Intravenous Lorazepam Research Articles

Exploring the Association Between Intravenous Lorazepam and Mortality Among Older Hospitalized Patients With and Without Cognitive Impairment

Exploring the Association Between Intravenous Lorazepam and Mortality Among Older Hospitalized Patients With and Without Cognitive Impairment

Use Of Ketamine In Refractory Status Epilepticus With Hemodynamic Instability

The use of benzodiazepines, such as midazolam, as a last-resort treatment for refractory status epilepticus is widely practiced, particularly in patients who are hemodynamically stable. However, as the dosage of this antiepileptic agent is increased, it potentiates γ-aminobutyric acid (GABA) activity, which can lead to hypotension and subsequently necessitate the administration of vasopressor agents, especially in cases involving hemodynamic instability, as illustrated by this case where a young man who arrived at the emergency department with complaints of epileptic seizures and was already on regular anti-epileptic medications. During a seizure episode in the department, he was administered intravenous Lorazepam according to standard protocol to stop the seizure, and then placed on an IV infusion of Midazolam. However, his hemodynamics became unstable due to the side effects of the benzodiazepines administered. To address this instability, the decision was made to initiate an infusion of Ketamine along with a low dose of Midazolam. This combination successfully terminated the epileptic activity and stabilized his hemodynamics. In these instances, either concurrent or standalone administration of N-methyl-D-aspartate (NMDA) receptor antagonists might prove beneficial for managing refractory status epilepticus. For example, ketamine infusion can inhibit the reuptake of catecholamines into the systemic circulation, thereby aiding in the maintenance of blood pressure in hemodynamically unstable patients. The initial application of a combined third-line therapy, which involves blocking NMDA receptors while simultaneously enhancing GABAergic activity, appears promising for the management of refractory status epilepticus

Analysis of Inflammatory Markers and Electroencephalogram Findings in Pediatric Patients with COVID-19: A Single-Center Study in Korea

Purpose: The Omicron variant wave spread rapidly from February 2022 in South Korea following the initial management of the coronavirus disease 2019 (COVID-19) outbreak. This study examined electroencephalogram (EEG) findings and serological inflammatory markers in pediatric patients with COVID-19 (Omicron variant).Methods: We retrospectively reviewed the medical records of 41 patients who presented at Gyeongsang National University Changwon Hospital between March and May 2022 and were diagnosed with COVID-19. All serological tests were performed within 24 hours of fever or seizure onset. Results: The median patient age was 3.6 years (range, 0.08 to 14.00), and the average hospital stay was 3.7 days (range, 1.0 to 7.0). Interleukin-6 (IL-6) levels were elevated above the normal range in all patients (median, 43.18 pg/mL; range, 7.0 to 190.0) and were higher among those who experienced seizures. Of the 41 total patients, 17 (41.5%; mean age, 5.4 years) visited the clinic for seizure. Three patients experienced prolonged seizures (lasting longer than 30 minutes) and received intravenous lorazepam, while eight presented with complex febrile seizures. Nine patients underwent EEG, of whom five exhibited abnormal initial findings. Linear regression demonstrated correlations between prolonged seizure duration and both serum IL-6 level and blood lymphocyte count.Conclusion: Numerous serological markers associated with the immune cascade were found to be elevated in children with COVID-19. Nevertheless, febrile seizures represent a relatively common neurological presentation among pediatric patients infected with Omicron variants. Consequently, COVID-19 infection exhibits both familiar and distinct characteristics regarding the mechanisms inducing seizures and fever in children.

Lorazepam Therapy for Canine Status Epilepticus

Canine status epilepticus is naturally occurring epilepsy in dogs, a life-threatening emergency needs to be treated immediately. Prolonged episodes are known to cause damage in multiple areas of brain. For instantly stopping the seizure activity benzodiazepines are chosen as first-line therapy in dogs. The effectiveness of intravenous lorazepam has not yet been well established in veterinary patients. The purpose of the study was to find the seizure free interval in status epilepticus dogs when compared to diazepam. Twelve actively seizing dogs were randomly divided into two groups and administered with intravenous lorazepam @ 0.2mg.kg and diazepam @ 0.5 mg/kg. The parameters like physical parameters, seizure free period, level of consciousness and motor activity were analysed in both the groups. On evaluating the physical parameters there was a significant post ictal temperature when compare to control animals. There was a significant increase in seizure free period when compare to diazepam group. Lorazepam didn’t alter the level of consciousness and motor activity in treated dogs. To conclude, lorazepam significantly increased the seizure free period when compared to diazepam in status epilepticus dogs.

Bihemispheric Seizure Without Generalization.

A 70-year-old male without prior psychiatric history presented with recurrent episodes (<60seconds each, every 5-10minutes) of left hemibody and right lower extremity jerking movements concerning for seizure with preserved awareness (Video). Examination showed left hemiparesis (leg > arm) in addition to right lower extremity weakness. Computed tomography showed a right parafalcine acute subdural hematoma (SDH). Clinical events did not recur after intravenous lorazepam (4mg) and levetiracetam load (3500mg), and his weakness improved. He was continued on levetiracetam and has since remained seizure free for 16months. A 60-minute awake/sleep electroencephalogram (EEG) obtained 12hours after administration of antiseizure medications showed low amplitude theta slowing (posterior predominant) in the range of 5-7Hz. There was no apparent epileptiform activity or other abnormalities during the awake and sleep recording or photic stimulation. Focal seizures originate from pathologic disruption of neuronal activity within an isolated brain region, almost exclusively from a single hemisphere. Focal seizures may generalize bilaterally with associated impaired awareness. This is the first visual report demonstrating focal, bihemispheric clinical seizures, without generalization or impaired awareness. Rarely patients with generalized motor involvement from seizures have had retained consciousness and memory. The parafalcine SDH likely promoted epileptogenicity of the bilateral hemispheres. Acute and chronic SDH commonly present with seizures. Although there were no supportive electrographic findings, parasagittal epileptogenic lesions may be difficult for both clinical and electrographic localization. Post-event paresis with clinical improvement in the hours after event cessation supports clinical seizure.

Acute Abortive Therapies for Seizure Clusters in Long-Term Care.

To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters. Narrative review. People with seizures in long-term care, including group residences. PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care. Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers or care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus. Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.

Intravenous Midazolam for Anxiolysis in MRI

ObjectiveThe purpose of this project was to understand the effect of administration of intravenous (IV) midazolam on duration of procedure times and anxiety levels experienced by adult outpatients having magnetic resonance imaging (MRI). Secondarily, this project sought to compare duration of procedure times and anxiety scores of adult outpatients receiving intravenous lorazepam or intravenous diazepam for MRI-associated anxiety. MethodsAll adult outpatients scheduled for MRI over the course of 12 months were assessed for self-reported anxiety and offered anxiolytic administration. In this group, 116 adult outpatients received a benzodiazepine, 50 patients received midazolam, 35 received lorazepam, and 31 received diazepam. Patients rated their anxiety as zero (none), 1 (mild), 2 (moderate), or 3 (severe). Nurses rated the level of patient sedation using the Richmond Agitation Sedation Scale (RASS), a 10-point scale rating patients from combative (+4) to unarousable (−5). These scores were recorded upon arrival to MRI, following medication administration at the start of the MRI, and at the completion of the MRI. Duration of procedure times were measured as the time from anxiolytic administration to the time of MRI completion. ResultsUpon arrival to MRI, the average patient-reported anxiety levels for midazolam, lorazepam, and diazepam were 2.3 ± 0.6, 2.3 ± 0.7, and 2.3 ± 0.6; RASS scores were 0.8 ± 0.5, 0.7 ± 0.7, and 1 ± 0.7. Following benzodiazepine administration at the beginning of the MRI, the average patient-reported anxiety levels for midazolam, lorazepam, and diazepam were 1.4 ± 0.9, 1.5 ± 0.8, and 0.9 ± 0.6; RASS scores were −0.04 ± 0.7, 0.02 ± 0.8, and 0.1 ± 0.6. Patient-reported anxiety levels for midazolam, lorazepam, and diazepam following the MRI were 0.2 ± 0.6, 0.6 ± 0.7, and 0.03 ± 0.1; RASS scores were −0.1 ± 0.4, −0.2 ± 0.6, and −0.2 ± 0.4.Duration of procedure times for midazolam, lorazepam, and diazepam were 42.5 ± 28.9, 55.6 ± 19.8, and 49 ± 19 minutes. Vital signs decreased slightly after administration of all 3 drugs; however, not one adverse or over sedation event occurred. ConclusionIntravenous midazolam appears to be a safe and effective anxiolytic for adult outpatients in MRI. Patient anxiety scores and nursing assessed level of sedation scores were comparable to those taking IV lorazepam or IV diazepam. Duration of procedure times were also comparable to those receiving IV lorazepam or IV diazepam.

Bronchoscopy-Associated Cerebral Arterial Air Embolism Presenting with Acute Ischemic Stroke and Status Epilepticus (P12-5.013)

<h3>Objective:</h3> To describe a rare cause of iatrogenic air embolism, causing acute ischemic stroke complicated by status epilepticus. <h3>Background:</h3> The incidence of vascular air embolism during bronchoscopy is estimated to be 2.65 per 100,000 hospitalizations, with 30% of these involving endovascular procedures. A recent case report and literature review identified only 5 cases of cerebral arterial air embolism following bronchoscopy. A small minority of acute ischemic strokes present with seizures, even fewer with status epilepticus. <h3>Design/Methods:</h3> NA <h3>Results:</h3> An 81-year-old woman with past medical history significant for hypertension and CREST syndrome presented to an outside hospital for elective bronchoscopy with biopsy of pulmonary nodules. Post-procedurally, she was noted to have new left-sided hemiparesis. Non-contrast CT head demonstrated a small arterial air embolism in the right frontal lobe. She was brought to the Emergency Department and sustained a bilateral tonic-clonic seizure lasting 30 seconds, resolving with intravenous lorazepam. Prior to returning to her mental status baseline, she had recurrent seizure activity, refractory to benzodiazepines, requiring an intravenous phenytoin load, intubation for airway protection, and sedation with propofol. She was transferred to our institution’s neurocritical care unit where repeat CT head exhibited sulcal effacement and she was treated with hypertonic saline for cerebral edema. Continuous EEG did not reveal any epileptiform patterns but the patient was started on levetiracetam for her acute symptomatic seizures. MRI later revealed small infarcts in multiple vascular territories. She was ultimately extubated and at the time of discharge to short-term rehabilitation, her only deficit was 4+/5 strength throughout the left arm, which normalized by 1-month follow-up. She was eventually weaned off of levetiracetam in the outpatient setting. <h3>Conclusions:</h3> This case adds to our understanding of this rare procedural complication and, given the complications of her stroke by status epilepticus and cerebral edema, highlights the potential severity of these injuries. <b>Disclosure:</b> Dr. Sutherland has received personal compensation in the range of $0-$499 for serving as a Consultant for McGraw-Hill. Dr. Gummerson has nothing to disclose. Dr. Sharma has nothing to disclose.

Efficacy and Safety Comparison Between Lorazepam and Diazepam in Treating Convulsive Status Epilepticus in Children: An Evidence-Based Case Report

Introduction: Indonesia still recommends diazepam for epilepsy, but the International League Against Epilepsy increasingly favours lorazepam. Some reports indicate diazepam being less effective and causing side effects. This report presents a difficult-to-treat convulsive status epilepticus (CSE) case in a 10-month infant who received diazepam, questioning if intravenous/rectal lorazepam is a better initial therapy than diazepam for hospitalized children with CSE. Methods: Following the patient-intervention-comparison-outcome (PICO) formula, we searched for evidence in four journal databases (Pubmed, Proquest, EBSCOHost, and Cochrane). Studies meeting inclusion and exclusion criteria were appraised. Results: Through three systematic reviews and meta-analyses, our clinical query was addressed. One study revealed that rectal lorazepam was more effective in stopping seizures than rectal diazepam (RR 2.86). Meanwhile, two studies found that intravenous lorazepam exhibited similar efficacy in seizure cessation compared to intravenous diazepam (RR 1.04 and OR 1.03, respectively). Both drugs showed no significant difference in the time required to stop seizures or the necessity for additional doses or adjunctive medications to achieve such cessation, nor in the likelihood of refractory seizure within 24 hours. Two studies indicated that intravenous lorazepam had a reduced risk of respiratory depression (RR 0.71 and OR 0.62, respectively). Regardless of the administration route, lorazepam was linked to a lower probability of ICU admission (RR 0.15) than diazepam. Conclusion: Intravenous lorazepam and diazepam are equally effective for treating CSE, but rectal lorazepam is considered better at stopping seizures and preventing their recurrence compared to diazepam. Furthermore, lorazepam is deemed safer, especially when given intravenously.

Efficacy of a pre-specified timeline-based treatment protocol in children with acute repetitive seizures or seizure clusters.

Acute repetitive seizures (ARSs) are one of the few commonly encountered neurological emergencies in children. There is a need for an appropriate timeline-based treatment protocol, which will be shown to be safe and efficacious in a clinical study. This was a retrospective chart review to determine the efficacy of a pre-specified treatment protocol for the management of ARSs in children aged 1-18 years. The treatment protocol was specifically applied in children with a diagnosis of epilepsy and not critically ill, who met the criteria for ARSs, with the exemption of new onset of ARSs. The first tier of treatment protocol focused on intravenous lorazepam, optimization of dose of existing anti-seizure medications (ASMs), and control of triggers like acute febrile illness, while second-tier focused on adding one or two additional ASMs, commonly used in cases with seizure clusters or status epilepticus. We included the first 100 consecutive patients (7.6 ± 3.2 years, 63% boys). Our treatment protocol was successful in 89 patients (58 and 31 required first-tier and second-tier treatment). The absence of pre-existing drug-resistant epilepsy and the presence of acute febrile illness as a triggering factor (P = 0.02 and 0.03) were associated with the success of the first tier of the treatment protocol. Excessive sedation (n = 29), incoordination (n = 14), transient gait instability (n = 11), and excessive irritability (n = 5) were the most common adverse effects observed during the initial 1 week. This pre-specified treatment protocol is safe and efficacious in controlling ARSs in cases with established epilepsy who are not critically sick. External validation from other parts of the world/centers and a more diverse epilepsy population are required before generalizing the protocol into clinical practice.

Seizure Occurring During Baclofen Monotherapy for Phenibut Withdrawal.

Phenibut is a widely available gamma-aminobutyric acid B receptor agonist. When taken chronically, phenibut causes dependence and subsequent withdrawal if stopped. Baclofen, a gamma-aminobutyric acid B receptor agonist structurally related to phenibut, has been used to manage phenibut withdrawal (PW), although baclofen doses for PW are not well defined and may exceed Food and Drug Administration-approved doses. Little data described outcomes from baclofen use. This case details a patient who experienced a seizure while on baclofen 10 mg thrice daily as monotherapy for PW and highlights a potential risk of underdosing baclofen as monotherapy in the management of PW. A man in his early 30s with anxiety, depression, and substance use disorder presented to the emergency department by family for lethargy and confusion starting earlier that day. He had been using 25-30 g of phenibut daily for the past 6 months. On arrival, he was hypertensive, tachycardic, tachypneic, and lethargic. The patient received 1 mg of intravenous lorazepam and was admitted to the hospital for presumed PW. His symptoms improved overnight, and he was discharged on 10 mg of baclofen thrice daily. He returned 28 hours later after having a seizure and required intensive care admission in addition to multimodal drug therapy. Phenibut use is rising, and treatment options for PW, such as baclofen, warrant additional study. Potential risks of underdosing baclofen if used as monotherapy in PW may include seizures as withdrawal progresses. Baclofen's role in therapy may be more appropriate as an adjunct than a cornerstone of therapy. Treatment done in consultation with providers experienced in managing withdrawal such as a toxicologist may help reduce this risk.

Status Epilepticus in Older Adults: Diagnostic and Treatment Considerations.

Status epilepticus (SE) is one of the leading life-threatening neurological emergencies in the elderly population, with significant morbidity and mortality. SE presents unique diagnostic and therapeutic challenges in the older population given overlap with other causes of encephalopathy, complicating diagnosis, and the common occurrence of multiple comorbid diseases complicates treatment. First-line therapy involves the use of rescue benzodiazepine in the form of intravenous lorazepam or diazepam, intramuscular or intranasal midazolam and rectal diazepam. Second-line therapies include parenteral levetiracetam, fosphenytoin, valproate and lacosamide, and underlying comorbidities guide the choice of appropriate medication, while third-line therapies may be influenced by the patient's code status as well as the cause and type of SE. The standard of care for convulsive SE is treatment with an intravenous anesthetic, including midazolam, propofol, ketamine and pentobarbital. There is currently limited evidence guiding appropriate therapy in patients failing third-line therapies. Adjunctive strategies may include immunomodulatory treatments, non-pharmacological strategies such as ketogenic diet, neuromodulation therapies and surgery in select cases. Surrogate decision makers should be updated early and often in refractory episodes of SE and informed of the high morbidity and mortality associated with the disease as well as the high probability of subsequent epilepsy among survivors.

The efficacy and safety of intravenous lorazepam therapy for status epilepticus and repetitive seizures in children with epilepsy

The efficacy and safety of intravenous lorazepam therapy for status epilepticus and repetitive seizures in children with epilepsy

Evaluation of intravenous lorazepam dosing strategies and the incidence of refractory status epilepticus

IntroductionStatus epilepticus (SE) is a neurological emergency associated with high mortality if not identified and treated promptly. For the emergent treatment of SE, the recommended intravenous (IV) lorazepam dose is 0.1 mg/kg/dose, up to a maximum of 4 mg. It has been shown that lorazepam is commonly under dosed in SE, but there is conflicting data on whether this has a negative impact on patient outcomes. This study assessed any dose less than 4 mg to help identify the effects of under dosing lorazepam in SE. MethodsThis was a retrospective cohort study of patients admitted to a quaternary health system between October 1, 2017 and September 30, 2019 that experienced SE and were initially treated with IV lorazepam. Patients were divided into two cohorts, less than 4 mg or 4 mg, based on the initial one-time dose of lorazepam received. The primary outcome was the proportion of patients that progressed to refractory status epilepticus (RSE) that received an initial IV lorazepam dose of 4 mg compared to less than 4 mg for the treatment of SE. Secondary outcomes evaluated include length of stay, mortality, time in SE, number of seizures, cumulative lorazepam dose prior to urgent therapy, number of lorazepam doses prior to urgent therapy, time to urgent therapy, appropriately dosed urgent therapy, and number of antiepileptic drugs given in SE. ResultsOne hundred twenty patients were included in this study (107 patients received less than 4 mg and 13 patients received 4 mg). All patients included in the study were greater than 40 kg. The primary outcome of progression to RSE was observed in a significantly greater proportion of patients in the less than 4 mg group compared to the 4 mg group (93 [87%] vs. 8 [62%], p = 0.03). There was no difference in hospital or intensive care unit length of stay. However, there was an increased rate of in-hospital mortality in patients who received 4 mg compared to less than 4 mg (5 [39%] vs. 12[11%], p = 0.02). DiscussionThe majority of patients in the study received less than the recommended dose of IV lorazepam for SE. Patients who received less than 4 mg experienced an increased progression to RSE, which supports current guideline recommended dosing. While there was an increased rate of mortality in patients who received 4 mg compared to less than 4 mg, time in SE was prolonged in the patient population and severity of illness was only available for a limited number of patients included.

Young patient with thunderclap headache, seizure activity, and fixed eye deviation.

A 39-year-old female with a history of iron deficiency anemia presented to the emergency department (ED) with a 3-hour history of severe headache followed by acute-onset projectile non-bilious, non-bloody vomiting, acute mental status change, and seizure-like activity. The onset of the headache was spontaneous and described as the worst headache of her life. Vomiting and seizure-like activity began several hours after the onset of headache, and emergency medical services (EMS) were called at that time. The patient was found to be unresponsive by EMS. Upon arrival to the ED, the physical examination was notable for fixed left eye deviation, intermittent withdrawal from noxious stimuli, and spells of sustained clonus in the lower extremities greater on the left than the right. The patient was given 2-mg intravenous lorazepam with minimal improvement in the tonic–clonic activity. The patient was hemodynamically stable and had an oxygen saturation of 98% on room air. Initial laboratory test results were significant for anemia (hemoglobin = 5.2 g/dL, hematocrit = 21%) and elevated platelets (426.5). Computed tomography (CT) of the head, CT angiogram of the head and neck, CT venogram of the head, and urgent neurology consult were obtained immediately after arrival to the ED. The patient continued to decline after CT and was intubated for airway protection. Imaging was suggestive of acute venous sinus thrombosis extending from the superior sagittal sinus to the right cranial jugular vein with no definite intracranial hemorrhage (Figures 1 and 2) and bilateral segmental and subsegmental pulmonary emboli (Figure 3). This case describes a typical presentation of cerebral venous sinus thrombosis (CVST). CVSTs are more commonly seen in women aged 30–50 years.1 Commonly, sinus thrombosis can lead to subarachnoid hemorrhage with a subsequent “thunderclap” headache that can lead to neurological symptoms.3 Neurology evaluated the patient in the ED, and the patient was taken to the operating room for an aspiration thrombectomy and started on a continuous heparin infusion. The patient had gradual improvement of symptoms after 1 week of inpatient care in the neurology intensive care unit. At discharge, she was started on indefinite anticoagulation and levetiracetam for seizure prophylaxis. Further workup showed no evidence of hypercoagulability, no recent trauma, and no oral contraceptive use. CVST is defined as occlusion of dural sinuses leading to decreased venous flow, an increase in intracranial pressure, decreased cerebral perfusion pressures, and dilation of the cerebral veins. Continued hypoperfusion can result in ischemic tissue damage, resulting in acute neurologic symptoms such as seizures, headaches, altered mental status, and increased intracranial pressure. Without treatment, the thrombus can damage vessel walls, increasing the chances of vessel rupture, leading to subarachnoid hemorrhages and decreased cerebrospinal fluid outflow.1 Common risk factors for CVSTs include recent trauma, malignancy, thrombophilia, infection, obesity, oral contraceptive use, and increased estrogen states such as pregnancy.2

Optimal Management of Status Epilepticus in Children in the Emergency Setting: A Review of Recent Advances.

Convulsive status epilepticus (CSE) is the most common neurological emergency in children and the second most common neurological emergency in adults. Mortality is low, but morbidity, including neuro-disability, learning difficulties, and a de-novo epilepsy, may be as high as 22%. The longer the duration of CSE, the more difficult it is to terminate, and the greater the risk of morbidity. Convulsive status epilepticus is usually managed using specific national or local algorithms. The first-line treatment is administered when a tonic-clonic or focal motor clonic seizure has lasted five minutes (impending or premonitory CSE). Second-line treatment is administered when the CSE has persisted after two doses of a first-line treatment (established CSE). Randomised clinical trial (RCT) evidence supports the use of benzodiazepines as a first-line treatment of which the most common are buccal or intra-nasal midazolam, rectal diazepam and intravenous lorazepam. Alternative drugs, for which there are considerably less RCT data, are intra-muscular midazolam and intravenous clonazepam. Up until 2019, phenobarbital and phenytoin (or fosphenytoin) were the preferred second-line treatments but with no good supporting RCT evidence. Robust RCT data are now available which has provided important information on second-line treatments, specifically phenytoin (or fosphenytoin), levetiracetam and sodium valproate. Lacosamide is an alternative second-line treatment but with no supporting RCT evidence. Current evidence indicates that first, buccal or intranasal midazolam or intravenous lorazepam are the most effective and the most patient and carer-friendly first-line anti-seizure medications to treat impending or premonitory CSE and second, that there is no difference in efficacy between levetiracetam, phenytoin (or fosphenytoin) or sodium valproate for the treatment of established CSE. Pragmatically, levetiracetam or sodium valproate are preferred to phenytoin (or fosphenytoin) because of their ease of administration and lack of serious adverse side-effects, including potentially fatal cardiac arrhythmias. Sodium valproate must be used with caution in children aged three and under because of the rare risk of hepatotoxicity and particularly if there is an underlying mitochondrial disorder.

The Midazolam RAMPART Study Medical Records Project: A Unique Use of Real-World Data in a Complex Collaborative Partnership to Support a New Drug Application

IntroductionThis project aimed to retrospectively obtain, review, and extract key safety data from medical records of participants enrolled in RAMPART, the NIH-supported Rapid Anticonvulsant Medication Prior to ARrival Trial of intramuscular midazolam versus intravenous lorazepam for pre-hospital treatment of status epilepticus, to support a US new drug application (NDA) for intramuscular midazolam.MethodsA collaborative partnership was established between the NDA sponsor, the RAMPART trial lead academic institution, US government agencies, and contract research organizations to retrieve, review, and extract relevant safety data from the medical records of RAMPART participants and summarize those data to include in an NDA submitted to the US Food and Drug Administration (FDA).ResultsKey data in the medical records of 890 RAMPART trial participants (1020 enrollments, including 130 repeat enrollments) were reviewed and extracted into a project database. Safety events occurred in 771 (86.6%) participants, and included additional information not collected in the RAMPART trial. This database also enabled subgroup analyses based on medical history and prior/concurrent medications, building upon previous analyses according to age, sex, and race. No previously unrecognized safety patterns were identified, and no association was observed between efficacy and medical history or medication usage.ConclusionsThe use of unstructured real-world retrospective medical record data can effectively support an NDA submission in place of conducting another interventional clinical trial. This retrospective medical records review and extraction of additional safety data contributed to the FDA approval of intramuscular midazolam for the pre-hospital treatment of status epilepticus in 2018.ClinicalTrials.govNCT00809146.

Benzodiazepine Withdrawal Catatonia: A Diagnostic Intervention.

In this report, the authors present the case of a man with a history of polysubstance use, who presented with benzodiazepine withdrawal symptoms with predominant catatonic features but responded well to intravenous lorazepam.

Termination of seizures in the paediatric age group, best benzodiazepine and route of administration: A network meta-analysis.

This network meta-analysis aims to compare various benzodiazepines and their route of administration using the data published exclusively in randomized controlled trials (RCTs). Two thousand two hundred sixty-three children presenting with an episode of seizure to ER or to a paramedic where they were administered a benzodiazepine as the first-line treatment were included. All the outcomes were measured for their mean with 95% CI and rank probability. The primary outcome was the number of successful seizure cessation. Secondary outcomes were the time interval between drug administration and seizure cessation, the time interval between patient arrival and seizure cessation and the number of episodes of seizure recurrence after drug administration. For the number of successful cessations, intramuscular midazolam showed the highest mean and best rank probability with a value of .881 (.065) and 57.9%, respectively. For the time of cessation, both intravenous lorazepam (IVL) and intravenous diazepam showed a mean of 3.30 (1.30) with IVL having the highest rank probability of 32%. For total time for cessation, intranasal midazolam showed the best mean and rank probability with a value of 4.3 (1.1) and 55%, respectively. Buccal midazolam showed the lowest mean with a value of .106 (.084) for rate of recurrence. Although there was no significant difference between the treatments, but based on the rank probability, IVL shows more promising results for patients who already have an established intravenous line, and for patients presenting in the ER without an intravenous line, the first line of treatment should be INM as it shows the highest rank probability in total time with second-highest successful cessation rate.

Pre-hospital and emergency department treatment of convulsive status epilepticus in adults: an evidence synthesis.

Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting. To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting. We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo®, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020. Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively. Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness. The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data. Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting. This study is registered as PROSPERO CRD42020201953. This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.