Midazolam Infusion Research Articles

Ketamine plus midazolam compared to midazolam infusion for the management of refractory status epilepticus

BackgroundData for the use of ketamine (Ket) in treatment of refractory and super-refractory status epilepticus (RSE, SRSE) is lacking despite its widespread growing use. We examined the efficacy of ketamine plus midazolam (MDZ) infusions for treating RSE versus midazolam alone. We hypothesized that ketamine initiation would result in earlier seizure termination. MethodsData was obtained from electronic health records (EHR) of adult patients who received intravenous anesthetic agents for RSE in our neurointensive care unit. Two cohorts were identified. The MDZ cohort received midazolam as the only intravenous anesthetic agent for RSE. The Ket+MDZ cohort received midazolam infusion followed by ketamine infusion. The primary outcomes were time from midazolam infusion start to SE end in both cohorts, and time from ketamine infusion start (Ket Start) to SE end in the Ket+MDZ cohort versus midazolam infusion start (MDZ start) to SE end in the MDZ cohort. Results73 patients were included (MDZ cohort n=17, Ket + MDZ cohort n=56). Cohorts did not differ significantly in age, sex, race, RSE etiology, or GCS on admission. Mean APACHE II score was higher in the Ket +MDZ cohort (26 ± 7.32SD) versus the MDZ cohort (22 ± 5.89SD)(P=.015). In survival analyses, cohorts did not differ significantly in time from midazolam start to SE end (HR=0.965, 95% CI=0.556-1.673, P=.899; median [IQR]: MDZ: 25hours [4.5-58]; Ket+MDZ: 21.5hours [IQR 13.5-49]). Time from Ket start (Ket+MDZ group) versus time from MDZ start (MDZ group) to SE end was significantly shorter in the Ket+MDZ cohort (HR=1.895, 95% CI=1.083-3.314, P=.025). The pattern of results was similar when including APACHE II and MDZ maximum dosage as covariates. ConclusionTime to SE end was significantly shorter after addition of ketamine infusion to midazolam infusion, versus after initiation of midazolam infusion monotherapy. Patients with higher disease severity favored Ket+MDZ. Randomized controlled trials are warranted in determining optimal anesthetics in RSE and SRSE.

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

Total intravenous anesthesia with Ketofol in rabbits: a comparison of the effects of constant rate infusion of midazolam, fentanyl or dexmedetomidine

BackgroundWhen inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain general anesthesia. Total intravenous anesthesia (TIVA) does not require endotracheal intubation, which may be more difficult to achieve in rabbits. A range of different injectable drug combinations have been used as continuous infusion rate in animals. Recently, a combination of ketamine and propofol (ketofol) has been used for TIVA in both human patients and animals. The purpose of this prospective, blinded, randomized, crossover study was to evaluate anesthetic and cardiopulmonary effects of ketofol total intravenous anesthesia (TIVA) in combination with constant rate infusion (CRI) of midazolam, fentanyl or dexmedetomidine in eight New Zealand White rabbits. Following IV induction with ketofol and endotracheal intubation, anesthesia was maintained with ketofol infusion in combination with CRIs of midazolam (loading dose [LD]: 0.3 mg/kg; CRI: 0.3 mg/kg/hr; KPM), fentanyl (LD: 6 µg/kg; CRI: 6 µg/kg/hr; KPF) or dexmedetomidine (LD: 3 µg/kg; CRI: 3 µg/kg/hr; KPD). Rabbits in the control treatment (KPS) were administered the same volume of saline for LD and CRI. Ketofol infusion rate (initially 0.6 mg kg− 1 minute− 1 [0.3 mg kg− 1 minute− 1 of each drug]) was adjusted to suppress the pedal withdrawal reflex. Ketofol dose and physiologic variables were recorded every 5 min.ResultsKetofol induction doses were 14.9 ± 1.8 (KPM), 15.0 ± 1.9 (KPF), 15.5 ± 2.4 (KPD) and 14.7 ± 3.4 (KPS) mg kg− 1 and did not differ among treatments (p > 0.05). Ketofol infusion rate decreased significantly in rabbits in treatments KPM and KPD as compared with saline. Ketofol maintenance dose in rabbits in treatments KPM (1.0 ± 0.1 mg/kg/min) and KPD (1.0 ± 0.1 mg/kg/min) was significantly lower as compared to KPS (1.3 ± 0.1 mg/kg/min) treatment (p < 0.05). Ketofol maintenance dose did not differ significantly between treatments KPF (1.1 ± 0.3 mg/kg/min) and KPS (1.3 ± 0.1 mg/kg/min). Cardiovascular variables remained at clinically acceptable values but ketofol infusion in combination with fentanyl CRI was associated with severe respiratory depression.ConclusionsAt the studied doses, CRIs of midazolam and dexmedetomidine, but not fentanyl, produced ketofol-sparing effect in rabbits. Mechanical ventilation should be considered during ketofol anesthesia, particularly when fentanyl CRI is used.

Bispectral Index monitoring of palliative sedation for home withdrawal of tracheostomy ventilation: A case report.

Tracheostomy ventilation in motor neurone disease is an uncommon life-sustaining treatment. Best practice is having a plan for ventilation withdrawal, but the literature to guide practice is limited. Case reports have documented standard doses of opioids and benzodiazepines used for sedation in such cases. A 49-year-old man was diagnosed with motor neurone disease in 2016. He commenced tracheostomy ventilation in 2018. In 2022 and 2023, planning was undertaken, at the patient's request, for withdrawal of tracheostomy ventilation at home, when he was no longer able to communicate with technology. Planning included Bispectral Index monitoring prior to cessation of ventilation, ensuring this only occurred when deep sedation was achieved. After ventilation withdrawal in 2023, a retrospective review of medications given and his level of sedation on monitoring was undertaken, with family consent. Ventilation withdrawal was initiated after deep sedation was achieved, 6 h after commencing subcutaneous infusions of morphine, midazolam, clonazepam and phenobarbital. Doses required to achieve acceptable sedation exceeded literature reports. Achieving deep sedation was a longer than expected process. More research using an objective measure of sedation is required, as clinical assessment of sedation in this context is compromised.

Dental treatments under sedation-analgesia in patients who are unable to collaborate: a prospective observational study.

Excessive fear of dental procedures leads to disruptive behavior during dental examinations and treatments. Dental examinations and treatments of these patients usually require additional techniques, such as sedation. The most commonly used techniques are inhalation of nitrous oxide, infusion of propofol with fentanyl, and premedication and infusion of midazolam. A prospective observational epidemiological study was conducted on patients who required sedoanalgesia techniques for dental exploration and procedures. The reasons for the inability of patients to cooperate (excessive fear or intellectual disability), age, sex, weight, systemic pathology, oral pathology, treatment performed, time of intervention, anesthetic technique performed, and occurrence of complications were recorded. In total, 218 patients were studied. Sixty-five patients came for fear of dental treatment and 153 for presenting with a diagnosis of intellectual disability and not collaborating in the treatment with local anesthesia. The average age of all patients was 30.54 ± 17.30 years. The most frequent oral pathologies found in patients with excessive fear were tartar (6.8%) and wisdom teeth (6.4%), followed by missing teeth (5%). In patients with disabilities, a combination of tartar and cavities appeared most frequently (41.3%), followed by cavities (15.6%). The most frequently used sedoanalgesia technique was the infusion of propofol with fentanyl in both groups of patients, followed by nitrous oxide. The combination of propofol and fentanyl was the most frequently used alternative in patients who were unable to collaborate because of intellectual disability or carry out longer or more complex treatments. Inhaled nitrous oxide and midazolam were the sedative techniques of choice for simpler oral treatments, such as tartrectomies, shallow obturations, and shorter interventions, or in younger patients.

Recurrent hyponatremia in neonate: a case of renal salt wasting syndrome

BackgroundRenal salt wasting (RSW) is primarily seen with central nervous disorders and is characterized by hyponatremia, elevated urinary sodium excretion, increased urine output, and hypovolemia. Although there have been reports of RSW in children, it has not been reported in newborns.Case presentationA term (38 weeks 2 days) female weighing 2060 g, born via normal vaginal delivery, to a primi-gravida mother, was admitted to our neonatal intensive care unit. At birth, the baby was non-vigorous, had aspirated meconium, and required bag-and-mask ventilation following which the baby cried. The child was put on CPAP and inotropes for respiratory distress and shock, respectively, along with first-line antibiotics. Over the next few days, the child was weaned off CPAP, inotropes were stopped, and feeds were started. On postnatal day (PND) 8, the baby developed repeated episodes of seizures requiring two-antiepileptics followed by midazolam infusion, had shock requiring inotropes, and also had a tense anterior fontanelle with altered sensorium and tone changes, for which mannitol and 3% saline were given. Antibiotics were upgraded, and neuroimaging (MRI) revealed left basal-ganglia bleed with intraventricular extension and cerebral venous thrombosis. The baby showed gradual clinical improvement with the above measures and was restarted on feeds. However, from PND-19 onwards the baby had repeated episodes of hyponatremia requiring 3% saline infusions, progressive weight loss, and polyuria. Considering RSW, urine sodium was done which was high (110 mmol/L). For polyuria and weight loss, feed volume was increased, whereas, for hyponatremia, table salt was added to the expressed breast milk (1 gm × tds). Subsequently, all the serum sodium values remained within normal limits, and the baby started gaining weight and was discharged on similar advice (PND 38). On further follow-up, table salt was gradually decreased in the feeds and was stopped after 1 month of discharge with normal serum sodium values.ConclusionManagement of recurrent hyponatremia in a neonate is challenging. Despite its rarity, RSW in newborns should be considered a differential.

Hashimoto's encephalitis - A case report

A 50 year-old woman with a background of focal epilepsy presented to Emergency Department (ED) in convulsive status epilepticus.After 1 year seizure-free on levetiracetam,she initially presented with headache, tremor, fatigue and general malaise. She was discharged, then re-presented to ED several days later in status epilepticus. Two doses of diazepam administered pre-hospital failed to terminate the seizure. She was loaded with phenytoin,intubated and ventilated and commenced on a midazolam infusion. She spent 7 days in neuro-intensive care and was discharged home on levetiracetam 1.5 g twice daily and phyentoin 250 mg twice daily.One month later, she re-presented to ED with 4 days of worsening tremors and reduced mobility. Physical examination revealed multifocal myoclonus. She had experienced significant cognitive decline and neuropsychiatric symptoms including severe anxiety, delusions and paranoia.InvestigationsImagingInitial MRI head with gadolinium showed marked symmetric abnormality within the white matter of both hemispheres extending into subcorticol regions, most predominant at the vertex and involving U fibres. The neuro-radiologist commented that the differential for these changes was broad, including an encephalitis, PML, meningitis or a leukoencephalopathy.Repeat MRI head 1 month later showed complete resolution of the white matter changes leaving no sequelae.Blood testsHer past medical history included subclinical hypothyroidism. Thyroid function tests showed an elevated TSH of 21.33 and thyroid peroxidase(TPO) antibody level of 188.0 IU/mL, with FT4 levels within normal range.Extensive relevant blood screen, including the following was all negative• NMDA, glycine receptor and anti-cardiolipin antibody• Connective tissue screen, anti-MPO and anti-PR3• Serum electrophoresis• Paraneoplastic antibody screen including Cerebellum IIF, MA2, MA1, amphiphysin, CV2(CRMP5), Anti-Ri (ANNA 2) Ab, Anti Yo Ab and Anti Hu Ab• HIV and syphilis serology• JC virus• Plasma amino acid, urine organic acid and ammoniaLumbar punctureCSF WCC 1/mm3CSF protein- 816 mg/LCSF viral PCR (including JC virus) and oligoclonal bands negativeEEG- normal background activity with no clear focal or diagnostic epileptiform abnormalities.Treatment and follow-upThe clinical picture, elevated TPO antibodies and absence of other relevant investigation abnormality raised Hashimoto's encephalitis as a potential unifying diagnosis. She had a good response to inpatient treatment with steroids, her neuropsychiatric features resolved and she has remained seizure-free since discharge. She remains under neurology outpatient follow-up.Discussion:It can be challenging to make a diagnosis of Hashimoto encephalitis, and other potential causes such as infection, metabolic or paraneoplastic processes must be rigorously ruled out (1). In this case, high titres of TPO alongside the clinical presentation with recurrent seizures and cognitive decline were key in making the diagnosis (2,3). Due to an overlap of features, including myoclonus and rapid cognitive decline, it was important to consider Creutzfeldt-Jakob disease (CJD) in the differential. We ruled out CJD due to the rapid response to steroid therapy and lack of typical EEG and MRI findings (4). Overall, due to low prevalence and non-specific MRI and EEG features, this diagnosis can be difficult to make and requires thorough systemic clinical assessment.

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUClast) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUClast: R2 = 0.59, p = 0.03; AUCinf: R2 = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time.

Comparison of hemodynamics changes after infusion of Dexmedetomidine versus Midazolam as a premedication in pediatric patients undergoing lower abdominal surgery

Comparison of hemodynamics changes after infusion of Dexmedetomidine versus Midazolam as a premedication in pediatric patients undergoing lower abdominal surgery

Anesthetic Challenges during Endobronchial Brachytherapy: A Case Report.

Lung cancer is the leading cause of cancer death worldwide. It may present as airway obstruction in a patient with endobronchial masses. Endobronchial brachytherapy (EBBT) has been shown to provide palliative therapy. It is the insertion of a radioactive material near the mass to reduce tumor size, thereby improving airway obstruction. This is the first case of EBBT done in our institution during the COVID-19 pandemic. A 53-year-old male, 60 kg, ASA Physical Status 2 for hypertension, smoker, malignancy, and previous pulmonary tuberculosis patient, presented with a cough and dyspnea. An endobronchial mass almost obstructing the right mainstem bronchus was seen on a computed tomography (CT) scan. He was diagnosed with squamous cell carcinoma of the lung and underwent radiotherapy and erlotinib chemotherapy. On repeat CT scan, there was no noted decrease in the size of the mass. EBBT was suggested, and a multi-disciplinary team was formed for the planned procedure. Pulmonology, radiation oncology, and anesthesiology teams were identified, and thorough planning was done prior to the actual procedure. Three fractions of EBBT were done under sedation using midazolam, fentanyl, and dexmedetomidine infusion. Lidocaine spray and transtracheal block were also performed as adjuncts prior to sedation. The procedure went as planned, and points for improvement were discussed for subsequent fractions. Due to persistent cough and discomfort from the catheter, additional ipratropium nebulization for minimization of secretions, and oral dextromethorphan for cough suppression were incorporated. After each fraction, the patient was monitored post-procedure for any side effects both from the radiotherapy and anesthetic technique. Qualitative reduction in mass size was noted in subsequent fractions. The patient was able to complete 3 fractions and was advised to follow-up after a month. EBBT is an emerging palliative and treatment modality for lung cancer, especially for intraluminal masses. Anesthetic considerations will depend on each case's characteristics such as airway anatomy, patient comfort and capacity, and procedural requirements. Conscious sedation with topical anesthesia is an adequate and appropriate anesthetic option, especially in cases where severe airway obstruction may compromise ventilation if airway reflexes are blunted. A multidisciplinary approach with different services and stakeholders is important for the proper planning, execution, and management of such patients.

Study protocol for Ketamine as an adjunctive therapy for major depression (2): a randomised controlled trial (KARMA-Dep [2

BackgroundDepression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine’s antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator.MethodsThis protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under “real world” conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness.DiscussionThere is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression.Trial registrationEudraCT 2019-003109-92. Registered 2 October 2019. ClinicalTrials.gov NCT04939649. Registered 25 June 2021.

Abstract 393: Distribution and Elimination Kinetics of Midazolam and Metabolites in Patients With Post-Cardiac Arrest Care

Background: Administration of midazolam (MDZ) can make neuroprognostication more complex, especially in determining the safe timing for avoiding inappropriately pessimistic prognostications. This study aims to investigate the distribution and elimination kinetics of MDZ and metabolites in patients with post-resuscitation care. Methods: This was a prospectively observational study between May 2020 and April 2022. Samples for analyzing plasma concentration of MDZ and seven metabolites were obtained immediately, at 4, 8, 12, and 24 h from discontinuation of MDZ infusion. Briefly, absolute and relative concentrations of MDZ and metabolites were determined by LC-MS/MS and LC-QTOF. The area under the plasma concentration-time curve from time 0 to last measurable time point (AUC last ) and estimated half-life ( t 1/2 ) were calculated according to pharmacokinetic rules. Results: Of the 13 enrolled patients, 8 (61.5%) awakened after discontinuation of MDZ administration. MDZ, 1-hydroxylmidazolam (1-OH-MDZ), 1-hydroxylmidazolam-glucuronide (1-OH-MDZ-Glu), and midazolam-glucuronide (MDZ-Glu) were identified as the major compounds, comprising approximately 96% of the total proportion. All compounds had individual mean t 1/2 (MDZ, 1-OH-MDZ, 1-OH-MDZ-Glc, and MDZ-Glc: 6.4, 7.6, 14.3, and 10.5 h, respectively). In the subgroup analysis for the awakened patients, the significant correlation between AUC last and awakening time measured from discontinuation of MDZ infusion was demonstrated in MDZ (r 2 = 0.66) and 1-OH-MDZ (r 2 = 0.55). Conclusions: Even in the normothermia state of the patients, t 1/2 of MDZ and metabolites was prolonged compared with that reported in healthy individuals. Among all compounds, MDZ and 1-OH-MDZ concentrations may be mainly active compounds related to the sedation effect. Hence, to prevent inappropriate WLST for patients with potential for recovery, we recommend clinicians consider the prolonged t 1/2 of the main active compounds.

Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

EFFECTS OF DETOMIDINE AND DEXMEDETOMIDINE ON PHYSIOLOGICAL PARAMETERS AND ANESTHETIC RECOVERY IN TAPIRUS TERRESTRIS ANESTHETIZED WITH KETAMINE, GLYCERYL GUAIACOL ETHER, AND MIDAZOLAM.

The aim of this study was to compare the effects of two anesthetic induction protocols for long procedures carried out in the field in Tapiridae. Sixteen tapirs were divided into two groups (n=8) receiving either detomidine (DET) or dexmedetomidine (DEX) for anesthetic induction. All animals were anesthetized by intramuscular administration of a combination of ketamine (1.5 mg/kg), midazolam (0.2 mg/kg), plus either DET (0.04 mg/kg) or DEX (0.007 mg/kg). Anesthetic maintenance was by continuous infusion of ketamine, midazolam, and glyceryl guaiacol ether at 2 mg/kg per hour, 0.1 mg/kg per hour, and 100 mg/kg per hour, respectively). The animals were kept anesthetized for a total of 50 min to allow physical examination and collection of biological material as part of a research program, and physiological variables (heart rate [HR], respiratory rate, oxyhemoglobin saturation [SpO2], rectal temperature [RT], mean arterial pressure [MAP], blood glucose [GLI], and cortisol) and electrocardiogram were recorded during anesthesia. Anesthetic recovery was monitored by two researchers who were not informed of the induction protocol group. The recorded results were statistically evaluated. In both groups there was an initial increase in MAP, which subsequently decreased; RT gradually decreased during anesthesia; HR and GLI increased throughout the procedure; SpO2 was below normal throughout the procedure. Cortisol levels were significantly higher in the DEX group than in the DET group. Also, the animals in the DEX group had a longer recovery time than those in the DET group. On the basis of the results, we conclude that the combination of alpha-2 agonists and midazolam, ketamine, and glyceryl guaicol ether is an appropriate protocol for the anesthesia of tapirs in the field. However, in moderately extended procedures oxygen supplementation is recommended. Additionally, DEX resulted in fewer cardiovascular effects and longer-lasting sedation than DET.

A Comparison of Ketamine and Midazolam as First-Line Anesthetic Infusions for Pediatric Status Epilepticus.

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. 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. 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. 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.

Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial

BackgroundKetamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation.MethodIn this randomized-controlled trial, 51 participants aged 13–18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12.ResultsIn the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05).ConclusionsThe present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed.Trial registration: This trial was registered in the Chinese Clinical Trials Registry (http://www.chictr.org.cn, ChiCTR2000041232).

Comparison of Propofol versus Midazolam Infusion for Conscious Sedation during Spinal Anaesthesia in Patients Undergoing Inguinal Hernia Repair

Abstract Background The operating room is an anxiety provoking environment. Supplemental sedation with an intravenous agent is often required to allay fear and anxiety in patients subjected to spinal anaesthesia. Sedation is a valuable tool to make surgery under regional anaesthesia convenient for the patient, the anaesthetist and the surgeon. Conscious sedation is a minimally depressed level of consciousness that retains the patient’s ability to maintain his or her airway independently and continuously and to respond appropriately to physical stimulation and verbal commands, produced by pharmacologic or non-pharmacologic methods alone or in combination. Aim of the Work This study will be designed to compare Propofol and Midazolam with regard to their suitability as sedative agents during spinal anaesthesia in terms of onset &amp; recovery from sedation, haemodynamic stability, dosage and side effects of both the drugs. Patients and Methods This Interventional clinical study (Randomized double blinded study was conducted in Ain Shams University Hospital’s operating rooms through 3 months on 50 patients. After obtaining approval from the medical ethical committee in Ain Shams University Hospital’s operating rooms, a written informed consent was obtained from every patient after explaining the procedure. Results Based on this study the following conclusions have been made: Cardiovascular parameters and respiration were well maintained in both the study groups, no incidence of apnea was noticed in both the study groups, pain during the injection of propofol was a side effect noticed, onset of action was faster in the propofol group, propofol group was less co-operative than midazolam group but this was clinically insignificant, midazolam group showed slower recovery than propofol group restricting and wasting the productive time of the patient, qualities such as short plasma half-life period, absence of postoperative nausea and vomiting, make propofol a better choice for sedation and thus propofol is a fast acting, safe and easily controllable sedative with rapid recovery. This offered the advantage of early patient discharge and better patient compliance. Conclusion When given as a sedative adjunct to spinal I, both propofol and midazolam in equisedative infusions offer good anxiolysis and good cardio respiratory stability. Propofol has the advantage of providing faster onset of sedation, a rapid clear headed recovery from the same and lesser postoperative impairment of recall while midazolam offers better intraoperative amnesia.

Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial

Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population. A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and the Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, the 4-week clinical treatment response was a key secondary outcome. The mean changes in C-SSRS Ideation and Intensity scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation,-2.6 [SD= 2.0] vs-1.7 [SD= 2.2], p= .007; Intensity,-10.6 [SD= 8.4] vs-5.0 [SD= 7.4], p= .002), and the changes in MADRS scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD= 11.2] vs-8.8 [SD= 9.4], p= .004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache, and dizziness. These preliminary findings indicate that 3-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation. A study to evaluate the efficacy and safety of Esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation; http://www.chictr.org.cn; ChiCTR2000041232. We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote sex and gender balance in our author group.

Midazolam infusion might preserve glucose and lipid homeostasis during surgery under general anesthesia: Placebo-controlled comparative study

Abstract Background Anesthesia and surgery each per se is a stressful condition that may affect the postoperative patients’ outcomes. Hyperglycemia is the commonest result of surgical stress response and must be adjusted not only in diabetics to improve outcomes. Aims To determine changes in blood glucose (BG) and serum lipids and cortisol levels after intraoperative midazolam infusion for patients undergoing surgery under general anesthesia. Patients and Methods: 160 ASA I or II non-diabetic patients were randomly divided as Control patients received placebo infusion and Study patients received midazolam infusion (0.35 µg/kg/min). All patients gave blood samples before (S1) and 30-min after the start (S2) and at the end of infusion (S3) for estimation of BG and serum lipids and cortisol levels. The study outcome was the change in the levels of estimated parameters in relation to their preoperative levels. Results BG levels estimated in S2 and S3 samples were significantly higher than S1 levels of all patients but were significantly lower in samples of study than control patients. Serum levels of triglycerides and very low-density lipoproteins (VLDL), and cortisol in S3 study samples were significantly lower than in S3 control samples. Conclusion Intraoperative midazolam infusion could minimize surgical stress response with a significant decrease in serum cortisol, triglycerides, and VLDL and significantly lower BG concentrations in comparison to placebo infusion.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202, with permission from American Psychiatric Association Publishing. Copyright © 2021.