Safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation of elderly patients undergoing ERCP.

BACKGROUND: Proper sedation of patients, particularly elderly individuals, who are more susceptible to sedation-related complications, is of significant importance in endoscopic retrograde cholangiopancreatography (ERCP). This study aims to assess the safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation in elderly patients undergoing ERCP, compared to a group of middle-aged patients. METHODS: The medical records of 610 patients with common bile duct stones who underwent elective ERCP under deep sedation with a three-drug regimen, including midazolam, alfentanil, and propofol at Shandong Provincial Third Hospital from January 2023 to September 2023 were retrospectively reviewed in this study. Patients were categorized into three groups: middle-aged (50-64 years, n = 202), elderly (65-79 years, n = 216), and very elderly (≥ 80 years, n = 192). Intraoperative vital signs and complications were compared among these groups. RESULTS: The three groups showed no significant difference in terms of intraoperative variation of systolic blood pressure (P = 0.291), diastolic blood pressure (P = 0.737), heart rate (P = 0.107), peripheral oxygen saturation (P = 0.188), bispectral index (P = 0.158), and the occurrence of sedation-related adverse events including hypotension (P = 0.170) and hypoxemia (P = 0.423). CONCLUSION: The results suggest that a low-dose three-drug regimen consisting of midazolam, alfentanil, and propofol seems safe and effective for deep sedation of elderly and very elderly patients undergoing ERCP procedures. However, further studies are required to verify these findings and clarify the benefits and risks of this method.

Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

Pharmacological Investigation of Hypoalbuminemia on the Prolonged and Potentiated Action of Midazolam in Rats.

Midazolam (MDZ) is clinically used for its sedative and anticonvulsant properties. However, its prolonged or potentiated effects are sometimes concerning. The main binding protein of MDZ is albumin, and reduced serum albumin levels could lead to MDZ accumulation, thereby potentiating or prolonging its effects. Previous investigations have not thoroughly examined these phenomena from a behavioral pharmacology standpoint. Consequently, this study aimed to evaluate both the prolonged and potentiated effects of MDZ, as well as the effects of serum albumin levels on the action of MDZ in low-albumin rats. Male Wistar rats were classified into control (20% protein diet), low-protein (5% protein), and non-protein groups (0% protein diet) and were fed the protein-controlled diets for 30 d to obtain low-albumin rats. The locomotor activity and muscle relaxant effects of MDZ were evaluated using the rotarod, grip strength, and open-field tests conducted 10, 60, and 120 min after MDZ administration. Serum albumin levels decreased significantly in the low-protein and non-protein diet groups compared with those in the control group. Compared with the control rats, low-albumin rats demonstrated a significantly shorter time to fall, decreased muscle strength, and a significant decrease in the distance traveled after MDZ administration in the rotarod, grip strength, and open-field tests, respectively. Decreased serum albumin levels potentiated and prolonged the effects of MDZ. Hence, serum albumin level is a critical parameter associated with MDZ administration, which should be monitored, and any side effects related to decreased albumin levels should be investigated.

The role of perioperative sedative anesthetics in preventing postoperative delirium: a systematic review and network-meta analysis including 6679 patients.

OBJECTIVE: Postoperative delirium is a common and debilitating complication that significantly affects patients and their families. The purpose of this study is to investigate whether there is an effective sedative that can prevent postoperative delirium while also examining the safety of using sedatives during the perioperative period. METHODS: The net-meta analysis was used to compare the incidence of postoperative delirium among four sedatives: sevoflurane, propofol, dexmedetomidine, and midazolam. Interventions were ranked according to their surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 41 RCT studies involving 6679 patients were analyzed. Dexmedetomidine can effectively reduce the incidence of postoperative delirium than propofol (OR 0.47 95% CI 0.25-0.90), midazolam (OR 0.42 95% CI 0.17-1.00), normal saline (OR 0.42 95% CI 0.33-0.54) and sevoflurane (OR 0.39 95% CI 0.18-0.82). The saline group showed a significantly lower incidence of bradycardia compared to the group receiving dexmedetomidine (OR 0.55 95% CI 0.37-0.80). In cardiac surgery, midazolam (OR 3.34 95%CI 2.04-5.48) and normal saline (OR 2.27 95%CI 1.17-4.39) had a higher rate of postoperative delirium than dexmedetomidine, while in non-cardiac surgery, normal saline (OR 1.98 95%CI 1.44-2.71) was more susceptible to postoperative delirium than dexmedetomidine. CONCLUSION: Our analysis suggests that dexmedetomidine is an effective sedative in preventing postoperative delirium whether in cardiac surgery or non-cardiac surgery. The preventive effect of dexmedetomidine on postoperative delirium becomes more apparent with longer surgical and extubation times. However, it should be administered with caution as it was found to be associated with bradycardia.

Bolus administration of remimazolam was superior to midazolam for deep sedation in elderly patients undergoing diagnostic bronchoscopy: A randomized, double-blind, controlled trial.

BACKGROUND: To date, there is no standardized practice for the use of pharmacological sedatives during flexible bronchoscopy, particularly for elderly patients. This exploratory study aimed to assess the efficacy and safety of remimazolam at a single induced dose for deep sedation in elderly patients undergoing diagnostic flexible bronchoscopy (DFB), and compare with midazolam, a commonly used sedative. METHODS: A total of 100 elderly patients (age range 65-80 yr; American Society of Anesthesiologists Physical Status I-III) undergoing DFB were randomly allocated into 2 groups according to the sedatives used for induction: the remimazolam group and the midazolam group. Sedation induction was initiated by an intravenous bolus of remimazolam (0.135 mg/kg) or midazolam (0.045 mg/kg), respectively, both groups were combined with a high-dose of alfentanil (18 µg/kg), and supplemented with high-flow nasal cannula (HFNC) oxygen supply at a flow rate of 45 L/min. If the target depth of sedation was not achieved, propofol would be titrated as a rescue. The primary outcome was the success rate of sedation at a single induced dose to achieve target depth (Ramsay sedation score [RSS] = 4) during induction, intraoperative changes in vital signs, postoperative follow-up situation and incidence of post-bronchoscopy adverse events were evaluated as secondary outcomes. RESULTS: The success rate of sedation in the remimazolam group was significantly higher than that in the midazolam group (65.2% vs 39.6%, P = .013), while the incidence of extra sleep within 6 hours after procedure was lower in the remimazolam group as compared to the midazolam group (10.9% vs 31.3%, P = .016). No statistically significant differences were observed between the 2 groups regarding hemodynamic fluctuations, incidence of hypoxemia, and cough response during the procedure, as well as postoperative recall, willingness to undergo reexamination, and other post-bronchoscopy adverse events. CONCLUSIONS: Bolus administration of remimazolam offers advantages over midazolam for deep sedation in elderly patients undergoing DFB, in terms of a higher success rate of sedation and a lower incidence of extra sleep within 6 hours after procedure, though the safety profiles of both groups were favorable.

Combined segmental spinal epidural for major spine surgery: a case report.

A woman in her mid-50s, hesitant about general anaesthesia due to a difficult airway, opted for neuraxial anaesthesia for L4 laminectomy with pedicle screw fixation (L3-L5). Preoperatively, she received 150 µg buprenorphine and 1 mg midazolam. In lateral position, a T8-T9 epidural catheter was placed, followed by segmental spinal anaesthesia (2.5 mL 0.5% hyperbaric bupivacaine+30 µg clonidine) at T10-T11. Prone positioning was executed using standard techniques. During the 6-7 hours surgery, three 7 mL epidural top-ups (2% lignocaine epinephrine) were administered at 90 min intervals. Haemodynamics remained stable with 2.5 L crystalloids, 350 mL packed red cells and three ephedrine doses (6 mg each). Sedation included 150 µg buprenorphine and two 1 mg midazolam doses. Postoperatively, she received epidural 0.25% bupivacaine for 2 days, systemic analgesics and was discharged on the sixth day.

Provider Experience With the Use of Ketamine for Refractory Status Epilepticus.

OBJECTIVE: Refractory status epilepticus (RSE) treated with anesthetic agents can be associated with complications including respiratory depression and hypotension. Ketamine is an emerging RSE treatment, but optimal dosing and timing are unknown. We studied provider attitudes and practices regarding the use of ketamine for RSE. METHODS: A literature review informed the creation of the survey, developed by professionals in epilepsy, pharmacy, and neurocritical care. The survey was distributed to members of the Critical Care EEG Monitoring and Research Consortium, Neurocritical Care Society, American Academy of Neurology Synapse community, American Epilepsy Society, and the Canadian League Against Epilepsy. Descriptive statistics were calculated. RESULTS: There were 109 respondents. First-line agents for RSE were midazolam (53%), propofol (42%), pentobarbital (2%), and ketamine (1%). Reasons for ketamine use included failure of midazolam/propofol to control seizures (81%) or hypotension on another anesthetic (35%). Perceived contraindications included hypertension (37%), elevated intracranial pressure (24%), and heart failure (18%). Perceived benefits included decreased use of vasopressors (53%) and more rapid RSE control when used adjunctively (49%). Routine ketamine users often treated more than 10 RSE cases per year, worked as intensivists or at academic institutions. Of the respondents, 59% found ketamine useful for RSE and 94% were interested in learning more about its use. CONCLUSIONS: Although most participants found ketamine helpful for RSE, it is mainly used as a second-line agent adjunctively with midazolam or propofol. Perceived ketamine benefits included decreased need for hemodynamic support and more rapid seizure control when used in conjunction with other anesthetics. Perceived contraindications centered on cardiac and intracranial pressure concerns.

COMPARISON OF THREE MIDAZOLAM-BASED SEDATION PROTOCOLS IN BUDGERIGARS (MELOPSITTACUS UNDULATUS) AND BLACK-CHEEKED LOVEBIRDS (AGAPORNIS NIGRIGENIS).

This randomized, crossover study evaluated three sedation protocols administered subcutaneously in nine budgerigars (Melopsittacus undulatus) and nine black-cheeked lovebirds (Agapornis nigrigenis). All protocols included midazolam (5 mg/kg), combined with butorphanol (5 mg/kg) (BM), medetomidine (20 lg/kg) (MM), or alfaxalone (13 mg/kg) (AM). Mortalities from suspected cardiorespiratory arrest were observed when AM was used in lovebirds, even after reduction of alfaxalone dosage to 3 mg/kg, and therefore this protocol was excluded from further use in this species. Induction and recovery times were recorded and their quality assessed. Sedation depth and heart and respiratory rates were measured every 5 min and radiographic positioning was attempted at 10 and 20 min. At 30 min, midazolam and medetomidine were reversed with flumazenil (0.05 mg/kg, SC), and atipamezole (0.2 mg/kg, SC), respectively. MM consistently provided deep sedation in both species, with successful radiographic positioning at every attempt. As expected, heart rate was often lower with MM than with other protocols, but no associated complications were noted. In budgerigars, BM had the lowest radiographic positioning success rate (10 min: 5/9, 20 min: 3/9), whereas in lovebirds it provided significantly deeper sedation (P < 0.001), allowing radiographic positioning in all subjects. In both species, BM provided the shortest recovery times. AM resulted in reliable radiographic positioning of all budgerigars at 10 min, but not at 20 min (5/ 9), and provided consistently poor recoveries. This study highlights how differently two psittacine species of similar size may react to the same sedation protocols. AM sedation cannot be fully reversed and produced significant undesirable effects, several of which have been previously reported with alfaxalone administration to avian species. The authors therefore caution against using alfaxalone-midazolam combinations in budgerigars and black-cheeked lovebirds. Both BM and MM provided reliable sedation in these species, and appear to be suitable alternatives to AM.

Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication.

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

La adición de midazolam intratecal al anestésico local mejora los bloqueos sensorial y motor y reduce la puntuación del dolor sin incrementar los efectos secundarios en la cirugía de miembros inferiores. Metaanálisis y revisión sistemática / Adding intrathecal midazolam to local anesthetics improves sensory and motor block and reduces pain score without increasing side effects in lower limb surgeries: A meta-analysis and systematic review

Este metaanálisis investiga el impacto de midazolam intratecal en la anestesia espinal, el control del dolor postoperatorio y los efectos secundarios relacionados con la anestesia en la cirugía de miembros inferiores. Realizamos una búsqueda en Medline, Science Direct, Google Scholar y Cochrane Library de los estudios que reportaron el inicio y la duración de los bloqueos sensorial y motor, el tiempo transcurrido hasta la primera solicitud de analgesia, el consumo de opioides durante 24h, el control del dolor postoperatorio y los efectos secundarios tras la administración de midazolam intratecal en pacientes sometidos a cirugía de miembros inferiores. Se identificaron 10 estudios, que se incluyeron en el metaanálisis. La revisión fue realizada siguiendo las directrices PRISMA, registrándose en la base de datos PROSPERO (ID-CRD42022346361) en agosto de 2022. Nuestros resultados muestran que los pacientes que reciben 1mg de midazolam intratecal reflejaron un tiempo de inicio de bloqueo significativamente más alto (p=0,001 [IC: −0,98, −0,31]), mayor duración de los bloqueos sensorial y motor (p<0,00001 [IC: 18,08, 39,12]; p=0,002 [IC: 0,45, 2]), y mayor tiempo transcurrido hasta la primera solicitud de analgesia de rescate (p=0,0003 [IC: 1,22, 4,14]). Las puntuaciones de dolor a las 4 y 12h postoperatorias fueron significativamente inferiores en los pacientes que recibieron midazolam intratecal (p=0,00001 [: −1,20, −0,47] y p=0,05 [IC: −0,52, −0,01] respectivamente). En conclusión, la adición de midazolam intratecal al anestésico local en la cirugía de miembros inferiores acorta el tiempo de inicio de los bloqueos sensorial y motor, incrementa la duración del bloqueo y prolonga el tiempo transcurrido hasta la primera solicitud de analgesia. Las puntuaciones del dolor a las 4 y 12horas postoperatorias fueron menores, no observándose efectos secundarios adicionales.(AU)

This meta-analysis was done to investigate the role of intrathecal midazolam in lower limb surgeries regarding prolongation of spinal block, postoperative pain control and associated side effects. The included studies reported onset and duration of sensory and motor block, time to first request analgesia, 24hours opioid consumption, postoperative pain control, and associated side effects following use of intrathecal midazolam for lower limb surgeries. This review was performed following the PRISMA guidelines and using the online databases, Medline, Science Direct, Google scholar and Cochrane library. We registered this review with the PROSPERO database (ID-CRD42022346361) in August 2022. A total of 10 randomised controlled trials were included in this meta-analysis. Our results showed patients receiving 1mg intrathecal midazolam showed significantly faster onset of sensory block (P=.001 [CI: −0.98, −0.31]). Duration of sensory and motor block were also significantly prolonged in intrathecal midazolam group (P<.00001 [CI: 18.08, 39.12], P=.002 [CI: 0.45, 2]). Intrathecal midazolam also increased the time to first request analgesia (P=.0003 [CI: 1.22, 4.14]). Pain scores at 4 and 12hours postoperatively were significantly lower in patients receiving intrathecal midazolam (P=.00001[CI: −1.20, −0.47] and P=0.05 [CI: −0.52, −0.01] respectively). In conclusion, the addition of intrathecal midazolam to local anesthetics in lower limb surgeries results in early onset of sensory and motor block. It also increases the duration of sensory and motor block. The time to first request analgesia is increased. VAS pain scores at 4 and 12hours postoperatively were also lower without any increased side effects.(AU)

Combined sedation in pediatric magnetic resonance imaging: determination of median effective dose of intranasal dexmedetomidine combined with oral midazolam.

BACKGROUND: The exact median effective dose (ED50) of intranasal dexmedetomidine combined with oral midazolam sedation for magnetic resonance imaging (MRI) examination in children remains unknow and the aim of this study was to determine the ED50 of their combination. METHODS: This is a prospective dose-finding study. A total of 53 children aged from 2 months to 6 years scheduled for MRI examination from February 2023 to April 2023 were randomly divided into group D (to determine the ED50 of intranasal dexmedetomidine) and group M (to determine the ED50 of oral midazolam). The dosage of dexmedetomidine and midazolam was adjusted according to the modified Dixon's up-and-down method, and the ED50 was calculated with a probit regression approach. RESULTS: The ED50 of intranasal dexmedetomidine when combined with 0.5 mg∙kg- 1 oral midazolam was 0.39 µg∙kg- 1 [95% confidence interval (CI) 0.30 to 0.46 µg∙kg- 1] while the ED50 of oral midazolam was 0.17 mg∙kg- 1 (95% CI 0.01 to 0.29 mg∙kg- 1) when combined with 1 µg∙kg- 1 intranasal dexmedetomidine. The sedation onset time of children with successful sedation in group D was longer than in group M (30.0[25.0, 38.0]vs 19.5[15.0, 35.0] min, P < 0.05). No other adverse effects were observed in the day and 24 h after medication except one dysphoria. CONCLUSION: This drug combination sedation regimen appears suitable for children scheduled for MRI examinations, offering a more precise approach to guide the clinical use of sedative drugs in children. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2300068611(24/02/2023).

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

BACKGROUND: Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. AREAS OF UNCERTAINTY: Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. THERAPEUTIC ADVANCES: Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. LIMITATIONS: Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. CONCLUSIONS: Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

RESPONSE AND PHYSIOLOGIC OUTCOMES AFTER BUTORPHANOL, MIDAZOLAM, AND MEDETOMIDINE IMMOBILIZATION AND REVERSAL IN CAPTIVE REINDEER (RANGIFER TARANDUS).

Sedation, recovery response, and physiologic outcomes were evaluated in five captive reindeer (Rangifer tarandus) in Minnesota using a completely reversible immobilization protocol. Reindeer were immobilized with butorphanol (0.23-0.32 mg/kg), midazolam (0.23-0.32 mg/kg), and medetomidine (0.15 mg/kg) (BMM) via IM dart. Induction time (IT), recumbency time (DT), and recovery time (RT) were recorded. Temperature (T), respiratory rate (RR), pulse rate (PR), pulse oximetry (SpO2), arterial blood gas values including oxygen (PaO2), and carbon dioxide (PaCO2) tensions and lactate (Lac) were recorded preoxygen supplementation and 15 min postoxygen supplementation. Reversal was done using naltrexone (2.3-3.0 mg/kg), flumazenil (0.008-0.01 mg/kg) and atipamezole (0.62-0.78 mg/kg) (NFA) IM, limiting recumbency to 1 h. Median IT, DT, and RT were 5 min, 46 min, and 7 min, respectively. SpO2 (92 to 99%, P = 0.125), PaO2 (45.5 to 97 mmHg, P = 0.25), and PaCO2 (46.5 to 54.6 mmHg, P = 0.25) all increased, whereas Lac (3.02 to 1.93 mmol/L, P = 0.25) decreased between baseline and 15 min postoxygen supplementation, without statistical significance. BMM immobilization, and reversal with NFA provided rapid and effective immobilization and recovery, respectively. Oxygen supplementation mitigated hypoxemia in all reindeer.

A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures.

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.

Physiologically based pharmacokinetic modeling to predict the clinical effect of azole antifungal agents as CYP3A inhibitors on azelnidipine pharmacokinetics.

In this study, a physiologically based pharmacokinetic (PBPK) model of the cytochrome P450 3A (CYP3A) substrate azelnidipine was developed using in vitro and clinical data to predict the effects of azole antifungals on azelnidipine pharmacokinetics. Modeling and simulations were conducted using the Simcyp™ PBPK simulator. The azelnidipine model consisted of a full PBPK model and a first-order absorption model. CYP3A was assumed as the only azelnidipine elimination route, and CYP3A clearance was optimized using the pharmacokinetic profile of single-dose 5-mg azelnidipine in healthy participants. The model reproduced the results of a clinical drug-drug interaction study and met validation criteria. PBPK model simulations using azole antifungals (itraconazole, voriconazole, posaconazole, fluconazole, fosfluconazole) and azelnidipine or midazolam (CYP3A index substrate) were performed. Increases in the simulated area under the plasma concentration-time curve from time zero extrapolated to infinity with inhibitors were comparable between azelnidipine (range, 2.11-6.47) and midazolam (range, 2.26-9.22), demonstrating that azelnidipine is a sensitive CYP3A substrate. Increased azelnidipine plasma concentrations are expected when co-administered with azole antifungals, potentially affecting azelnidipine safety. These findings support the avoidance of azole antifungals in patients taking azelnidipine and demonstrate the utility of PBPK modeling to inform appropriate drug use.

Safety and efficacy of dexmedetomidine vs. midazolam in complex gastrointestinal endoscopy: A systematic review and meta-analysis.

OBJECTIVE: This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence. METHODS: Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis. RESULTS: Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients. CONCLUSION: Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.