Comparison of propofol-based sedation and midazolam sedation in pediatric bidirectional endoscopy conducted by pediatric gastroenterologists.

Objectives: The effectiveness and safety of propofol-based sedation and midazolam sedation in pediatric bidirectional endoscopy were compared. Methods: We retrospectively analyzed the cases of pediatric patients (≤15 years old) who had undergone bidirectional endoscopy, esophagogastroduodenoscopy, and colonoscopy by pediatric gastroenterologists. Demographic data, indications, sedatives/dosages, clinical outcomes, endoscopic findings, adverse events, and total patient time requirements (total time in which patients stay in our hospital) were compared in the two sedation groups. Results: Ninety-one children (51 boys, 40 girls, mean age 13 years, range 9-15) treated at our hospital were enrolled. Propofol alone or in combination with midazolam and/or pentazocine was administered to 51 patients (propofol-based sedation group). Midazolam alone or in combination with pentazocine was administered to the other 40 patients (midazolam sedation group). In the propofol group, the following mean doses were used: propofol, 96 mg (range 40-145 mg); midazolam, 4.9 mg (range 3-5 mg); and pentazocine, 7.5 mg. In the midazolam group, the mean doses of midazolam and pentazocine were 6.2 mg (range 4-10 mg) and 15 mg, respectively. All procedures were successfully completed by pediatric gastroenterologists. The total procedure times and endoscopic findings were similar in the two groups, but the median patient time requirement in the propofol group was significantly shorter versus the midazolam group (7.3 h vs. 8.4 h, p < 0.001). No adverse events occurred in either group. Conclusions: Propofol-based sedation in pediatric bidirectional endoscopy was safely and effectively performed by pediatric gastroenterologists, and its patient time requirement was shorter than that for midazolam sedation.

Effects of ketamine on the severity of depression and anxiety following postoperative mechanical ventilation: a single-blind randomized clinical trial in Iran.

BACKGROUND: In this study, we compare the effects of ketamine and the combination of midazolam and morphine on the severity of depression and anxiety in mechanically ventilated patients after discharge from the intensive care unit (ICU). METHODS: This randomized single-blind clinical trial included 50 patients who were candidates for craniotomy and postoperative mechanical ventilation in the ICU of 5 Azar Teaching Hospital in Gorgan City, North Iran, from 2021 to 2022. Patients were allocated to two groups by quadruple block randomization. In group A, 0.5 mg/kg of ketamine was infused over 15 minutes after craniotomy and then continued at a dose of 5 µ/kg/min during mechanical ventilation. In group B, midazolam was infused at a dose of 2-3 mg/hr and morphine at a dose of 3-5 mg/hr. After patients were discharged from the ICU, if their Glasgow Coma Scale scores were ≥14, Beck's anxiety and depression inventories were completed by a psychologist within 2 weeks, 2 months, and 6 months after discharge. RESULTS: The mean scores of depression at 2 months (P=0.01) and 6 months (P=0.03) after discharge were significantly lower in the ketamine group than in the midazolam and morphine group. The mean anxiety scores were significantly lower in the ketamine group 2 weeks (P=0.006) and 6 months (P=0.002) after discharge. CONCLUSIONS: Ketamine is an effective drug for preventing and treating anxiety and depression over the long term in patients discharged from the ICU. However, further larger volume studies are required to validate these results.

An evaluation of dexmedetomidine in combination with midazolam in pediatric sedation: a systematic review and meta-analysis.

BACKGROUND: Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of sedation provided by dexmedetomidine combined with midazolam versus other sedatives including chloral hydrate, midazolam and other sedatives in pediatric sedation. METHODS: The Embase, Web of Science, Cochrane Library, and PubMed databases, and Clinicaltrials.gov register of controlled trials were searched from inception to June 2022. All randomized controlled trials used dexmedetomidine-midazolam in pediatric sedation were enrolled. The articles search, data extraction, and quality assessment of included studies were performed independently by two researchers. The success rate of sedation was considered as the primary outcome. The secondary outcomes included onset time of sedation, recovery time of sedation and occurrence of adverse events. RESULTS: A total of 522 studies were screened and 6 RCTs were identified; 859 patients were analyzed. The administration of dexmedetomidine combined with midazolam was associated with a higher sedation success rate and a lower incidence of nausea and vomiting in computed tomography, magnetic resonance imaging, Auditory Brainstem Response test or fiberoptic bronchoscopy examinations than the other sedatives did (OR = 2.92; 95% CI: 1.39-6.13, P = 0.005, I2 = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I2 = 0%, respectively). Two groups did not differ significantly in recovery time and the occurrence of adverse reactions (WMD = - 0.27, 95% CI: - 0.93 to - 0.39, P = 0.42; OR 0.70; 95% CI: 0.48-1.02, P = 0.06, I2 = 45%. respectively). However, the results of the subgroup analysis of ASA I-II children showed a quicker onset time in dexmedetomidine-midazolam group than the other sedatives (WMD=-3.08; 95% CI: -4.66 to - 1.49, P = 0.0001, I2 = 30%). CONCLUSIONS: This meta-analysis showed that compared with the control group, dexmedetomidine combined with midazolam group provided higher sedation success rates and caused a lower incidence of nausea and vomiting in completing examinations, indicating a prospective outpatient clinical application for procedural sedation.

[Oral sedation in pediatric outpatient dentistry]. / Primenenie peroral'noi sedatsii pri ambulatornom stomatologicheskom vmeshatel'stve u detei.

THE AIM OF THE STUDY: Was to improve the quality of treatment in pediatric outpatient dentistry with the effective use of oral sedation. MATERIALS AND METHODS: The study comprised 60 children aged 3-12 years who were undergoing therapeutic/surgical dental treatment. All children's somatic state was assessed as ASAI-II. All children met a number of psychological, anamnestic and procedural criteria. Midazolam and chloropyramine in a dose calculated for the patient's body weight were used as components of oral sedation. The estimated sedation depth was Ramsay II-III. The study included an analysis of objective (the time of comfortable treatment, the amount of treated or removed teeth per visit, the possibility of treatment without anesthesia during further visits) and subjective (the possibility of contact with the child during treatment, behavioral reactions at home and on further visits) criteria. Negative behavioral reactions and dental effects were also assessed. RESULTS: The treatment features correlated with the age category and gender of the patient. In the older age group of 7-12 years, the amount of comfortable treatment time was higher, the possibility of contact with the child reached 100% (which is twice as much as in the younger one), and also a larger number of patients were treated during further visits without an anesthetic aid. At the same time, in the younger age group of 3-6 years, the volume of treatment per visit was higher, since it takes less time to treat a primary tooth than for a permanent one. Side effects (visual hallucinations, diplopia, hyperactivity, tearfulness and aggressiveness) were more often recorded in the younger age group, but emotional instability was equally manifested in both groups. CONCLUSION: In order to maximize the effectiveness of using oral sedation as a method, it is necessary to take into account the duration and traumatism of the proposed procedure, the peculiarities of age psychology and the peculiarities of the psychological development of boys and girls.

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics).

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY.

Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway.

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.

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.

Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns.

Understanding the intricate relationship between cancer clinicopathological features and anesthetics dosage is crucial for optimizing patient outcomes and safety during surgery. This retrospective study investigates this relationship in patients with non-small cell lung cancer (NSCLC) undergoing video-assisted thoracic surgery (VATS). A comprehensive analysis of medical records was undertaken for NSCLC patients who underwent VATS with intravenous compound inhalation general anesthesia. Patients were categorized based on histological, chemotherapy, radiotherapy, and epidural anesthesia factors. Statistical analysis was performed to compare the differences between the groups. The results revealed compelling insights. Specifically, patients with lung adenocarcinoma (LUAD) undergoing VATS exhibited higher dosages of rocuronium bromide and midazolam during general anesthesia, coupled with a shorter post-anesthesia care unit (PACU) stay compared to those with squamous cell carcinoma (sqCL). Furthermore, chemotherapy patients undergoing VATS demonstrated diminished requirements for phenylephrine and remifentanil in contrast to their non-chemotherapy counterparts. Similarly, radiotherapy patients undergoing VATS demonstrated a decreased necessity for rocuronium bromide compared to non-radiotherapy patients. Notably, patients who received epidural anesthesia in combination with general anesthesia manifested reduced hydromorphone requirements and prolonged hospital stays compared to those subjected to general anesthesia alone. In conclusion, the findings from this study indicate several important observations in diverse patient groups undergoing VATS. The higher dosages of rocuronium bromide and midazolam in LUAD patients point to potential differences in drug requirements among varying lung cancer types. Additionally, the observed shorter PACU stay in LUAD patients suggests a potentially expedited recovery process. The reduced anesthetic requirements of phenylephrine and remifentanilin chemotherapy patients indicate distinct responses to anesthesia and pain management. Radiotherapy patients requiring lower doses of rocuronium bromide imply a potential impact of prior radiotherapy on muscle relaxation. Finally, the combination of epidural anesthesia with general anesthesia resulted in reduced hydromorphone requirements and longer hospital stays, suggesting the potential benefits of this combined approach in terms of pain management and postoperative recovery. These findings highlight the importance of tailoring anesthesia strategies for specific patient populations to optimize outcomes in VATS procedures.

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

BACKGROUND: When 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. RESULTS: Ketofol 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. CONCLUSIONS: At 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.

Optimising the oral midazolam dose for premedication in people with intellectual disabilities and/or autism spectrum disorder.

BACKGROUND: In people with intellectual disabilities and/or autism spectrum disorder, oral midazolam (OM) is very effective as premedication for facilitating medical treatment. In this retrospective study, we investigated the optimal dosage of OM for premedication. METHODS: Patients with intellectual disability and/or autism spectrum disorder who were given OM as a premedication were selected from anaesthesia records. The primary outcome variable was the dose of OM (mg/kg) required to produce an adequate sedation. RESULTS: The mean OM dose required was 0.32 ± 0.10 mg/kg. The required OM dose decreased significantly as age and weight increased, and age and weight were also shown to be significantly associated with the dose of OM in the multivariate linear regression analysis. CONCLUSION: The dosage of OM to achieve adequate sedation should decrease as the patient ages. Furthermore, adequate sedation can be achieved with even lower doses of OM in obese people.

Evaluating the effectiveness of the maximum permitted dose of midazolam in seizure termination: Insights from New South Wales, Australia.

OBJECTIVE: Out-of-hospital seizures demand rapid management. Midazolam plays a key role in stopping seizures. At times the first dose of midazolam proves insufficient, necessitating additional doses. Within the New South Wales Ambulance (NSWA) service, the upper limit for midazolam administration is set at 15 mg. However, the outcomes and safety of using midazolam at this maximum dosage have not been thoroughly investigated. METHODS: A retrospective analysis of out of hospital electronic health records from New South Wales, Australia, over the year 2022, was conducted. The study manually reviewed cases where adult patients received the maximum dose of midazolam for seizure management by paramedics. It focused on seizure cessation success rates and the incidence of adverse effects to evaluate the clinical implications of high-dose midazolam administration. RESULTS: Of 818 790 individual attendances by NSWA clinicians, a total of 11 392 (1.4%) adults had seizures noted, of which midazolam was administered in 2565 (22.5%). An algorithm shows that in 2352 (91.7%) instances the midazolam was associated with the apparent termination of seizures. Analysis revealed that 176 (1.5%) proportion of all adult's seizure patients required the maximum dose of midazolam for seizure control. These higher doses successfully terminate seizures in about half of the instances. AEs following the maximum dose of midazolam included hypoxia in 26.7% of patients and respiratory depression in 9.7%, indicating significant side effects at higher dosages. CONCLUSION: In New South Wales, Australia, administering the maximum dose of midazolam to seizure patients is rare but proves effective in approximately half of the refractory seizure cases. Therefore, assessing the potential for additional doses of midazolam or the use of a second-line agent is advisable.

A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

AIMS: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. METHODS: Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. RESULTS: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. CONCLUSIONS: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

Comparison of intranasal dexmedetomidine versus oral midazolam for premedication in pediatric patients: an updated meta-analysis with trial-sequential analysis.

BACKGROUND: Midazolam is routinely used as preanesthetic medication in pediatric patients. Recently, dexmedetomidine has emerged as an alternative as a premedicant. We aimed to add more evidence about the efficacy and safety of two common routes of administration for pediatric premedication: oral midazolam versus intranasal dexmedetomidine. METHODS: We systematically searched Randomized Controlled Trials (RCTs) involving patients ≤ 18 years old undergoing preanesthetic medication and comparing intranasal dexmedetomidine with oral midazolam. Risk Ratio (RR) and Mean Difference (MD) with 95% Confidence Intervals (95% CI) were computed using a random effects model. Trial-sequential analyses were performed to assess inconsistency. RESULTS: Sixteen RCTs (1,239 patients) were included. Mean age was 5.5 years old, and most procedures were elective. There was no difference in satisfactory induction or mask acceptance (RR = 1.15, 95% CI 0.97-1.37; p = 0.11). There was a higher incidence of satisfactory separation from parents in the dexmedetomidine group (RR = 1.40; 95% CI 1.13-1.74; p = 0.002). Dexmedetomidine was also associated with a reduction in the incidence of emergence agitation (RR = 0.35; 95% CI 0.14-0.88; p = 0.02). Heart rate and mean arterial pressure were marginally lower in the dexmedetomidine group but without clinical repercussions. CONCLUSION: Compared with oral midazolam, intranasal dexmedetomidine demonstrated better separation from parents and lower incidence of emergence agitation in pediatric premedication, without a difference in satisfactory induction. Intranasal dexmedetomidine may be a safe and effective alternative to oral midazolam for premedication in pediatric patients.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

The Effect of a Subsequent Dose of Dexmedetomidine or Other Sedatives following an Initial Dose of Dexmedetomidine on Sedation and Quality of Recovery in Cats: Part I.

Dexmedetomidine is an a2-agonist commonly used in veterinary practice. Occasionally, the administered dose of dexmedetomidine may result in insufficient sedation, and an additional dose or drug may be required. The sedative effects of seven different drugs administered at subsequent time points after an initial, insufficient dose of dexmedetomidine were evaluated. Seven adult cats participated in this crossover, blind, randomised study. The groups consisted of two consecutive doses of dexmedetomidine (15 + 10 µg/kg) (DD) or a dose of dexmedetomidine (15 µg/kg) followed by either NS 0.9% (DC-control group), tramadol 2 mg/kg (DT), butorphanol 0.2 mg/kg (DBT), buprenorphine 20 µg/kg (DBP), ketamine 2 mg/kg (DK), or midazolam 0.1 mg/kg (DM). Sedation was evaluated using the Grint sedation scale. In all groups, atipamezole was administered at the end of the evaluation, and recovery was assessed using the Lozano and Sams recovery scales. The DC and DM groups exhibited minimal sedative effects. The maximum sedative effect was observed in the DD and DK groups, while sedation in the DD and DK groups was significantly higher compared to the DC group. Recovery in all groups was uneventful, except in the DM group, where it was prolonged and difficult, although no statistically significant difference was detected. Therefore, insufficient sedation with dexmedetomidine can be enhanced by a subsequent dose of dexmedetomidine, ketamine, or butorphanol, whereas the addition of midazolam reduces sedation and prolongs recovery.

Enhancing ketamine anesthesia with midazolam and fentanyl for children's ear surgery: a prospective randomized study.

Background: Myringotomy with tympanostomy tube insertion (MTI) is a superficial surgical procedure used to prevent hearing loss in children with serous otitis media. Intravenous anesthesia, often ketamine, is preferred for this procedure because of its ability to induce sedation without compromising airway reflexes. However, ketamine alone may be insufficient and potentially lead to spontaneous movement during surgery. This study evaluated the effectiveness of midazolam and fentanyl as adjuvants to ketamine in reducing spontaneous movement during MTI and enhancing the quality of recovery. Methods: This study involved two groups of 30 patients each: one group received intravenous ketamine (1.5 mg/kg) with an equal volume of normal saline (K group), while the other received a combination of midazolam, fentanyl, and ketamine (0.05 mg/kg, 1 µg/kg, and 1.5 mg/kg, respectively; MFK group). We assessed side effects, intraoperative patient movement, surgeon satisfaction, and emergence agitation scores. Results: The MFK group exhibited significantly lower scores for patient movement (p<0.01) and emergence agitation (p<0.01) and markedly higher surgeon satisfaction scores (p<0.01) than the K group. Conclusion: Administering a midazolam-fentanyl-ketamine combination effectively reduced spontaneous movement during surgery and emergence agitation during recovery without prolonging discharge times in children undergoing MTI.

Survey of Pediatric Status Epilepticus Treatment Practices and Adherence to Management Guidelines (Pedi-SPECTRUM e-Survey).

Aim: Survey of treatment practices and adherence to pediatric status epilepticus (PSE) management guidelines in India. Methods: This eSurvey was conducted over 35 days (15th October to 20th November 2023) and included questions related to hospital setting; antiseizure medications (ASMs); ancillary treatment; facilities available; etiology; and adherence to PSE management guidelines. Results: A total of 170 respondents participated, majority of them were working in tertiary level hospitals (94.1%) as pediatric intensivists (56.5%) and pediatricians (19.4%), and were in clinical practice for 2-10 years (46.5%). Majority use intravenous (IV) midazolam and levetiracetam as first- and second-line ASMs (67.1 and 51.2%, respectively). In cases with refractory status epilepticus (RSE), the most commonly used ASM is midazolam infusion (92.4%). For super-refractory status epilepticus (SRSE), the commonly used third-line ASMs include midazolam infusion (34.1%), thiopentone infusion (26.5%), high dose phenobarbitone (18.2%), and ketamine infusion (15.3%). Overall, in cases with SRSE, 44.7% respondents use ketamine infusion, 42.5% use add-on oral topiramate, and 34.7% use high-dose phenobarbitone (1-3 mg/kg/hour) infusion. Most respondents targeted both clinical and EEG seizure control (48.8%). Ancillary treatment used for SRSE included IV pyridoxine (57.1%), methylprednisolone (45.3%), IVIG (42.4%), ketogenic diet (40.6%), and second-line immunomodulation (33.5%). Most common causes were febrile SE, viral encephalitis, and febrile illness-related epilepsy syndrome (60.6%, 52.4%, and 37.1%, respectively). Facilities available included pediatric intensive care units (PICU) (97.1%), mechanical ventilation (98.2%), pediatric neurologist (68.8%), MRI brain (86.5%), EEG (69.4%), and viral PCR (58.2%). The compliance with guidelines for timing of initiation of ASM ranged from 63.5 to 88.8%. Conclusion: Intravenous midazolam bolus/es, levetiracetam, and midazolam infusion are commonly used first-, second-, and third-line ASMs, respectively. There were wide variations in use of ASMs for RSE and SRSE, ancillary treatment, and compliance to PSE management guidelines. How to cite this article: Suthar R, Angurana SK, Nallasamy K, Bansal A, Muralidharan J. Survey of Pediatric Status Epilepticus Treatment Practices and Adherence to Management Guidelines (Pedi-SPECTRUM e-Survey). Indian J Crit Care Med 2024;28(5):504-510.

Continuous Sedation in Palliative Care in Portugal: A Prospective Multicentric Study.

Objective: This study aimed to survey the practice of palliative sedation in Portugal, where data on this subject were lacking. Methods: This was a prospective multicentric study that included all patients admitted to each team that agreed to participate. Patients were followed until death, discharge, or after 3 months of follow-up. Results: The study included 8 teams: 4 as palliative care units (PCU), 1 as a hospital palliative care team (HPCT), 2 as home care (HC), and 1 as HPCT and HC. Of the 361 patients enrolled, 52% were male, the median age was 76 years, and 285 (79%) had cancer. Continuous sedation was undergone by 49 (14%) patients: 26 (53%) were male, and the median age was 76. Most patients, 46 (94%), had an oncological diagnosis. Only in a minority of cases, the family, 16 (33%), or the patient, 5 (10%), participated in the decision to sedate. Delirium was the most frequent symptom leading to sedation. The medication most used was midazolam (65%). In the multivariable analysis, only age and the combined score were independently associated with sedation; patients <76 years and those with higher levels of suffering had a higher probability of being sedated. Conclusions: The practice of continuous palliative sedation in Portugal is within the range reported in other studies. One particularly relevant point was the low participation of patients and their families in the decision-making process. Each team must have a deep discussion on this aspect.

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults.

INTRODUCTION: Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. METHODS: In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10 mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax). RESULTS: Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10 min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1 h post-injection. DISCUSSION/CONCLUSION: This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10 min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.

Seizures require urgent treatment when they last longer than 5 min. Indeed, when prolonged, seizures can lead to damage to the brain, coma, and ultimately death. Midazolam injected in the muscle (i.e., intramuscular (IM) injection) has become the first-line treatment of choice for long-lasting seizures and is usually administered with a syringe and 30-mm needle. The ZENEO^® needle-free auto-injector is an innovative, pre-filled, single-dose, disposable, ready-to-use, two-step device that could become an alternative method for midazolam IM administration. This study therefore compared midazolam IM injections with the ZENEO^® auto-injector versus IM injections with a conventional syringe and needle. The ZENEO^® auto-injector was tested in different conditions (on bare skin, through clothing, in the thigh, and in the hip) in healthy volunteers. The study showed, with a pharmacokinetic analysis (how much and how fast a drug is taken in the bloodstream), that midazolam absorption was similar in all tested conditions, indicating that the ZENEO^® auto-injector is a suitable method for midazolam administration. In addition, the study showed that in the first 10 min of the injection, the amount of midazolam in the blood seemed to be higher when injections were performed with the ZENEO^® auto-injector, suggesting that seizure treatment may start working sooner if injected with the device. This is particularly important and relevant in emergency situations and prehospital settings in order to prevent long-lasting seizures and irreversible damage to the brain (which can occur when a crisis lasts for 30 min) and ultimately improve the patient's outcome.

Evaluating Sedation Strategies for Magnetic Resonance Imaging: A Comprehensive Review of Intravenous Fentanyl, Butorphanol, and Midazolam in Adult and Pediatric Populations.

Magnetic resonance imaging (MRI) is a critical diagnostic tool that often requires patient sedation to ensure optimal image quality and patient comfort, particularly in those with anxiety or an inability to remain still. This comprehensive review examines the efficacy, safety, and practical considerations of three commonly used intravenous sedatives, namely, fentanyl, butorphanol, and midazolam, in adult populations undergoing MRI procedures. This review highlights the pharmacological profiles, advantages, and limitations associated with each sedative agent through a detailed analysis of current literature, clinical guidelines, and practice-based evidence. Fentanyl is noted for its potent analgesic properties and rapid onset of action, making it suitable for painful procedures. Butorphanol, with its unique opioid agonist-antagonist activity, presents an alternative with a balance between analgesia and sedation, potentially offering a safer profile for certain patient populations. Midazolam, widely recognized for its anxiolytic and amnestic effects, remains a staple in managing procedure-related anxiety. The review further discusses patient selection criteria, dosing strategies, and the importance of individualized sedation planning to enhance patient experience and procedural outcomes. Future directions highlight the potential of emerging sedation agents and non-pharmacological approaches to improve patient comfort and compliance. The findings underscore the necessity for healthcare providers to adapt sedation practices to the specific needs of each patient, considering both the clinical context and the inherent characteristics of the sedative agents. This review aims to guide clinicians in selecting the most appropriate sedation strategy for adult patients undergoing MRI, optimizing patient care and diagnostic efficacy.