OPs poisoning can result in irreversible brain damage and death. Despite termination of SE, recurrent seizures and abnormal brain activity remain common sequelae often associated with long-term neural damage and cognitive dysfunction. Therefore, early treatment for prevention of seizures is of high interest. Using a rat model of paraoxon poisoning, we tested the efficacy of different neuroprotective and anti-epileptic drugs (AEDs) in suppressing early seizures and preventing brain damage. Electrocorticographic recordings were performed prior, during and after injection of 4.5 LD50 paraoxon, followed by injections of atropine and toxogonin (obidoxime) to prevent death. Thirty minutes later, rats were injected with midazolam alone or in combination with different AEDs (lorazepam, valproic acid, phenytoin) or neuroprotective drugs (losartan, isoflurane). Outcome measures included SE duration, early seizures frequency and epileptiform activity duration in the first 24 -hs after poisoning. To assess delayed brain damage, we performed T2-weighted magnetic resonance imaging one month after poisoning. SE duration and the number of recurrent seizures were not affected by the addition of any of the drugs tested. Delayed brain injury was most prominent in the septum, striatum, amygdala and piriform network. Only isoflurane anesthesia significantly reduced brain damage. We show that acute treatment with isoflurane, but not AEDs, reduces brain damage following SE. This may offer a new therapeutic approach for exposed individuals.

Objective Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication. Methods Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30‐100 mg/kg) and progression of seizure activity was monitored by video‐EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology. Results Phenobarbital produced a dose‐dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death. Significance Phenobarbital appears as an alternate anticonvulsant for OP‐induced refractive SE in hospital settings. A careful risk‐benefit analysis is required because of negative outcomes on survival and cardio‐respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.

The purpose of this study was to evaluate the safety and efficacy of a single parenteral dose of phenobarbital in addition to symptom-triggered lorazepam for the acute management of alcohol withdrawal syndrome (AWS).This was a retrospective chart review of adult patients who presented to the Emergency Department with moderate or severe symptoms of alcohol withdrawal. Patients were included if they received at least 4 mg of lorazepam through the hospital's Alcohol Withdrawal Order Set on hospital day one. Patients who received a single parenteral dose of phenobarbital on hospital day one were compared to those who did not.Forty patients received phenobarbital and 38 patients received lorazepam only. Median daily lorazepam requirements, disposition, hospital length of stay, and median maximum daily CIWA-Ar scores were not statistically significant different between the groups. Significantly more patients in the phenobarbital group were discharged within three days in comparison to the lorazepam only group (9 patients vs. 2 patients, respectively, p 0.05). In the lorazepam only group, two patients were intubated, one patient had delirium tremens, and no patients seized. In the phenobarbital group no adverse events were observed.More patients were discharged within three days if they received a single parenteral dose of phenobarbital on hospital day one, in addition to symptom-triggered lorazepam for the acute management of AWS. Emergency Medicine physicians should consider ordering one parenteral phenobarbital dose on hospital day one to patients presenting with AWS.

A symptom-triggered lorazepam regimen is the standard for treating alcohol withdrawal syndrome (AWS) in an inpatient setting. However, in severe AWS, lorazepam requirements can reach significant amounts and lead to risk of delirium and propylene glycol toxicity. Phenobarbital has been shown to be an effective adjunctive therapy for AWS, reducing benzodiazepine use, in the emergency department. The purpose of this study is to determine the efficacy and safety of phenobarbital in adjunct to symptom-triggered lorazepam for severe AWS vs. lorazepam alone in the intensive care unit (ICU). A retrospective cohort was conducted at Cleveland Clinic hospitals from 2013 to 2018 of ICU patients with AWS receiving either phenobarbital adjunct to symptom-triggered lorazepam or lorazepam alone. The primary outcome was the total duration of treatment. Secondary outcomes include ICU length of stay, change in CIWA-Ar score at 24 h, incidence of hypotension, mechanical ventilation, and serum osmolar gap. A total of 72 ICU patients were included with 36 patients in each arm. The median duration of treatment in the phenobarbital adjunct arm was 2.7 days (IQR = 1.7–6.4), compared to 3.1 days (IQR = 1.6–4.8) in the lorazepam arm (p = 0.578). The median ICU length of stay was similar between both arms [4.1 days (IQR = 2.4–8.4) vs. 4.5 days (IQR = 2.8–6.1), p = 0.727]. The average change in CIWA-Ar from baseline at 24 h was significantly lower for those who received phenobarbital (1.8 ± 9.0 vs. 6.5 ± 8.5, p = 0.028). Three patients in the phenobarbital-adjunct group received mechanical ventilation after starting phenobarbital treatment. There were no new incidences of hypotension or increased osmol gap >10 mmol/L after starting treatment in both groups. In conclusion, phenobarbital is an effective adjunct to symptom-triggered lorazepam in severe alcohol withdrawal in the ICU with no significant difference in adverse events.

A. Rapimelt tablet of Lorazepam was prepared by direct compression method using Indion 414, Cross Carmellose Sodium and sodium starch glycolate as superdisintegrants with aim to get rapid onset of action, improve bioavailability and to give pleasant taste and better mouth feel. The tablets prepared were evaluated for various parameters like various density parameters, thickness, hardness, friability, disintegration time, wetting time and invitro dissolution time and were found to be within limits as per Indian Pharmacopoeia. FT-IR spectra of physical mixture of Lorazepam with Indion 414showedretention of basic peaks of Lorazepam. The developed formulation of Lorazepam batch F5 (10% Indion 414) showed good palatability and dispersed within 30 seconds as compared to Crosscarmellose Sodium batches F1-F3 and Sodium starch glycolate batches F6-F9.

The treatment of severe agitation, aggression, and violent behavior in behavioral health patients who present to the emergency department (ED) often requires the intramuscular administration of a sedative. However, administering an intramuscular sedative to an uncooperative patient is associated with the risk of needlestick injuries to both patients and health care providers, and times to onset of sedation range from 15 to 45 minutes. Intranasal absorption is more rapid than intramuscular, with sedatives such as lorazepam reaching peak serum concentrations up to 6 times faster when administered intranasally. We present the first report of using intranasal lorazepam as a needle-free method of providing rapid and effective sedation to treat severe agitation in a pediatric behavioral health patient presenting to the ED.

Purpose We performed this analysis to evaluate the efficacy and safety of intravenous levetiracetam (IV LEV) in patients with status epilepticus. Method Studies were searched in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for available randomized controlled trials(RCTs) comparing the efficacy and/or safety of IV LEV with other antiepileptic drugs (AEDs). Meta-analysis was performed using the random-effects model to calculate risk ratio with the RevMan 5.3 software. Results Six RCTs with a total of 543 patients were included. There was no significant differences in clinical seizure cessation and hospital mortality, either between IV LEV and IV phenytoin (PHT) or between IV LEV and IV valproate (VPA). Compared with IV PHT, IV LEV had a lower risk of poor neurological outcome. For IV LEV compared with IV lorazepam (LOR), no significant difference in efficacy was found, but IV LEV patients had significantly lower need for ventilatory assistance. Adding IV LEV to clonazepam (CNP), compared with adding placebo showed no significant differences in seizure cessation at 15 min. Conclusions Our results suggested that IV LEV was comparable to IV PHT,VPA, or LOR in efficacy, and IV LEV as add-on therapy of CNP had no superiority in seizure cessation than CNP plus placebo. IV LEV may have a better tolerability than other AEDs do. More RCTs are needed to validate the role of IV LEV in status epilepticus.

Purpose The primary objective was to evaluate the impact of an analgosedation protocol in a cardiac intensive care unit (CICU) on daily doses and costs of analgesic, sedative, and antipsychotic medications. Methods We conducted a single-center quasi-experimental study in 363 mechanically ventilated patients admitted to our CICU from March 1, 2011, to April 13, 2013. On March 1, 2012, an analgosedation protocol was implemented. Patients in the pre-implementation group were managed at the cardiologist’s discretion, which consisted of a continuous sedative-hypnotic approach and opioids as needed. Patients in the implementation group were managed using this protocol. Results The mean ± S.D. per-patient doses (mg/day) of propofol, lorazepam, and clonazepam decreased with the use of an analgosedation protocol (propofol 132,265.7 ± 12,951 versus 87,980.5 ± 10,564 [p = 0.03]; lorazepam 10.5 ± 7.3 versus 3.3 ± 4.0 [p < 0.001]; clonazepam 9.9 ± 8.3 versus 1.1 ± 0.5 [p = 0.03]). The mean daily cost of propofol and lorazepam also significantly decreased (33.5% reduction in propofol cost [p = 0.03]; 69.0% reduction in lorazepam cost [p < 0.001]). The per-patient dose and cost of fentanyl (mcg/day) declined with analgosedation protocol use (fentanyl 2,274.2 ± 2317.4 versus 1,026.7 ± 981.4 [p < 0.001]; 54.8% decrease in fentanyl cost [p < 0.001]). Conclusion The implementation of an analgosedation protocol significantly decreased both the use and cost of propofol, lorazepam, and fentanyl. Further investigation of the clinical impact and cost-effectiveness of a critical care consultation service with implementation of an analgosedation protocol is warranted in the CICU.

An 18 year-old woman presented to an outside hospital with seizure activity after a massive ingestion of lamotrigine, bupropion, trazodone, buspirone, and possibly isoretinoin. Her initial vital signs were remarkable for tachycardia (120 bpm). She was intubated for airway protection. For treatment of status epilepticus, she received a total of 12 mg of IV lorazepam along with a lorazepam infusion titrated to 15 mg/hr, a propofol infusion of unknown dosing, and phenobarbital 650 mg. She was transferred to a receiving hospital. Her initial ECG at the receiving hospital showed a QRS of 117 ms which narrowed with 50 mEq of sodium bicarbonate after approximately 6 hours. She required norepinephrine intermittently for blood pressure support for approximately 2 days. The patient had no dysrhythmias. EEG showed no epileptiform activity from approximately 11 hours-32 hours post ingestion. At the receiving hospital, her serum lamotrigine concentration was 109 mcg/mL (reference 3.0-14.0 mcg/mL) 7 hours after ingestion. Her bupropion concentration was 92 ng/mL (reference 50-100 ng/mL). She was extubated on hospital day 5 and discharged to a psychiatric facility on hospital day 13.

Objective: To test the compatibility of intravenous (IV) lactated Ringer’s injection (LR) with 94 injectable (IV) drugs during simulated Y-site administration. Methods: Ninety-four IV drugs were investigated for compatibility with LR (Baxter). Each sample was prepared in duplicate and performed at room temperature. Two observers performed visual evaluation independently immediately upon mixing and then 15 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after admixture. Another observer performed a particle counting test on 1 of the 2 duplicates of each admixture that did not immediately show incompatibility and then after 4 hours by a light obscuration particle count test. Results: Of the 94 tested drugs, 86 were found to be compatible with LR. A total of 8 drugs were found to be physically incompatible. Of these incompatible drugs, 7 were directly identified visually and 1 was confirmed by the light obscuration particle count test. Conclusion: Lactated Ringer’s injection was physically compatible for 4 hours with 86 tested drugs during simulated Y-site administration. Eight drugs, ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol, were found to be incompatible and should not be administered with LR.

Background Vilazodone was approved by the U.S. Food and Drug Administration in 2011 as a treatment for major depression disorder. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A agonist used in the treatment of depression in adults. Vilazodone increases the availability and activity of serotonin and its neural pathways. Vilazodone blocks the serotonin reuptake pump and desensitizes serotonin receptors (especially 5HT1A autoreceptors), therefore increasing serotonergic neurotransmission. Its partial agonist actions at presynaptic somatodendritic 5HT1A autoreceptors theoretically enhance serotonergic activity, contributing to antidepressant actions. There are limited reports exploring its effects in children after unintentional ingestion. Typical adult dosing is titrated from an initial dose of 10 mg up to a maximum dose of 40 mg daily. Serotonin syndrome classically manifests with restlessness, hyperthermia, tachycardia, mydriasis, and increased tone, and is typically treated with benzodiazepines, cyproheptadine, and supportive care. Dexmedetomidine has also been used in case reports to treat serotonin syndrome. Case Report We report the case of a toddler with a laboratory-confirmed vilazodone overdose exhibiting symptoms of serotonin syndrome, including restlessness, hyperthermia, mydriasis, dystonia, agitation, seizure-like activity, roving eye movement, tachycardia, and elevated creatine kinase. The patient was admitted and initially treated with supportive care and lorazepam per recommendations of the poison center, which did not recommend cyproheptadine use. On decompensation with suspected serotonin syndrome, the patient was treated with dexmedetomidine. In addition, urine toxicology screening (Amphetamines II assay; Roche, Indianapolis, IN) was positive for amphetamines; however, confirmatory testing (gas chromatography-mass spectrometry) was negative. The patient improved and was discharged after returning to her baseline status at 74 h post ingestion. Importantly, this patient did not require intubation and mechanical intubation, in spite of the large amount of vilazodone ingested. Why Should an Emergency Physician Be Aware of This? With increasing prescription of vilazodone, emergency physicians should have a high level of suspicion so as not to miss this toxidrome. The possibility of false-positive amphetamine screenings when an overdose of vilazodone is suspected should be investigated. Finally, systematic evaluation of the use of dexmedetomidine as treatment for serotonin syndrome or vilazodone ingestion should be done to confirm efficacy.

Background Scrub typhus is prevalent in the Tsutsugamushi belt and may manifest with meningoencephalitis and seizures. We report a patient with scrub typhus who had non-convulsive status epilepticus (NCSE). Methods A 50-y-old female with fever and altered sensorium for 5 d was diagnosed as scrub typhus based on serum IgM ELISA. She was on mechanical ventilation and received doxycycline and ceftriaxone, but did not improve until the third day of admission. Results An EEG revealed >2.5 Hz generalised epileptiform discharges, which were suppressed by intravenous lorazepam suggesting NCSE. Following valproate and levetiracetam, she became conscious and had a full recovery. Conclusion A scrub typhus patient recovers even after prolonged NCSE.

Febrile infection-related epilepsy syndrome (FIRES) is an acute-onset epilepsy syndrome usually refractory to conventional antiepileptics and immunomodulation. Here, we report an adolescent male child whose seizures were refractory to multiple anticonvulsants, high-dose phenobarbitone, and ketogenic diet. He subsequently responded to coma induction with midazolam, though with seizure recurrences following multiple attempts at weaning of midazolam over the next 2½ months. Due to continuing prolonged intensive care stay, we substituted intravenous midazolam for equivalent dose of enteral lorazepam with good seizure control.

Funding Acknowledgements Type of funding sources: None. Background the role of Cardiovascular Magnetic Resonance has gained the more and more importance in the field of cardiovascular disease. Claustrophobia remains a frequent cause of failure to complete a CMR. It is estimated that 2 million scans worldwide cannot be performed annually either due to premature termination or refusal of the patient to be scanned due to claustrophobia. In this setting, medical hypnosis may prove useful to overcome this main limitation. Methods we propose an observational study of consecutive patients referred to CMR and known for severe claustrophobia. Patients were proposed to undergo CMR examination with the help of medical hypnosis according to Milton H. Erickson’s method or with administration of mild sedation (lorazepam 2.5 mg). Results 20 severe claustrophobic patients were considered in the study. 1 patient was excluded due to psychiatric condition, 1 patient undergo to general anesthesia, 5 patients refused the examination. Among the 13 patients, 10 underwent medical hypnosis while 3 patients accepted to undergo to CMR examination with the administration of lorazepam 2.5 mg. All patients treated with medical hypnosis were able to complete the examination with a great tolerance and no sign of stress or anxiety were reported. CMR protocol was performed according to clinical request and was not different form non-claustrophobic patients. None of the patients treated with lorazepam 2.5mg was able to complete the exam. Conclusion we prove medical hypnosis to be safe and effective in controlling patients’ anxiety, allowing optimal diagnostic imaging quality without the need to adapt the examination. Further studies in larger populations are needed to confirm our results.

Benzodiazepines are one of the most commonly used medications in the field of anesthesia. They offer excellent anxiolytic and amnestic properties ideal for the perioperative period when patient anxiety is understandably heightened. Remimazolam has presented a favorable alternative to some of the common intravenous anesthetic agents used given its fast onset of action, high safety profile, and reasonably short duration of action. The drugs within the four classes of benzodiazepines, 2-keto-benzodiazepines, 3-hydroxy-benzodiazepines, triazolo-benzodiazepines, and 7-nitro-benzodiazepines provide varying degrees of anxiolysis, sedation, and amnesia. This is provided by the benzodiazepine molecule binding and causing a conformational change to the chloride ion channel to cause hyperpolarization and thus inhibition of the central nervous system. Each type of benzodiazepine has a preferred role within the realm of medicine. For instance, diazepam is used for the treatment of seizures and anxiety. Midazolam’s anxiolytic and anterograde amnestic properties are taking advantage of during the perioperative period. Lorazepam is beneficial for anxiety and status epilepticus. Remimazolam, currently in phase II and III clinical trials, has demonstrated a very short during of action and low context-sensitive half-time, allowing for its rapid removal even during a prolonged infusion. Much of its properties may be credited to being a soft drug, meaning it is a metabolically active drug that is rapidly inactivated in the body. This provides anesthesiologists and other practitioners administering it with a more predictable sedative. These properties have the potential to push it towards becoming the drug of choice for premedication during the perioperative period and sedation in the ICU. Furthermore, remimazolam does not seem to rely on any specific organ to be metabolized. The drug’s ester moiety makes it a substrate for non-specific tissue esterase enzymes, meaning its metabolism and elimination are not impaired in patients with hepatic and/or renal disease. Its addictive potential closely resembles that of its parent compound, midazolam. Reports of its adverse reactions include headache and somnolence after an involuntary movement during infusion. Benzodiazepines are a great adjunct to anesthetic care. Remimazolam’s safety profile, pharmacokinetics, pharmacodynamics, and potential practical use make it quite favorable in this regard. It has the potential to equip anesthesiologists and other medical practitioners with a more predictable medication that has a good safety profile. However, further large clinical trials will provide us with a better understanding of the advantages and disadvantages of remimazolam.

Dissociative stupor is a common psychiatric disease lacking an established standard treatment. The lack of therapeutic options may be due to the spontaneous and quick complete remission of most patients. However, since some patients experience multiple relapses and prolonged stupor, investigating potential prevention and treatment options is critical. We reported the case of a 61-year-old Japanese woman who presented with intermittent dissociative stupor for several months. Despite her prolonged symptoms, the administration of lorazepam, escitalopram, and aripiprazole, which selectively enhance GABAergic and serotoninergic activity, improved her stupor and prevented relapse. These findings may help with the treatment of persistent dissociative stupor.

Perampanel is an antiepileptic drug that blocks amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. To date, little is known about the management of perampanel intoxication. We report a case of “zombielike” behavior secondary to intentional perampanel overdose. An 18-year-old male with idiopathic generalized epilepsy and focal features presented with aggressive and “zombielike” behavior after suicide attempt via intentional perampanel overdose, amounting to approximately 128 mg. Clinical symptoms gradually improved with continuous dexmedetomidine infusion and intravenous lorazepam boluses five days after being admitted to the intensive care unit. While perampanel intoxication has been reported to be associated with central nervous system-related adverse effects, awareness of this association is necessary to prompt more appropriate management tailored to perampanel toxicity.