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.

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.

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.

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.

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.

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.

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.

Ketamine as an Alternative Anesthetic for Augmenting Seizure Durations During Electroconvulsive Therapy: A Retrospective Observational Study.

OBJECTIVE: Electroconvulsive therapy (ECT) is highly effective for severe psychiatric disorders; however, short seizure durations may lead to ineffective therapy. This retrospective study aimed to examine the risks and benefits of switching to ketamine anesthesia to augment seizure durations during an acute course of ECT. METHODS: We included 33 patients who underwent ketamine anesthesia due to suboptimal seizures during an acute course of ECT. We assessed seizure duration, stimulus dose, hemodynamic variability, and postseizure complications before and after switching to ketamine. RESULTS: Age was significantly associated with suboptimal seizures during ECT ( P = 0.040). After switching to ketamine, 32 patients (97%) experienced prolonged seizure duration. Ketamine significantly prolonged both electroencephalogram and motor seizure durations with a mean difference of 34.6 seconds (95% confidence interval [CI], 26.4-42.7 seconds; P < 0.001) and 26.6 seconds (95% CI, 19.6-33.6 seconds; P < 0.001), respectively. It also significantly reduced stimulus dose (mean difference, -209.5 mC [95% CI, -244.9 to -174.1 mC]; P < 0.001). In addition, maximum changes in systolic blood pressure and heart rate during ECT sessions significantly increased with ketamine (mean difference, 27.2 mm Hg [95% CI, 12.0-42.4 mm Hg; P = 0.001]; 25.7 beats per minute [95% CI, 14.5-36.8 beats per minute; P < 0.001], respectively). Patients reported more headaches with ketamine ( P = 0.041). CONCLUSIONS: Our results provide evidence that ketamine as an alternative anesthetic can augment seizure durations in specific patients experiencing suboptimal seizures during an acute course of ECT. However, its use requires greater attention to circulatory management and postseizure complications.

Pharmacokinetics of Ketamine Transfer Into Human Milk.

PURPOSE/BACKGROUND: Ketamine is an N -methyl- d -aspartate-antagonistic dissociative anesthetic infused intermittently for off-label management of treatment-resistant depression, acute suicidality, and postpartum depression. Despite the prevalence of postpartum depression nearing upward of 15% of deliveries, almost no research has been done to evaluate its safety during lactation. METHODS: In this study, human milk samples were released from the InfantRisk Center's Human Milk Biorepository of 4 participants treated with intermittent ketamine infusions (49-378 mg) to determine the levels of the drug and its active norketamine metabolite using liquid chromatography-mass spectrometry. RESULTS: The absolute infant dose of ketamine from human milk was 0.003 to 0.017 mg/kg per day, and norketamine was 0.005 to 0.018 mg/kg per day. The relative infant dose (RID) for ketamine ranged from 0.34% to 0.57%. The RID for norketamine ranged from 0.29% to 0.95%. There were no reported infant adverse effects. CONCLUSION: The findings of this study suggest that the transfer of ketamine, as well as its active metabolite, norketamine, into human milk is minimal, as estimated by RIDs less than 1% in all participants. These relative doses are well below standardly accepted safety thresholds.

Longitudinal effects of ketamine on cell proliferation and death in the CNS of zebrafish.

Zebrafish is known for its widespread neurogenesis and regenerative capacity, as well as several biological advantages, which turned it into a relevant animal model in several areas of research, namely in toxicological studies. Ketamine is a well-known anesthetic used both in human as well as veterinary medicine, due to its safety, short duration and unique mode of action. However, ketamine administration is associated with neurotoxic effects and neuronal death, which renders its use on pediatric medicine problematic. Thus, the evaluation of ketamine effects administration at early stages of neurogenesis is of pivotal importance. The 1-41-4 somites stage of zebrafish embryo development corresponds to the beginning of segmentation and formation of neural tube. In this species, as well as in other vertebrates, longitudinal studies are scarce, and the evaluation of ketamine long-term effects in adults is poorly understood. This study aimed to assess the effects of ketamine administration at the 1-4 somites stage, both in subanesthetic and anesthetic concentrations, in brain cellular proliferation, pluripotency and death mechanisms in place during early and adult neurogenesis. For that purpose, embryos at the 1-4 somites stage (10.5 h post fertilization - hpf) were distributed into study groups and exposed for 20 min to ketamine concentrations at 0.2/0.8 mg/mL. Animals were grown until defined check points, namely 50 hpf, 144 hpf and 7 months adults. The assessment of the expression and distribution patterns of proliferating cell nuclear antigen (PCNA), of sex-determining region Y-box 2 (Sox 2), apoptosis-inducing factor (AIF) and microtubule-associated protein 1 light chain 3 (LC3) was performed by Western-blot and immunohistochemistry. The results evidenced the main alterations in 144 hpf larvae, namely in autophagy and in cellular proliferation at the highest concentration of ketamine (0.8 mg/mL). Nonetheless, in adults no significant alterations were seen, pointing to a return to a homeostatic stage. This study allowed clarifying some of the aspects pertaining the longitudinal effects of ketamine administration regarding the CNS capacity to proliferate and activate the appropriate cell death and repair mechanisms leading to homeostasis in zebrafish. Moreover, the results indicate that ketamine administration at 1-4 somites stage in the subanesthetic and anesthetic concentrations despite some transitory detrimental effects at 144 hpf, is long-term safe for CNS, which are newly and promising results in this research field.