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.

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.

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.

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.

EVALUATION OF A COMBINATION OF TILETAMINE-ZOLAZEPAM, MEDETOMIDINE, AND AZAPERONE WITH NASAL OXYGEN SUPPLEMENTATION FOR THE IMMOBILIZATION OF CAPTIVE CHACOAN PECCARIES (CATAGONUS WAGNERI) IN THE CHACO REGION OF PARAGUAY.

A combination of tiletamine-zolazepam, medetomidine, and azaperone was used to immobilize captive Chacoan peccaries (Catagonus wagneri) for health assessments and biological sample collection at the Centro Chaqueño para la Conservación e Investigación (CCCI) in the Paraguayan Chaco during July in 2017 and 2018. In total, 83 peccaries kept in 0.25-1.50 hectare enclosures were immobilized via dart-administered anesthetic. Mean animal weight was 33.89±3.74 kg (standard deviation; n=77). The mean intramuscular (IM) anesthetic drug and dosages were 0.03±0.00 mg/kg of medetomidine, 0.91±0.10 mg/kg of Zoletil 50 (tiletamine-zolazepam), and 0.30±0.03 mg/kg azaperone. The mean time to recumbency after darting was 6.07±2.65 min. The mean time to reach the anesthetic plane postdarting was 10.00±2.00 min. Muscle relaxation was adequate to allow minor veterinary procedures. A mean dosage of 0.15±0.02 mg/kg of atipamezole was given IM to reverse the medetomidine. Recoveries were smooth and animals were standing by 59.17±30.18 min postreversal. Full recovery and release back to enclosures occurred 90±30 min postreversal. A single dose of this drug combination provided adequate anesthesia for 88% of adult Chacoan peccaries; 12% needed a supplemental dose of tiletamine-zolazepam because of failure to receive the full dose from the anesthetic dart. Sex and age did not impact the dosage required to achieve immobilization. Confinement during recovery from anesthesia is required with this protocol. Aside from mild hypoxemia, no adverse effects from anesthesia were observed. However, oxygen supplementation as a part of this protocol is recommended to support circulatory and respiratory capacity.

Several reasons why ketamine as a neuroplastic agent may have failed to prevent postoperative delirium: Implications for future protocols.

Ketamine exerts anti-inflammatory, neuroprotective and neuroplastic activity, therefore it may counteract the neurotoxic processes underlying postoperative delirium. However, the majority of studies in this field failed. We identified several pharmacological reasons why these studies may have failed, together with suggestions of how to remediate them. Among them, the interaction with intravenous general anesthetics exerting the opposite effect on GABA interneurons than ketamine may be of principal importance. We suggest biomarkers which may elucidate the influence of this interaction on the different steps of neuroplastic pathways. We hypothesize that administering ketamine before or after general anesthesia could both prevent the interactions and strengthen the effect of ketamine by timing surgery within the climax of ketamine-induced neuroplastic changes or by stabilizing AMPA receptors. It is vital to deal with these questions because the protocols of ongoing studies are based again on the administration of ketamine during general anesthesia (the major identified pitfall).

Intubation Rates following Prehospital Administration of Ketamine for Acute Agitation: A Systematic Review and Meta-Analysis.

BACKGROUND: Ketamine is a fast-acting, dissociative anesthetic with a favorable adverse effect profile that is effective for managing acute agitation as a chemical restraint in the prehospital and emergency department (ED) settings. However, some previously published individual studies have reported high intubation rates when ketamine was administered prehospitally. OBJECTIVE: This systematic review aims to determine the rate and settings in which intubation following prehospital administration of ketamine for agitation is occurring, as well as associated indications and adverse events. METHODS: We searched PubMed, Scopus, Ovid MEDLINE, Embase, CINAHL Plus, PsycINFO, the Cochrane Library, ClinicalTrials.gov, OpenGrey, Open Access Theses and Dissertation, and Google Scholar from the earliest possible date until 13/February/2022. Inclusion criteria required studies to describe agitated patients who received ketamine in the prehospital setting as a first-line drug to control acute agitation. Reference lists of appraised studies were screened for additional relevant articles. Study quality was assessed using the Newcastle-Ottawa quality assessment scale. Synthesis of results was completed via meta-analysis, and the GRADE tool was used for certainty assessment. RESULTS: The search yielded 1466 unique records and abstracts, of which 50 full texts were reviewed, resulting in 18 being included in the analysis. All studies were observational in nature and 15 were from USA. There were 3476 patients in total, and the overall rate of intubation was 16% (95% confidence interval [CI] = 8%-26%). Most intubations occurred in the ED. Within the studies, the prehospital intubation rate ranged from 0% to 7.9% and the ED intubation rate ranged from 0 to 60%. The overall pooled prehospital intubation rate was 1% (95% CI = 0%-2%). The overall pooled ED intubation rate was 19% (95% CI = 11%-30%). The most common indications for intubation were for airway protection and respiratory depression/failure. CONCLUSIONS: There is wide variation in intubation rates between and within studies. The majority of intubations performed following prehospital administration of ketamine for agitation took place in the ED.

Ketamine-dexmedetomidine combination for sedation in pediatric major surgery in a low-income country.

Anorectal malformations are one of the most frequent congenital malformations treated by pediatric surgeons. In low-income countries, the surgical and anesthetic management of children in need of these procedures can be challenging. Limited oxygen supply, lack of equipment, especially pediatric, and intensive care units make the use of regional anesthesia appealing. We present a series of four cases of anorectal malformations corrections in Guinea Bissau, in children up to 13 months of age, under regional anesthesia and sedation with ketodex, a mixture of ketamine and dexmedetomidine (in a proportion of 1 mg to 1 µg). No child developed respiratory depression requiring airway intervention or supplemental oxygen, or had hemodynamic instability.

Electrocardiography, Blood Pressure Measurements, Vital Parameters and Anaesthetic Indices in the African Giant Rat (Cricetomys Gambianus Waterhouse) Immobilized with Diazepam or Ketamine.

In spite of the increasing use and importance of the African giant rat (Cricetomys gambianus Waterhouse) in research, and other fields, like location of landmines, there is still not enough information on their physiology. In this study, we assessed the electrocardiogram, blood pressure, vital parameters and anaesthetic indices of the African giant rat (Cricetomys gambianus Waterhouse), both genders, using diazepam or ketamine as chemical restraints. A total of 24 adult African Giant Rats (AGR), 12 males and 12 females were used in this experiment. The animals were divided into two groups of twelve animals each (6 males and 6 females). One group was assessed for the effect of diazepam, and the other group ketamine. Diazepam (Roche®, Switzerland) was administered intraperitoneally at a dose rate of 7.5 mg/kg, while ketamine was administered intraperitoneally at a dose rate of 45 mg/kg. Parameters measured were recorded from the time desirable sedation was achieved, and every 15 minutes till the animal was awake. Animals administered diazepam took a longer time to sleep or achieve desirable sedative state, a longer time to respond to stimuli before waking up fully and a longer time to be fully awake, relative to ketamine-induced sedation. Ketamine caused a continuous increase in respiratory rate and blood pressure, while diazepam caused a continuous decrease in the respiratory rate. The electrocardiogram showed tachycardia throughout the experiment with the use of both drugs, although this was more pronounced with the use of diazepam, causing a decrease in QRS interval and a decrease in QT interval. Gender differences were observed in most parameters measured. The results obtained gave baseline values for electrocardiogram and blood pressure readings, while also detailing the changes and gender differences observed with sedation. In addition, results indicated ketamine is best used for short procedures and diazepam at a higher dose used for procedures requiring longer time in the African giant rat.