Developmental anaesthesia neurotoxicity in humans: finding the sweet spot?

A recent human epidemiological study in this issue of British Journal of Anaesthesia examined the association between anaesthesia exposure in pregnant women undergoing appendicectomy or cholecystectomy and the subsequent diagnosis of behavioural disorders in their offspring. When compared with unexposed children, prenatally exposed children had ∼30% greater likelihood of a diagnosis of disruptive or internalising behavioural disorders. Although these data are new and interesting, they should be interpreted with caution. Indeed, appendicitis and cholecystitis can produce acute and chronic systemic inflammation, and maternal immune activation can affect fetal neurodevelopment through inflammatory and epigenetic mechanisms. It is, therefore, possible that the findings are related to maternal and fetal inflammation than to anaesthesia exposure. As there is no causal evidence for the implication that anaesthesia and surgery induce such pathologies, it is unwise to consider alternative treatments when surgery is indicated in pregnant patients.

Dexmedetomidine in paediatric anaesthesia: a call for action?

Dexmedetomidine is increasingly used in paediatric anaesthesia practice. In this issue of the British Journal of Anaesthesia, a retrospective hospital registry study in anaesthetised children showed that intraoperative use of dexmedetomidine was dose-dependently associated with a longer postanaesthesia care unit length of stay. Dexmedetomidine administration was also associated with higher total hospital costs and higher odds of unwarranted haemodynamic effects, while the onset of emergence delirium was not reduced. Although these results could curb enthusiasm for paediatric use of dexmedetomidine, they might also trigger discussion about our approach in the postoperative period to children having received dexmedetomidine intraoperatively.

Pediatric anesthesia in Europe: Variations within uniformity.

Organization of healthcare strongly differs between European countries and results in country-specific requirements in postgraduate medical training. Within the European Union (EU), the European Board of Anaesthesiology has set recommendations of training for the Specialty of Anaesthesiology including standards for Postgraduate Medical Specialist training including a description for providing service in pediatric anesthesia. However, these standards are advisory and not mandatory. Here we aimed to review the current state and associated challenges of pediatric anesthesia training in Europe. We report an important country-specific variability both in training and regulations of practice of pediatric anesthesia in the EU and in the United Kingdom. The requirements for training in pediatric anesthesia varies between nothing specified (Belgium) or providing anesthesia with direct supervision to a minimum of 50 cases below 5 years of age (Germany) to 3-6 month clinical practice in a specialized pediatric hospital (France). Likewise, the regulations for providing anesthesia to children varies from no regulations at all (Belgium) to age specific requirements and centralization of all children below 4 years of age to specified centers (United Kingdom). Officially recognized pediatric anesthesia fellowship programs are not available in most countries of Europe. It remains unclear if and how country-specific differences in pediatric anesthesia training are associated with clinical outcomes in pediatric perioperative care. There is converging interest and support for the establishment of a European pediatric anesthesia curriculum.

Carbonic anhydrase seven bundles filamentous actin and regulates dendritic spine morphology and density.

Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO2 , intracellular carbonic anhydrase (CAi ) isoforms CA2 and CA7 contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms in neurons suggests that they may serve isozyme-specific functions unrelated to CO2 -(de)hydration. Here, we show that CA7, unlike CA2, binds to filamentous actin, and its overexpression induces formation of thick actin bundles and membrane protrusions in fibroblasts. In CA7-overexpressing neurons, CA7 is enriched in dendritic spines, which leads to aberrant spine morphology. We identified amino acids unique to CA7 that are required for direct actin interactions, promoting actin filament bundling and spine targeting. Disruption of CA7 expression in neocortical neurons leads to higher spine density due to increased proportion of small spines. Thus, our work demonstrates highly distinct subcellular expression patterns of CA7 and CA2, and a novel, structural role of CA7.

Opioids and autism spectrum disorder: liaisons dangereuses?

A recent laboratory study in the Journal examined the effects of repeated exposures of neonatal mice to fentanyl on autism-like behaviour via opioid receptor-mediated DNA hypermethylation of the Grin2B gene, which encodes the GluN2B subunit of the NMDA receptor. These experiments provide mechanisms and biological plausibility but do not directly demonstrate that opioid exposure in early life induces autism spectrum disorder in humans. Experimental modelling of human neuropsychiatric disorders is extremely challenging since most subjective psychiatric symptoms used to establish diagnosis in humans cannot be convincingly ascertained in laboratory rodents. While some human epidemiological data show associations between repeated exposures to opioids during early life, it remains undetermined whether opioid exposure is an independent risk factor for developing autism spectrum disorder in the young.

Unanswered questions of anesthesia neurotoxicity in the developing brain.

PURPOSE OF REVIEW: This article reviews recent advances and controversies of developmental anesthesia neurotoxicity research with a special focus on the unanswered questions in the field both from clinical and preclinical perspectives. RECENT FINDINGS: Observational cohort studies of prenatal and early childhood exposure to anesthesia have reported mixed evidence of an association with impaired neurodevelopment. Meta-analyses of currently available studies of early childhood exposure to anesthesia suggest that, while limited to no change in general intelligence can be detected, more subtle deficits in specific neurodevelopmental domains including behavior and executive function may be seen. Several studies have evaluated intraoperative blood pressure values and neurocognitive outcomes and have not found an association. Although many animal studies have been performed, taking into consideration other peri-operative exposures such as pain and inflammation may help with translation of results from animal models to humans. SUMMARY: Advances have been made in the field of developmental anesthetic neurotoxicity over the past few years, including the recognition that anesthetic exposure is associated with deficits in certain cognitive domains but not others. Although the most important question of whether anesthetic agents actually cause long-term neurodevelopmental effects in children has still not been answered, results from recent studies will guide further studies necessary to inform clinical decision-making in children.

Isoelectric Electroencephalography in Infants and Toddlers during Anesthesia for Surgery: An International Observational Study.

BACKGROUND: Intraoperative isoelectric electroencephalography (EEG) has been associated with hypotension and postoperative delirium in adults. This international prospective observational study sought to determine the prevalence of isoelectric EEG in young children during anesthesia. The authors hypothesized that the prevalence of isoelectric events would be common worldwide and associated with certain anesthetic practices and intraoperative hypotension. METHODS: Fifteen hospitals enrolled patients age 36 months or younger for surgery using sevoflurane or propofol anesthetic. Frontal four-channel EEG was recorded for isoelectric events. Demographics, anesthetic, emergence behavior, and Pediatric Quality of Life variables were analyzed for association with isoelectric events. RESULTS: Isoelectric events occurred in 32% (206 of 648) of patients, varied significantly among sites (9 to 88%), and were most prevalent during pre-incision (117 of 628; 19%) and surgical maintenance (117 of 643; 18%). Isoelectric events were more likely with infants younger than 3 months (odds ratio, 4.4; 95% CI, 2.57 to 7.4; P < 0.001), endotracheal tube use (odds ratio, 1.78; 95% CI, 1.16 to 2.73; P = 0.008), and propofol bolus for airway placement after sevoflurane induction (odds ratio, 2.92; 95% CI, 1.78 to 4.8; P < 0.001), and less likely with use of muscle relaxant for intubation (odds ratio, 0.67; 95% CI, 0.46 to 0.99; P = 0.046]. Expired sevoflurane was higher in patients with isoelectric events during preincision (mean difference, 0.2%; 95% CI, 0.1 to 0.4; P = 0.005) and surgical maintenance (mean difference, 0.2%; 95% CI, 0.1 to 0.3; P = 0.002). Isoelectric events were associated with moderate (8 of 12, 67%) and severe hypotension (11 of 18, 61%) during preincision (odds ratio, 4.6; 95% CI, 1.30 to 16.1; P = 0.018) (odds ratio, 3.54; 95% CI, 1.27 to 9.9; P = 0.015) and surgical maintenance (odds ratio, 3.64; 95% CI, 1.71 to 7.8; P = 0.001) (odds ratio, 7.1; 95% CI, 1.78 to 28.1; P = 0.005), and lower Pediatric Quality of Life scores at baseline in patients 0 to 12 months (median of differences, -3.5; 95% CI, -6.2 to -0.7; P = 0.008) and 25 to 36 months (median of differences, -6.3; 95% CI, -10.4 to -2.1; P = 0.003) and 30-day follow-up in 0 to 12 months (median of differences, -2.8; 95% CI, -4.9 to 0; P = 0.036). Isoelectric events were not associated with emergence behavior or anesthetic (sevoflurane vs. propofol). CONCLUSIONS: Isoelectric events were common worldwide in young children during anesthesia and associated with age, specific anesthetic practices, and intraoperative hypotension.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons.

KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Independently of its canonical function as a K-Cl cotransporter, KCC2 regulates the actin cytoskeleton via molecular interactions mediated through its large intracellular C-terminal domain (CTD). Contrary to the common assumption that embryonic neocortical projection neurons express KCC2 at non-significant levels, here we show that loss of KCC2 enhances apoptosis of late-born upper-layer cortical projection neurons in the embryonic brain. In utero electroporation of plasmids encoding truncated, transport-dead KCC2 constructs retaining the CTD was as efficient as of that encoding full-length KCC2 in preventing elimination of migrating projection neurons upon conditional deletion of KCC2. This was in contrast to the effect of a full-length KCC2 construct bearing a CTD missense mutation (KCC2R952H ), which disrupts cytoskeletal interactions and has been found in patients with neurological and psychiatric disorders, notably seizures and epilepsy. Together, our findings indicate ion transport-independent, CTD-mediated regulation of developmental apoptosis by KCC2 in migrating cortical projection neurons.

Lasting impact of general anaesthesia on the brain: mechanisms and relevance.

General anaesthesia is usually considered to safely induce a reversible brain state allowing the performance of surgery under optimal conditions. An increasing number of clinical and experimental observations, however, suggest that anaesthetic drugs, especially when they are administered at the extremes of age, can trigger long-term morphological and functional alterations in the brain. Here, we review available mechanistic data linking general-anaesthesia exposure to impaired cognitive performance in both young and mature nervous systems. We also provide a critical appraisal of the translational value of animal models and highlight the important challenges that need to be addressed to strengthen the link between laboratory work and clinical investigations in the field of anaesthesia-neurotoxicity research.

Morbidity and mortality after anaesthesia in early life: results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE).

BACKGROUND: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. METHODS: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. RESULTS: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04-1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15-1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7-3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64-7.71) and mortality (RR=19.80; 95% CI, 5.87-66.7). CONCLUSIONS: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants. CLINICAL TRIAL REGISTRATION: NCT02350348.

Standards for preclinical research and publications in developmental anaesthetic neurotoxicity: expert opinion statement from the SmartTots preclinical working group.

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work.

An approach to using pharmacokinetics and electroencephalography for propofol anesthesia for surgery in infants.

Safe and effective techniques for propofol total intravenous anesthesia (TIVA) in infants are not well imbedded into clinical practice, resulting in practitioner unfamiliarity and potential for over- and under-dosing. In this education article, we describe our approach to TIVA dosing in infants and toddlers (birth to 36 months) which combines the use of pharmacokinetic models with EEG multi-parameter analysis. Pharmacokinetic models describe propofol and remifentanil effect site concentrations (Ce) over time in different age groups for a given dosing regimen. These models display substantial biological variability between individuals within age groups, impeding their application to clinical practice. Nevertheless, they reveal that younger infants require a higher propofol loading dose, a lower propofol maintenance dose, and a higher remifentanil dose compared with older infants. Proprietary EEG indices (eg, Bispectral Index) can serve as a biomarker of propofol Ce in adults and children to guide dosing to the individual patient; however, they are not recommended for infants as their validity remains uncertain this population. In our experience, EEG waveforms and processed parameters can reflect propofol Ce in infants, reflected by spectral edge frequency (SEF), density spectral array (DSA), and waveform patterns. In our practice, we use a "lookup table" of age-based dosing regimens or target-controlled infusion (TCI) based on the pharmacokinetic models to deliver a target propofol Ce and co-administer remifentanil and/or regional technique for analgesia. We analyze Electroencephalogram (EEG) waveforms, SEF, and DSA to adjust the propofol dose or TCI target concentration to the individual infant. EEG analysis mitigates against biological variability inherent in the pharmacokinetic models and has improved our experience with TIVA for infants.

A systematic review of outcomes reported inpediatric perioperative research: A report from the Pediatric Perioperative Outcomes Group.

The Pediatric Perioperative Outcomes Group (PPOG) is an international collaborative of clinical investigators and clinicians within the subspecialty of pediatric anesthesiology and perioperative care which aims to use COMET (Core Outcomes Measures in Effectiveness Trials) methodology to develop core outcome setsfor infants, children and young people that are tailored to the priorities of the pediatric surgical population.Focusing on four age-dependent patient subpopulations determined a priori for core outcome set development: i) neonates and former preterm infants (up to 60 weeks postmenstrual age); ii) infants (>60 weeks postmenstrual age - <1 year); iii) toddlers and school age children (>1-<13 years); and iv) adolescents (>13-<18 years), we conducted a systematic review of outcomes reported in perioperative studies that include participants within age-dependent pediatric subpopulations. Our review of pediatric perioperative controlled trials published from 2008 to 2018 identified 724 articles reporting 3192 outcome measures. The proportion of published trials and the most frequently reported outcomes varied across pre-determined age groups. Outcomes related to patient comfort, particularly pain and analgesic requirement, were the most frequent domain for infants, children and adolescents. Clinical indicators, particularly cardiorespiratory or medication-related adverse events, were the most common outcomes for neonates and infants < 60 weeks and were the second most frequent domain at all other ages. Neonates and infants <60 weeks of age were significantly under-represented in perioperative trials. Patient-centered outcomes, heath care utilization, and bleeding/transfusion related outcomes were less often reported. In most studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the post-anesthesia care unit or the first 24 postoperative hours. The outcomes identified with this systematic review will be combined with patient centered outcomes identified through a subsequent stakeholder engagement study to arrive at a core outcome set for each age-specific group.

Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: The antidepressant effect of ketamine is associated with increased activity in the reward circuitry of the brain and a suppression of circuitry that mediates perceptual processing of negative emotions. The duration of ketamine effect on these brain structures remains to be defined. WHAT THIS ARTICLE TELLS US THAT IS NEW: As expected, ketamine administration led to an improvement in mood and global vigilance. The improvement in mood was accompanied by an increased recruitment of the orbitofrontal cortex, ventral striatum, medial substantial nigra and ventral tegmental area, structures that are part of the reward circuitry.Responses in the mesolimbic structures (amygdala, medial substantial nigra and ventral tegmental area, orbitofrontal cortex) to negative stimuli were decreased after ketamine administration.The data are consistent with the premise that ketamine induces sustained changes in the mesolimbic neural circuits to reset pathological reward and emotional processing. BACKGROUND: Ketamine rapidly improves maladaptive mood states in major depressive disorder, and some of the neural substrates underlying this therapeutic effect have been identified. This study aimed to identify functional changes within neural networks that may underlie the impact of ketamine on both reward and emotional processing in patients with treatment-resistant major depression. METHODS: Ten adult patients with a Montgomery-Åsberg Depression Rating Scale score above 25 were enrolled to receive a single intravenous administration of ketamine (0.5 mg/kg). Patients' performance along with related neural network activations were analyzed in a game-like reward task and in an emotional judgment task using functional magnetic resonance imaging 1 day before and 1 and 7 days after ketamine administration. RESULTS: A significant correlation (R = 0.46, P = 0.03) between the improvement of depression scores and the enhanced reaction time for positive items was found in the game-like reward task 1 day after ketamine administration. This enhanced sensitivity for rewarded items was accompanied by increased activity of reward-related brain regions, including the orbitofrontal cortex, ventral striatum, and the ventral tegmental area, an effect that persisted up to 1 week after ketamine injection. In the emotional judgment task, it was found that ketamine rapidly modified local brain activities in response to emotionally negative, positive, or neutral stimuli in the amygdala, insula, anterior cingulate cortex, and in the ventral tegmental area. CONCLUSIONS: Single bolus ketamine administration rapidly triggers lasting changes in mesolimbic neural networks to improve pathologic reward and emotional processing in patients with major depressive disorder.

European Society of Anaesthesiology Task Force on Nitrous Oxide: a narrative review of its role in clinical practice.

Nitrous oxide (N2O) is one of the oldest drugs still in use in medicine. Despite its superior pharmacokinetic properties, controversy remains over its continued use in clinical practice, reflecting in part significant improvements in the pharmacology of other anaesthetic agents and developing awareness of its shortcomings. This narrative review describes current knowledge regarding the clinical use of N2O based on a systematic and critical analysis of the available scientific literature. The pharmacological properties of N2O are reviewed in detail along with current evidence for the indications and contraindications of this drug in specific settings, both in perioperative care and in procedural sedation. Novel potential applications for N2O for the prevention or treatment of chronic pain and depression are also discussed. In view of the available evidence, we recommend that the supply of N2O in hospitals be maintained while encouraging its economic delivery using modern low flow delivery systems. Future research into its potential novel applications in prevention or treatment of chronic conditions should be pursued to better identify its role place in the developing era of precision medicine.

Statistical Analysis Plan for "An international multicenter study of isoelectric electroencephalography events in infants and young children during anesthesia for surgery".

This Statistical Analysis Plan details the statistical procedures to be applied for the analysis of data for the multicenter electroencephalography study. It consists of a basic description of the study in broad terms and separate sections that detail the methods of different aspects of the statistical analysis, summarized under the following headings (a) Background; (b) Definitions of protocol violations; (c) Definitions of objectives and other terms; (d) Variables for analyses; (e) Handling of missing data and study bias; (f) Statistical analysis of the primary and secondary study outcomes; (g) Reporting of study results; and (h) References. It serves as a template for researchers interested in writing a Statistical Analysis Plan.

An open label pilot study of a dexmedetomidine-remifentanil-caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study.

BACKGROUND: Concern over potential neurotoxicity of anesthetics has led to growing interest in prospective clinical trials using potentially less toxic anesthetic regimens, especially for prolonged anesthesia in infants. Preclinical studies suggest that dexmedetomidine may have a reduced neurotoxic profile compared to other conventional anesthetic regimens; however, coadministration with either anesthetic drugs (eg, remifentanil) and/or regional blockade is required to achieve adequate anesthesia for surgery. The feasibility of this pharmacological approach is unknown. The aim of this study was to determine the feasibility of a remifentanil/dexmedetomidine/neuraxial block technique in infants scheduled for surgery lasting longer than 2 hours. METHODS: Sixty infants (age 1-12 months) were enrolled at seven centers over 18 months. A caudal local anesthetic block was placed after induction of anesthesia with sevoflurane. Next, an infusion of dexmedetomidine and remifentanil commenced, and the sevoflurane was discontinued. Three different protocols with escalating doses of dexmedetomidine and remifentanil were used. RESULTS: One infant was excluded due to a protocol violation and consent was withdrawn prior to anesthesia in another. The caudal block was unsuccessful in two infants. Of the 56 infants who completed the protocol, 45 (80%) had at least one episode of hypertension (mean arterial pressure >80 mm Hg) and/or movement that required adjusting the anesthesia regimen. In the majority of these cases, the remifentanil and/or dexmedetomidine doses were increased although six infants required rescue 0.3% sevoflurane and one required a propofol bolus. Ten infants had at least one episode of mild hypotension (mean arterial pressure 40-50 mm Hg) and four had at least one episode of moderate hypotension (mean arterial pressure <40 mm Hg). CONCLUSION: A dexmedetomidine/remifentanil neuraxial anesthetic regimen was effective in 87.5% of infants. These findings can be used as a foundation for designing larger trials that assess alternative anesthetic regimens for anesthetic neurotoxicity in infants.

Efficacy and Safety of a Rapid Intravenous Injection of Ketamine 0.5 mg/kg in Treatment-Resistant Major Depression: An Open 4-Week Longitudinal Study.

BACKGROUND: Ketamine has been documented for its rapid antidepressant effects. However, optimal dose and delivery route have not yet been thoroughly investigated. The objectives of this study were to document the safety and test the antidepressant and antisuicidal effects of a single rapid 1-minute injection of ketamine 0.5 mg/kg in treatment-resistant depression (TRD). METHODS: Ten patients with TRD were included in an open, noncontrolled 4-week study and received a rapid intravenous dose of ketamine 0.5 mg/kg. Main outcome measure was the Montgomery-Åsberg Depression Rating Scale and suicidality was assessed using the Scale for Suicide Ideation. RESULTS: Rapid injection of ketamine elicited transient increase of blood pressure and altered states of consciousness in all patients and mild psychotomimetic effects in 4 patients, which all resolved without any intervention. Decrease of depression severity was observed from 40-minute postinjection until day 15. Eight patients became responders within 1 day and all were nonresponders after 4 weeks. The decrease of suicidal ideation was significant until day 7. Analysis indicated that higher severity of depression and anxiety at baseline predicted a larger Montgomery-Åsberg Depression Rating Scale decrease after 4 weeks. CONCLUSIONS: This study suggests that in well-controlled medical settings with adequate monitoring, a single rapid 1-minute injection of ketamine 0.5 mg/kg can be well tolerated and is efficacious in rapidly reducing depression symptoms and suicidal thoughts in outpatients with TRD. These findings are relevant to the practice of general clinical psychiatry and emergency departments were ketamine can have a place in acute management of TRD. Larger studies are necessary to confirm these results.