Ketamine for conscious sedation in pediatric emergency care

The literature concerning the efficacy and safety of ketamine for conscious sedation during procedures in pediatric emergency departments was reviewed. Data were obtained from the Guidelines for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures developed by the American Academy of Pediatrics Committee on Drugs, and from a MEDLINE search (January 1966-July 2004). Search terms were conscious sedation, ketamine, and emergency department; articles relevant to pediatric age group were selected. Clinical end points were efficacy and adverse effects associated with ketamine. Ketamine was effective for conscious sedation in 89-100% of patients in various studies using intravenous, intramuscular, or oral routes of administration. The efficacy of ketamine was similar to or greater than that of other drugs, such as midazolam and the combination of meperidine, promethazine, and chlorpromazine. The main adverse effects of ketamine were emesis, recovery agitation, and emergence phenomena. Ketamine appears to be an effective and well-tolerated agent for conscious sedation in pediatric patients. Overall physician and parent satisfaction with the administration of this agent for conscious sedation was high.     

Ketamine for Bipolar Depression: A Systematic Review

BackgroundKetamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, its efficacy in bipolar depression is less clear. This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression.MethodsWe conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since each database’s inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies.ResultsWe identified 6 studies, with 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials.ConclusionsThere is some preliminary evidence supporting use of intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.     

Intranasal Ketamine and Its Potential Role in Cancer‐Related Pain

Cancer‐related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment using a tiered approach of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N‐methyl‐d ‐aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations but has also been investigated for depression, bipolar disorder, and general and postoperative pain management. As an analgesic, low‐dose ketamine decreases morphine requirements and rates of nausea and vomiting, suggesting a potentially beneficial role in cancer‐related pain. Ketamine is typically administered intravenously and has a rapid onset of action with a relatively short half‐life (2–3 hours) but is inconvenient for use in an ambulatory setting. Oral bioavailability is low and erratic, limiting application of this route for chronic use. Intranasal administration has a number of potential advantages, including avoidance of first‐pass hepatic metabolism, no need for venous access, ability to repeat doses quickly, and rapid absorption. Although early studies of intranasal ketamine are promising in a number of indications, information is more limited in its use as an adjunct in cancer‐related pain. We review the background, rationale, pharmacokinetics, and clinical and safety data using intranasal ketamine as an adjunctive agent and its potential in cancer‐related pain.     

Appetitive nature of drug cues <Emphasis Type="Italic">re</Emphasis>-confirmed with physiological measures and the potential role of stage of change

Rationale A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies. Objective To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset. Materials and methods Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. The safety of ketamine administration was monitored in these subjects. Results Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed. Conclusion Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation. Other members of the Yale Ketamine Study Group are listed in the Acknowledgements.     

Developing an IV Ketamine Clinic for Treatment-Resistant Depression: a Primer

The efficacy of subanesthetic intravenous ketamine for treatment resistant depression (TRD) has spurred a growth of clinics nationwide that provide this service. Ketamine is an FDA-approved drug as an anesthetic but remains unapproved for psychiatric indications, and this status raises a number of short- and long-term safety and efficacy concerns that need to be addressed when implementing and developing this type of clinic. Using a framework of systems, provider, and patient domains, we provide a review of the key challenges in providing ketamine infusions and suggest potential approaches. Under systems issues, we highlight broad stakeholder engagement involving cross-departmental and multidisciplinary considerations, business case development, and delineation of administrative standard operating procedures. In the provider domain, we highlight specific roles for different treatment team members as well as suggested training requirements. In the patient domain, we identify a variety of standard operating procedures involving initial patient assessment parameters, ketamine dosing and administration guidelines, and safety monitoring procedures. Together, this review provides key considerations for developing a ketamine clinic for depression, in an effort to meet the pressing demand for this novel treatment option while helping to ensure its safe implementation.     

Use of cannabidiol in anxiety and anxiety-related disorders

ObjectiveCannabidiol (CBD) has a proposed novel role in the management of anxiety owing to its actions on the endocannabinoid system. The purpose of this systematic review was to evaluate the current evidence on the safety and efficacy of CBD in anxiety and anxiety-related disorders.Data sourcesA literature search was conducted on PubMed, Google Scholar, and International Pharmaceutical Abstracts from database inception through June 2019. A bibliographic search of relevant articles was also conducted.Study selectionArticles published from case reports, case series, or randomized controlled trials on human subjects were included in the review if they examined the safety and efficacy of CBD therapy in anxiety and anxiety-related disorders.Data extractionTwo reviewers independently extracted the following data from the articles: year of publication; study design; patient characteristics (sex; type of anxiety disorder; use of concomitant anxiolytic therapy); dosing strategy and route of CBD administration; and safety and efficacy outcomes.ResultsEight articles were included in the review: 6 small, randomized controlled trials; 1 case series; and 1 case report. These studies examined the role of CBD in the anxiety response of healthy volunteers; in generalized anxiety disorder; in social anxiety disorder; and in the anxiety component of posttraumatic stress syndrome. No articles that evaluated CBD in panic disorder, specific phobia, separation anxiety, and obsessive-compulsive disorder were identified. In the studies, CBD was administered orally as a capsule or as a sublingual spray and as either monotherapy or adjunctive therapy. Doses varied widely, with studies employing fixed CBD doses ranging from 6 mg to 400 mg per dose. Various anxiety assessment scales were used in the studies to assess efficacy, with CBD demonstrating improved clinical outcomes among the instruments. In general, CBD was well-tolerated and associated with minimal adverse effects, with the most commonly noted adverse effects being fatigue and sedation.ConclusionCBD has a promising role as alternative therapy in the management of anxiety disorders. However, more studies with standardized approaches to dosing and clinical outcome measurements are needed to determine the appropriate dosing strategy for CBD and its place in therapy.     

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Ketamine is a glutamate N‐methyl‐D‐aspartate receptor antagonist that is a rapid‐acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well‐characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography–mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non‐compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co‐administration with the SOC following nerve agent exposure in animal models.     

Cyclosporine exacerbates ketamine toxicity in zebrafish: Mechanistic studies on drug–drug interaction

Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium‐permeable N‐methyl‐d ‐aspartic acid receptors. Adverse drug–drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug–drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24 h post‐fertilization (hpf), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl l ‐carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65 , a zebrafish ortholog of human CYP3A4 , both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.     

A review of the nonmedical use of ketamine: use, users and consequences

Ketamine is a dissociative anesthetic with an accepted place in human medicine. Ketamine also has psychedelic properties, and there has been a recent increase in nonmedical use linked with the growth of the "dance culture." This has attracted little comment in the formal literature but has been the subject of many reports in the media. Myths and misunderstandings are common. The psychedelic properties of ketamine have also led to its use as an adjunct to psychotherapy. This review is intended as a resource for the wide range of persons now requesting accurate information about the nonmedical use of ketamine. It accepts the current necessity of sometimes referring to anecdotal reports while seeking to encourage an increase in formal research. The review includes the history of ketamine, its growing role as a "dance drug," the sought-after effects (including the near-death experience) for which it is taken in a nonmedical context, how these are produced, common mental and physical adverse effects, and the ketamine model of schizophrenia.     

A pilot study of intramuscular ziprasidone in the short-term treatment of patients with acute exacerbation of schizophrenia

Ziprasidone is a novel antipsychotic which, in oral formulation, has been shown to be effective and well tolerated in the treatment of acute psychosis. This pilot study examined the efficacy and tolerability of the intramuscular (IM) formulation and the transition from IM to oral ziprasidone in patients with acute schizophrenia. The study design was an open, prospective, 5-day treatment trial of IM ziprasidone followed by oral dosing in 12 patients with acute exacerbation of schizophrenia. Various doses (2.5, 5, 10, or 20 mg) up to 60 mg/day total were administered over 3 days, followed by transition to oral ziprasidone on Days 4-5. All patients completed the study. Mean improvements between baseline and Day 3 were observed in Brief Psychiatric Rating Scale (47.8 to 28.9) and Clinical Global Impression of Severity (6.1 to 5.3), and improvements were maintained on Days 4 and 5. No extrapyramidal syndrome, acute dystonia, or serious adverse events were reported. In these patients, IM ziprasidone 20-60 mg/day reduced psychomotor agitation and other symptoms of psychosis. The transition from IM to oral ziprasidone was well tolerated. Copyright 2000 John Wiley & Sons, Ltd.     

The health and psycho-social consequences of ketamine use

Ketamine is a non-competitive NMDA receptor antagonist that acts as a dissociative anaesthetic with analgesic and amnestic properties. Ketamine has broad areas of application and is a rapidly acting, relatively safe analgesic and anaesthetic agent, particularly for children and is widely used in veterinary practice. Ketamine can induce schizophrenic-like symptoms in healthy adults and schizophrenic patients. It has a wide margin of safety and there are very few cases of pure ketamine overdose recorded, with the majority of deaths due to the dangerous activities or contexts of its use. Information on ketamine is not routinely collected in population surveys and morbidity and mortality data collections. Levels of use in the general population, however, appear to be very low with higher levels in groups with access to the drug, medical and veterinarian professionals, and party drug users. There are a number of potential ketamine effects that may be seen as adverse or harmful, with growing evidence of the physical and psychological symptoms of ketamine dependence among recreational ketamine users. A withdrawal syndrome, including psychotic features, is beginning to be described. The use of ketamine with other neurotoxic drugs, such as alcohol, should be avoided. Increased rates of high risk sexual and injecting behaviours in association with ketamine use, however, have been reported by gay men and marginalised youth in the US. In conclusion, ketamine does not appear to currently pose a significant public health risk, however, at the individual level the usual harm minimisation strategies should be observed.     

Ketamine impairs multiple cognitive domains in rhesus monkeys

Available evidence suggests that recreational use and abuse of the dissociative anaesthetic ketamine is increasing. Characterization of the cognitive risks of ketamine exposure contributes substantially to understanding this growing public health threat. Although prior human studies demonstrate that ketamine impairs a range of cognitive skills, investigation in nonhuman models permits more precise exploration of neurochemical mechanisms which may underlie detrimental behavioral effects. Adult male rhesus monkeys (N=7) were trained on a neuropsychological battery including tests of memory (delayed match-to-sample, DMS; self-ordered spatial search, SOSS), reaction time (RT), reinforcer efficacy and sustained attention (progressive ratio, PR) and fine motor coordination (bimanual motor skill, BMS). Battery performance was then serially challenged with acute doses of ketamine (0.3, 1.0, 1.78 mg/kg IM). Ketamine impaired DMS and SOSS in a dose x difficulty dependent manner with the most difficult task conditions disrupted at the 1.0 and 1.78 mg/kg doses. Thus, both visual recognition memory and working memory indices were affected. Ketamine also slowed RT and BMS performance and interfered with PR performance at the 1.78 mg/kg dose. Overall the present findings confirm that ketamine interferes with multiple aspects of cognition at subanesthetic doses in monkeys.     

Pharmacological properties of ketamine

Ketamine is a dissociative anaesthetic that is being used in non-medical contexts. The effects of ketamine are very similar to those of phencyclidine, another dissociative anaesthetic that has enjoyed considerable popularity as a recreational drug. The effects of ketamine include analgesia, cardiovascular and respiratory stimulation, dissociation, hallucinations and anaesthesia. The potential dangers of uncontrolled ketamine use include psychosis and violence, accidents and marked psychomotor and cognitive impairment. Although studies have shown potential for tolerance to and physical dependence on ketamine, further investigation of these phenomena is needed. Ketamine is thought to produce most of its effects through antagonist activity at the PCP site of the NMDA receptor complex. Ketamine has sympathomimetic properties resulting from enhancement of catecholamine, and particularly dopamine, activity. While opioid receptor activity has been identified, this is relatively weak and the contribution to the effects of ketamine is not clear. Although much is known of the clinical uses and effects of ketamine, as yet little is understood of ketamine as a recreational drug and potential drug of dependence.     

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Aliment Pharmacol Ther 2012; 35: 15–36

Summary

Background Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter‐individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. Aim To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic‐based therapeutic recommendations. Methods We conducted a query on PubMed database using ‘inflammatory bowel disease’, ‘thiopurine’, ‘azathioprine’, ‘6‐mercaptopurine’, ‘TPMT’, ‘pharmacogenetics’, ‘TDM’, and selected relevant articles, especially clinical studies. Results Thiopurine metabolism – key enzyme: thiopurine S‐methyltransferase (TPMT) – modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6‐TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S‐transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP‐binding cassette sub‐family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. Conclusions Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.     

105例小儿氯胺酮手术麻醉的探讨

目的：探讨小儿氯胺酮麻醉术的效果。方法：对105例小儿氯胺酮麻醉术的临床现象进行分析。结果：所有患儿均在5min内安静入睡。患儿术中安静,呼吸平稳,术后清醒时间短,术中及术后无躁动、呕吐等不良反应发生。结论：通过对小儿氯胺酮麻醉术的观察和护理,可以使患儿安全地渡过麻醉危险期,并早日康复出院。     

The effects of phencyclidine and ketamine on sensory thresholds and reaction times in the baboon

Adult male baboons were trained on a reaction time procedure, and absolute thresholds and reaction times to both a 16.0 kHz pure tone and a white light were obtained. Acute IM injections of phencyclidine (0.0032 to 0.1 mg/kg) or ketamine (0.032 to 3.2 mg/kg) were given at the beginning of 2-hr test sessions. Phencyclidine had no effect on auditory thresholds, visual thresholds, or visual reaction times, but selectively elevated auditory reaction times. Ketamine, on the other hand, elevated auditory thresholds and both auditory and visual reaction times, while having no effect on visual thresholds. Ketamine was also less potent than phencyclidine in elevating auditory reaction times, and recovery from these impairments was evident during the two-hour test sessions for ketamine, but not for phencyclidine.