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Intensive Care Medicine Jan 2024Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to... (Review)
Review
Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to improve outcomes, with the most severe cases frequently being managed in the intensive care unit (ICU). Diagnosis of convulsive SE can be made without electroencephalography (EEG), but EEG is required to reliably diagnose nonconvulsive SE. Rapidly narrowing down underlying causes for SE is crucial, as this may guide additional management steps. Causes may range from underlying epilepsy to acute brain injuries such as trauma, cardiac arrest, stroke, and infections. Initial management consists of rapid administration of benzodiazepines and one of the following non-sedating intravenous antiseizure medications (ASM): (fos-)phenytoin, levetiracetam, or valproate; other ASM are increasingly used, such as lacosamide or brivaracetam. SE that continues despite these medications is called refractory, and most commonly treated with continuous infusions of midazolam or propofol. Alternatives include further non-sedating ASM and non-pharmacologic approaches. SE that reemerges after weaning or continues despite management with propofol or midazolam is labeled super-refractory SE. At this step, management may include non-sedating or sedating compounds including ketamine and barbiturates. Continuous video EEG is necessary for the management of refractory and super-refractory SE, as these are almost always nonconvulsive. If possible, management of the underlying cause of seizures is crucial particularly for patients with autoimmune encephalitis. Short-term mortality ranges from 10 to 15% after SE and is primarily related to increasing age, underlying etiology, and medical comorbidities. Refractoriness of treatment is clearly related to outcome with mortality rising from 10% in responsive cases, to 25% in refractory, and nearly 40% in super-refractory SE.
Topics: Humans; Anticonvulsants; Midazolam; Propofol; Status Epilepticus; Intensive Care Units
PubMed: 38117319
DOI: 10.1007/s00134-023-07263-w -
Critical Care (London, England) Oct 2023Sepsis-associated encephalopathy is a severe neurologic syndrome characterized by a diffuse dysfunction of the brain caused by sepsis. This review provides a concise... (Review)
Review
Sepsis-associated encephalopathy is a severe neurologic syndrome characterized by a diffuse dysfunction of the brain caused by sepsis. This review provides a concise overview of diagnostic tools and management strategies for SAE at the acute phase and in the long term. Early recognition and diagnosis of SAE are crucial for effective management. Because neurologic evaluation can be confounded by several factors in the intensive care unit setting, a multimodal approach is warranted for diagnosis and management. Diagnostic tools commonly employed include clinical evaluation, metabolic tests, electroencephalography, and neuroimaging in selected cases. The usefulness of blood biomarkers of brain injury for diagnosis remains limited. Clinical evaluation involves assessing the patient's mental status, motor responses, brainstem reflexes, and presence of abnormal movements. Electroencephalography can rule out non-convulsive seizures and help detect several patterns of various severity such as generalized slowing, epileptiform discharges, and triphasic waves. In patients with acute encephalopathy, the diagnostic value of non-contrast computed tomography is limited. In septic patients with persistent encephalopathy, seizures, and/or focal signs, magnetic resonance imaging detects brain injury in more than 50% of cases, mainly cerebrovascular complications, and white matter changes. Timely identification and treatment of the underlying infection are paramount, along with effective control of systemic factors that may contribute to secondary brain injury. Upon admission to the ICU, maintaining appropriate levels of oxygenation, blood pressure, and metabolic balance is crucial. Throughout the ICU stay, it is important to be mindful of the potential neurotoxic effects associated with specific medications like midazolam and cefepime, and to closely monitor patients for non-convulsive seizures. The potential efficacy of targeted neurocritical care during the acute phase in optimizing patient outcomes deserves to be further investigated. Sepsis-associated encephalopathy may lead to permanent neurologic sequelae. Seizures occurring in the acute phase increase the susceptibility to long-term epilepsy. Extended ICU stays and the presence of sepsis-associated encephalopathy are linked to functional disability and neuropsychological sequelae, underscoring the necessity for long-term surveillance in the comprehensive care of septic patients.
Topics: Humans; Sepsis-Associated Encephalopathy; Sepsis; Brain; Seizures; Brain Injuries
PubMed: 37798769
DOI: 10.1186/s13054-023-04655-8 -
Clinical Pharmacology and Therapeutics Sep 2023Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and...
Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUC ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUC by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC.
Topics: Humans; Adult; Cannabinoids; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Caffeine; Midazolam; Cytochrome P-450 CYP3A; Losartan; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cannabis; Cytochrome P-450 CYP2D6; Cannabidiol; Drug Interactions; Omeprazole; Hallucinogens; Plant Extracts; Dronabinol
PubMed: 37313955
DOI: 10.1002/cpt.2973 -
Journal of Clinical Anesthesia Feb 2024To evaluate the association between midazolam premedication and postoperative delirium in a large retrospective cohort of patients ≥70 years.
STUDY OBJECTIVE
To evaluate the association between midazolam premedication and postoperative delirium in a large retrospective cohort of patients ≥70 years.
DESIGN
Retrospective cohort study.
SETTING
A single tertiary academic medical center.
PATIENTS
Patients ≥70 years having elective non-cardiac surgery under general anesthesia from 2020 to 2021.
INTERVENTIONS
Midazolam premedication, defined as intravenous midazolam administration prior to induction of general anesthesia.
MEASUREMENTS
The primary outcome, postoperative delirium, was a collapsed composite outcome including at least one of the following: a positive 4A's test during post-anesthesia care unit stay and/or the initial 2 postoperative days; physician or nursing records reporting new-onset confusion as captured by the CHART-DEL instrument; or a positive 3D-CAM test. The association between midazolam premedication and postoperative delirium was assessed using multivariable logistic regression, adjusting for potential confounding variables. As secondary analysis, we investigated the association between midazolam premedication and a composite of other postoperative complications. Several sensitivity analyses were performed using similar regression models.
MAIN RESULTS
In total, 1973 patients were analyzed (median age 75 years, 47% women, 50% ASA score ≥ 3, 32% high risk surgery). The overall incidence of postoperative delirium was 15.3% (302/1973). Midazolam premedication was administered to 782 (40%) patients (median [IQR] dose 2 [1,2] mg). After adjustment for potential confounding variables, midazolam premedication was not associated with increased odds of postoperative delirium, with adjusted odds ratio of 1.09 (95% confidence interval 0.82-1.45; P = 0.538). Midazolam premedication was also not associated with the composite of other postoperative complications. Furthermore, no association was found between midazolam premedication and postoperative delirium in any of the sensitivity analyses preformed.
CONCLUSIONS
Our results suggest that low doses of midazolam can be safely used to pre-medicate elective surgical patients 70 years or older before non-cardiac surgery, without significant effect on the risk of developing postoperative delirium.
Topics: Humans; Female; Aged; Male; Midazolam; Emergence Delirium; Retrospective Studies; Premedication; Postoperative Complications
PubMed: 37280146
DOI: 10.1016/j.jclinane.2023.111113 -
Neurocritical Care Jun 2024Pediatric refractory status epilepticus (RSE) often requires management with anesthetic infusions, but few data compare first-line anesthetics. This study aimed to... (Comparative Study)
Comparative Study
BACKGROUND
Pediatric refractory status epilepticus (RSE) often requires management with anesthetic infusions, but few data compare first-line anesthetics. This study aimed to compare the efficacy and adverse effects of midazolam and ketamine infusions as first-line anesthetics for pediatric RSE.
METHODS
Retrospective single-center study of consecutive study participants treated with ketamine or midazolam as the first-line anesthetic infusions for RSE at a quaternary care children's hospital from December 1, 2017, until September 15, 2021.
RESULTS
We identified 117 study participants (28 neonates), including 79 (68%) who received midazolam and 38 (32%) who received ketamine as the first-line anesthetic infusions. Seizures terminated more often in study participants administered ketamine (61%, 23/38) than midazolam (28%, 22/79; odds ratio [OR] 3.97, 95% confidence interval [CI] 1.76-8.98; P < 0.01). Adverse effects occurred more often in study participants administered midazolam (24%, 20/79) than ketamine (3%, 1/38; OR 12.54, 95% CI 1.61-97.43; P = 0.016). Study participants administered ketamine were younger, ketamine was used more often for children with acute symptomatic seizures, and midazolam was used more often for children with epilepsy. Multivariable logistic regression of seizure termination by first-line anesthetic infusion (ketamine or midazolam) including age at SE onset, SE etiology category, and individual seizure duration at anesthetic infusion initiation indicated seizures were more likely to terminate following ketamine than midazolam (OR 4.00, 95% CI 1.69-9.49; P = 0.002) and adverse effects were more likely following midazolam than ketamine (OR 13.41, 95% CI 1.61-111.04; P = 0.016). Survival to discharge was higher among study participants who received midazolam (82%, 65/79) than ketamine (55%, 21/38; P = 0.002), although treating clinicians did not attribute any deaths to ketamine or midazolam.
CONCLUSIONS
Among children and neonates with RSE, ketamine was more often followed by seizure termination and less often associated with adverse effects than midazolam when administered as the first-line anesthetic infusion. Further prospective data are needed to compare first-line anesthetics for RSE.
Topics: Humans; Ketamine; Midazolam; Status Epilepticus; Male; Female; Infant; Retrospective Studies; Child, Preschool; Child; Infant, Newborn; Infusions, Intravenous; Adolescent
PubMed: 37783824
DOI: 10.1007/s12028-023-01859-2 -
Indian Pediatrics Aug 2023Benzodiazepines are the first-line anti-seizure medication (ASM) for generalized convulsive status epilepticus (GCSE), but they fail to end seizures in a third of cases.... (Randomized Controlled Trial)
Randomized Controlled Trial
Levetiracetam and Midazolam vs Midazolam Alone for First-Line Treatment of Children With Generalized Convulsive Status Epilepticus (Lev-Mid Study): A Randomized Controlled Trial.
BACKGROUND
Benzodiazepines are the first-line anti-seizure medication (ASM) for generalized convulsive status epilepticus (GCSE), but they fail to end seizures in a third of cases. Combining benzodiazepines with another ASM that acts by a different pathway could be a potential strategy for rapid control of GCSE.
OBJECTIVES
To evaluate the efficacy of adding levetiracetam to midazolam in the initial treatment of pediatric GCSE.
DESIGN
Double-blind randomized controlled trial.
SETTING
Pediatric emergency room at Sohag University Hospital between June, 2021 and August, 2022.
PARTICIPANTS
Children aged between 1 month and 16 years with GCSE lasting more than 5 min.
INTERVENTIONS
Intravenous levetiracetam (60 mg/kg over 5 min) and midazolam (Lev-Mid group) or placebo and midazolam (Pla-Mid group) as first-line anticonvulsive therapy.
OUTCOME MEASURES
Primary: cessation of clinical seizures at 20-min study time point. Secondary: cessation of clinical seizures at 40-min study time point, need for a second midazolam dose, seizure control at 24-hr, need for intubation, and adverse effects.
RESULTS
Cessation of clinical seizures at 20-min occurred in 55 children (76%) in Lev-Mid group compared with 50 (69%) in the Pla-Mid group [RR (95% CI) 1.1 (0.9-1.34); P=0.35]. No significant difference was found between the two groups regarding the need for a second midazolam dose [44.4% vs 55.6%; RR (95% CI) 0.8 (0.58-1.11); P=0.18] as well as cessation of clinical seizures at 40-min [96% vs 92%; RR (95% CI)1.05 (0.96-1.14); P=0.49] and seizure control at 24-hr [85% vs 76%; RR (95% CI) 1.12 (0.94-1.3); P=0.21]. Intubation was required for three patients in the Lev-Mid group and six patients in the Pla-Mid group [RR (95%CI) 0.5 (0.13- 1.92); P=0.49]. No other adverse effects or mortality were observed during the 24-hour study timeframe.
CONCLUSION
Combined levetiracetam and midazolam for initial management of pediatric GCSE presents no significant advantage over midazolam alone in cessation of clinical seizures at 20-min.
Topics: Humans; Child; Infant; Levetiracetam; Midazolam; Anticonvulsants; Treatment Outcome; Status Epilepticus
PubMed: 37211889
DOI: No ID Found