High-order brain interactions in ketamine during rest and task: a double-blinded cross-over design using portable EEG on male participants.

Ketamine is a dissociative anesthetic that induces a shift in global consciousness states and related brain dynamics. Portable low-density EEG systems could be used to monitor these effects. However, previous evidence is almost null and lacks adequate methods to address global dynamics with a small number of electrodes. This study delves into brain high-order interactions (HOI) to explore the effects of ketamine using portable EEG. In a double-blinded cross-over design, 30 male adults (mean age = 25.57, SD = 3.74) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Ketamine induced an increase in redundancy in brain dynamics (copies of the same information that can be retrieved from 3 or more electrodes), most significantly in the alpha frequency band. Redundancy was more evident during resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine's HOI and experiences of derealization. Ketamine appears to increase redundancy and HOI across psychometric measures, suggesting these effects are correlated with alterations in consciousness towards dissociation. In comparisons with event-related potential (ERP) or standard functional connectivity metrics, HOI represent an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations between electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

A systematic review and meta-analysis of ketamine in pediatric status epilepticus.

OBJECTIVE: Status epilepticus (SE) is a common neurological medical emergency in the pediatric population, with 10%-40% of cases progressing to refractory SE (RSE), requiring treatment with anesthetic infusions. We present a systematic review and meta-analysis of the use of ketamine for the treatment of pediatric SE and its potential advantages over other anesthetic infusions. METHODS: This review follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Electronic databases, including PubMed, Cochrane Library, Ovid, Embase, and Google Scholar, were searched with the keywords "pediatrics," "status epilepticus," and "ketamine treatment." Randomized trials, prospective and retrospective cohort studies, and case reports were considered for inclusion. RESULTS: Eighteen publications met the initial inclusion criteria. The 18 publications comprise 11 case reports, one nonconclusive clinical trial, two case series, and four retrospective cohorts. After excluding the case reports because of reporting bias, only the six case series and cohorts were included in the final analysis. There were 172 patients in the six included studies. The weighted age was 9.93 (SD = 10.29) years. The weighted maximum dose was 7.44 (SD = 9.39) mg/kg/h. SE cessation was attained in 51% (95% confidence interval = 43-59) of cases with the addition of ketamine. The heterogeneity was I2 = 0%, t2 = 0, χ2 (5) = 3.39 (p = .64). SIGNIFICANCE: Pediatric RSE is difficult to treat, resulting in increased morbidity and mortality. Without strong recommendations and evidence regarding preferred agents, this review provides evidence that ketamine may be considered in managing SE in the pediatric population.

Dependence of rhythmic activity and oddball effects in the rat cortex on the depth of sedation during dissociative anesthesia.

The reactions to novelty manifesting in mismatch negativity in the rat brain were studied. During dissociative anesthesia, mismatch negativity-like waves were recorded from the somatosensory cortex using an epidural 32-electrode array. Experimental animals: 7 wild-type Wistar rats and 3 transgenic rats. During high-dose anesthesia, deviant 1,500 Hz tones were presented randomly among many standard 1,000 Hz tones in the oddball paradigm. "Deviant minus standard_before_deviant" difference waves were calculated using both the classical method of Naatanen and method of cross-correlation of sub-averages. Both methods gave consistent results: an early phasic component of the N40 and later N100 to 200 (mismatch negativity itself) tonic component. The gamma and delta rhythms power and the frequency of down-states (suppressed activity periods) were assessed. In all rats, the amplitude of tonic component grew with increasing sedation depth. At the same time, a decrease in gamma power with a simultaneous increase in delta power and the frequency of down-states. The earlier phasic frontocentral component is associated with deviance detection, while the later tonic one over the auditory cortex reflects the orienting reaction. Under anesthesia, this slow mismatch negativity-like wave most likely reflects the tendency of the system to respond to any influences with delta waves, K-complexes and down-states, or produce them spontaneously.

Exploring the impact of music on response to ketamine/esketamine: A scoping review.

Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of music and ketamine-or esketamine (the S(+) enantiomer of ketamine)-in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.

British Association of Urological Surgeons Consensus statements on the management of ketamine uropathy.

OBJECTIVES: To provide guidance in the form of consensus statement in the management of ketamine uropathy. METHODS: A literature review of ketamine uropathy was performed. The consensus method was of a modified nominal group technique and has been use in the previous British Association of Urological Surgeons (BAUS) consensus documents and was led by the Female, Neurological and Urodynamic Urology Section of the BAUS. RESULTS: A number of consensus statements detailing the assessment and management of urological complications relate to the recreational use of ketamine (ketamine uropathy) in both elective and emergency urology settings. CONCLUSION: Comprehensive management pathway for ketamine-related urinary tract dysfunction and uropathy has been detailed.

The impact of scheduling ketamine as an internationally controlled substance on anaesthesia care in Sub-Saharan Africa: a case study and key informant interviews.

BACKGROUND: Access to anaesthesia and surgical care is a major problem for people living in Sub-Saharan Africa. In this region, ketamine is critical for the provision of anaesthesia care. However, efforts to control ketamine internationally as a controlled substance may significantly impact its accessibility. This research therefore aims to estimate the importance of ketamine for anaesthesia and surgical care in Sub-Saharan Africa and assess the potential impact on access to ketamine if it were to be scheduled. METHODS: This research is a mixed-methods study, comprising of a cross-sectional survey at the hospital level in Rwanda, and key informant interviews with experts on anaesthesia care in Sub-Saharan Africa. Data on availability of four anaesthetic agents were collected from hospitals (n = 54) in Rwanda. Semi-structured interviews with 10 key informants were conducted, collecting information on the importance of ketamine, the potential impact of scheduling ketamine internationally, and opinions on misuse of ketamine. Interviews were transcribed verbatim and analysed using a thematic analysis approach. RESULTS: The survey conducted in Rwanda found that availability of ketamine and propofol was comparable at around 80%, while thiopental and inhalational agents were available at only about half of the hospitals. Significant barriers impeding access to anaesthesia care were identified, including a general lack of attention given to the specialty by governments, a shortage of anaesthesiologists and migration of trained anaesthesiologists, and a scarcity of medicines and equipment. Ketamine was described as critical for the provision of anaesthesia care as a consequence of these barriers. Misuse of ketamine was not believed to be an issue by the informants. CONCLUSION: Ketamine is critical for the provision of anaesthesia care in Sub-Saharan Africa, and its scheduling would have a significantly negative impact on its availability for anaesthesia care.

Effects of ketamine on penile tissues in an experimental priapism model in rats.

BACKGROUND: This study aimed to evaluate the histopathological and biochemical effects of ketamine on penile tissues following ischemia-reperfusion injury induced by priapism. METHODS: Twenty-four male rats were randomized into three groups. Group 1 served as the control group. Group 2 underwent the priapism model to induce ischemia-reperfusion injury. Group 3, the treatment group, experienced a similar ischemia-reperfusion model as Group 2; additionally, 50 mg/kg of ketamine was administered intraperitoneally just before reperfusion. Blood biochemical analyses and penile histopathological evaluations were performed. RESULTS: In Group 3, significant improvements were observed in all histopathological scores, including desquamation, edema, inflammation, and vasocongestion compared to Group 2 (p<0.001). Blood biochemical analyses showed that the malondialdehyde (MDA) levels were recorded as 10 in Group 2, with a significant decrease in Group 3 (p=0.013). Similarly, proinflammatory cytokine levels, including interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were found to be suppressed in Group 3 compared to Group 2 (p=0.003, p=0.022, and p=0.028, respectively). Antioxidant enzyme activities, such as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), were higher in Group 3 compared to Group 2 (p=0.016 and p=0.024, respec-tively). CONCLUSION: Ketamine is an effective anesthetic agent in alleviating the effects of penile ischemia-reperfusion injury.

Current concepts in ketamine therapy in the emergency department.

Ketamine has been in use since its development as a dissociative anesthetic in the 1960s, but it was largely confined to the operating theater or austere environments until used by emergency physicians to facilitate painful procedures in children. As the unique effects of ketamine across its dose-response curve were understood, new applications emerged. In low doses, ketamine has found an important role alongside or instead of opioids in the management of severe pain, and methods to slow its absorption allow higher, more effective doses while attenuating psychoperceptual effects. Ketamine's unique anesthetic properties have inspired its use as an induction agent for intubation without a paralytic and for the rapid, safe control of dangerously agitated patients. Emerging uses for ketamine in acute care include treatment for status epilepticus and alcohol withdrawal syndrome; however, its most important rising indication may be as an emergency treatment of depression and suicidality.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

FIRST REPORT OF CHEMICAL IMMOBILIZATION AND PHYSIOLOGICAL PARAMETERS FOR FREE-RANGING MANED SLOTH (BRADYPUS TORQUATUS), USING A COMBINATION OF KETAMINE AND MEDETOMIDINE.

The maned sloth (Bradypus torquatus) is an endemic and endangered species of two Brazilian states, with much unknown biological information needed to direct conservation actions. Other sloth species have been studied regarding anesthesia; however, there is a lack of anesthesia research for the maned sloth. Anesthetic data were collected from 12 free-range maned sloths that were immobilized for a field examination. Individuals were anesthetized using a combination of ketamine (4.0 mg/kg) and medetomidine (0.03 mg/kg), and antagonized with atipamezole (0.1 mg/kg). Time to induction and recovery were recorded and compared with sex and age classes. After the induction and until antagonist administration, physiological parameters (rectal temperature, heart rate, respiratory rate, and oxygen saturation) were recorded every 10 min during anesthesia and were statistically evaluated over time. Induction was fast (3.21 ± 0.76), but recovery was longer (113.3 ± 18) when compared to other studies. Induction and recovery times were not different across sex or age classes. Rectal temperature, heart rate, and oxygen saturation remained stable throughout the procedure. Respiratory rate significantly decreased over time, from 18.25 ± 7.03 to 13.17 ± 3.66 movements per minute. Our results indicate that the described combination of ketamine and medetomidine is a safe and effective choice for anesthesia of maned sloths.

Efficacy and safety of ketamine alone and ketamine-dexmedetomidine combination for sedation for brain computed tomography in paediatric patients with head injuries: A retrospective study.

OBJECTIVE: To compare the efficacy and safety of ketamine alone with those of ketamine-dexmedetomidine combination for sedation during brain CT in paediatric patients with head injuries. METHODS: We retrospectively analysed the data of paediatric patients who underwent sedation for brain CT at the ED. We included patients aged 6 months to 6 years with American Society of Anesthesiologists physical status I or II. The sedative protocol involved the administration of intramuscular (IM) ketamine 3 mg/kg (K), ketamine 2 mg/kg with dexmedetomidine 1.5 µg/kg (KD) or ketamine 1.5 mg/kg with dexmedetomidine 1.5 µg/kg (low-KD). The primary and secondary outcomes were sedation failure and adverse events, respectively. RESULTS: We included 77 patients; among them, 28, 23 and 26 were in the K, KD and low-KD groups, respectively. In multivariable analysis, the combination groups (KD and low-KD groups) were significantly associated with a lower possibility of sedation failure compared to the K group (adjusted odds ratio, 0.12; 95% confidence interval, 0.02-0.56). Moreover, there were no significant differences in adverse events between the groups, and the sedation-related time variables also did not significantly differ among the three groups. CONCLUSIONS: Our findings indicated that a combination of IM ketamine-dexmedetomidine provides effective sedation for paediatric patients undergoing brain CT without significant adverse events. Further research is needed to investigate the potential benefits of using lower doses of ketamine in combination.

Review article: Efficacy of prophylactic ondansetron versus placebo or control in reducing vomiting in children undergoing ketamine procedural sedation in the emergency department: A systematic review and meta-analysis.

Ketamine is commonly used for procedural sedation anaesthesia in paediatric patients undergoing painful procedures in the ED. Ketamine's safety profile is excellent, but ketamine-associated vomiting (KAV) is common. Routine ondansetron prophylaxis could reduce KAV incidence. This literature review evaluated the efficacy of prophylactic ondansetron in reducing KAV incidence. A systematic literature review was performed on databases and trial registries on 14 January 2023 to identify randomised controlled trials. The primary outcome was reduction in KAV incidence, for any route of prophylactic ondansetron, in ED and up to 24 h post-discharge. ED length of stay, parental satisfaction and time to resumption of normal diet were secondary outcomes. Data analysis was performed using Revman 5.3. Meta-analysis was performed using random effects modelling. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Evidence quality was assessed using Grading of Recommendation, Assessment Development and Evaluation methodology. Five trials with 920 participants met the eligibility criteria. Prophylactic ondansetron resulted in a reduction in KAV incidence overall odds ratio of 0.51 (95% confidence interval: 0.36-0.73). Intravenous and intramuscular prophylactic ondansetron showed benefit whereas the effect of oral administration was unclear. There was no difference between groups for secondary outcomes overall. The quality of evidence was deemed to be low overall because of high risk of bias and imprecision in outcome measures. This review found low to moderate certainty evidence that prophylactic ondansetron reduces KAV incidence. Methodologically rigorous research, with appropriately timed prophylactic ondansetron based on the route of administration, would further elucidate prophylactic oral ondansetron's efficacy.

Dual-responsive in situ gelling polymer matrix for tunable ketamine general anesthesia in experimental animals.

Animal experimentation is a critical part of the drug development process and pharmaceutical research. General anesthesia is one of the most common procedures. Careful administration and dosing of anesthetics ensure animal safety and study success. However, repeated injections are needed to maintain anesthesia, leading to adverse effects. Ketamine, a dissociative anesthetic, is commonly used for inducing anesthesia in animals and suffers from a short half-life requiring repeated dosing. Herein, we report a novel system for controlled anesthesia post-intraperitoneal administration. A polymer solution called "premix" was developed using two stimuli-responsive polymers, Pluronic (PF) and Carbopol (CP). As the premix was mixed with ketamine solution and injected, it underwent in situ gelation, hence controlling ketamine release and anesthesia. The PF and CP concentrations were optimized for the gelation temperature and viscosity upon mixing with the ketamine solution. The optimal premix/ketamine formulation (1.5:1) was liquid at room temperature and gel at physiological conditions with favorable mucoadhesion and rheology. Premix retarded the release of ketamine, translating to tunable anesthesia in vivo. Anesthesia duration and recovery were tunable per ketamine dose with minimal side effects. Therefore, we propose the implementation of PF/CP premix as a vehicle for general anesthesia in animals for optimal duration and effect.

Current practice for the chemical immobilisation of non-domestic feline species: An online survey study.

BACKGROUND: Safe chemical immobilisation of wild felids is essential for both conservational management and clinical purposes. However, little is known about drug protocols and current practice. METHODS: This study was designed as an online survey based on a questionnaire. Descriptive/correlation statistics and analysis of proportions were used for data analysis. RESULTS: The preferred immobilisation technique was the use of darts (37% of the respondents), while the most popular drug combination was a mixture of benzodiazepines, alpha-2 adrenoreceptor agonists and dissociative anaesthetics (27%). The inclusion of ketamine in the drug mixture was associated with a quicker anaesthetic onset, as estimated by the participants (p < 0.001). Common complications were prolonged recovery (46%), bradycardia (35%), hypoventilation (32%), hypothermia (26%) and arousal (26%). Commonly encountered problems were inappropriate equipment (39%), lack of suitable drugs (27%) and inadequate knowledge of species-specific pharmacology (29%) and physiology (24%). LIMITATIONS: Incomplete adherence to the Checklist for Reporting Results of Internet E-Surveys is acknowledged. CONCLUSIONS: Drug protocols including both alpha-2 adrenoreceptor agonists and dissociative anaesthetics are preferred in wild felids, and the inclusion of ketamine may be useful to achieve a quick onset. Equipment/drug availability and species-specific knowledge are potential areas of improvement to improve wild felid anaesthesia.