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.

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.

Paraphimosis Pain Treatment with Nebulized Ketamine in the Emergency Department.

BACKGROUND: Paraphimosis is an acute urological emergency occurring in uncircumcised males that can lead to strangulation of the glans and painful vascular compromise. Ketamine has been used in the emergency department (ED) as an anesthetic agent for procedural sedation, and when administrated in a sub-dissociative dose (low dose) at 0.1-0.3 mg/kg, ketamine has been utilized in the ED and prehospital settings for pain control as an adjunct and as an alternative to opioid, as well as for preprocedural sedation. This report details the case of a pediatric patient who presented to our Pediatric ED with paraphimosis and had his procedural pain treated with ketamine administrated via a breath-actuated nebulizer (BAN). CASE REPORT: This case report illustrates the potential use of ketamine via BAN to effectively achieve minimal sedation for a procedure in pediatric patients in the ED. The patient was a 15-year-old boy admitted to the Pediatric ED complaining of groin pain due to paraphimosis. The patient was given 0.75 mg/kg of nebulized ketamine via BAN, and 15 min after the medication administration the pain score was reduced from 5 to 1 on the numeric pain rating scale. The patient underwent a successful paraphimosis reduction without additional analgesic or sedative agents 20 min after the administration of nebulized ketamine. The patient was subsequently discharged home after 60 min of monitoring, with a pain score of 0. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The use of nebulized ketamine via BAN might represent a viable, noninvasive way to provide a mild sedative and be an effective analgesic option for managing a variety of acute painful conditions and procedures in the pediatric ED.

Ketamine Alleviates Depressive Symptoms in Patients Undergoing Intracranial Tumor Resection: A Randomized Controlled Trial.

BACKGROUND: Depressive symptoms occur in over 40% of neurosurgical patients during the perioperative period. However, no measure has been suggested to have a rapid effect on depressive surgical patients during increasingly shorter stays in the hospital. This study aimed to determine whether ketamine could improve depressive symptoms rapidly and safely during the hospital stay. METHODS: This was a randomized, placebo-controlled, and double-blinded trial. Patients with moderate-to-severe depressive symptoms undergoing elective supratentorial brain tumor resection were randomized to intravenously receive either (1) 0.5 mg·kg-1 ketamine for 40 minutes or (2) an identical volume of normal saline. The primary outcome was treatment response on postoperative day 3, defined as a ≥50% reduction from the baseline depressive score. The secondary outcomes included the rate of remission and safety outcomes. The Montgomery-Åsberg Depression Rating Scale was applied by trained psychiatrists to evaluate depressive symptoms. RESULTS: A total of 84 neurosurgical patients were enrolled in the trial. The response rate was increased by the administration of ketamine (41.5% [17/41] vs 16.3% [7/43]; relative risk [RR]: 2.51, 95% confidence interval [CI], 1.18-5.50) relative to the administration of placebo at 3 days. Furthermore, the remission rate at discharge (29.3% [12/41] vs 7.0% [3/43]; RR: 4.20, 95% CI, 1.28-13.80) was also improved by ketamine. No psychotic symptoms or adverse events were reported to be substantially higher in the ketamine group. CONCLUSIONS: The trial indicates that the intraoperative administration of ketamine could alleviate moderate-to-severe depressive symptoms in neurosurgical patients without worsening safety.

Dissociative symptoms with intravenous ketamine in treatment-resistant depression exploratory observational study.

ABSTRACT: There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety and tolerability concerns arise regarding adverse drug reactions and specific subpopulations. This paper aims to investigate the relationship between dissociative and psychometric measures in course of intravenous ketamine treatment in TRD inpatients with major depressive disorder and bipolar disorder.This study result represents safety data in a population of 49 inpatients with major depressive disorder and bipolar disorder subjects receiving eight 0.5 mg/kg of ketamine intravenous infusions, with a duration of 40 min each, as an add-on treatment to standard-of-care pharmacotherapy, registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). The safety psychometrics assessed dissociation and psychomimetic symptomatology with the Clinician-Administered Dissociative States Scale (CADSS) the Brief Psychiatric Rating Scale (BPRS).The significant differences in CADSS scores between measurements in course of the treatment were observed (P = .003). No significant differences between BPRS measurements were made after infusions. In each case, both BPRS and CADSS values dropped to the "absent" level within 1 hour from the infusion. Neither CADSS nor BPRS scores were associated with the treatment outcome.The study demonstrates a good safety profile of intravenous ketamine as an add-on intervention to current psychotropic medication in TRD. The abatement of dissociation was observed in time with no sequelae nor harm. The study provides no support for the association between dissociation and treatment outcome.This study may be underpowered due to the small sample size. The protocol was defined as a study on acute depressive symptomatology without blinding.

Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial.

STUDY OBJECTIVE: We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation. METHODS: We conducted a randomized clinical trial comparing the rapidity of onset, level of sedation, and adverse effect profile of ketamine compared to a combination of midazolam and haloperidol for behavioral control of emergency department patients with severe psychomotor agitation. We included patients with severe psychomotor agitation measured by a Richmond Agitation Score (RASS) ≥+3. Patients in the ketamine group were treated with a 5 mg/kg intramuscular injection. Patients in the midazolam and haloperidol group were treated with a single intramuscular injection of 5 mg midazolam and 5 mg haloperidol. The primary outcome was the time, in minutes, from study medication administration to adequate sedation, defined as RASS ≤-1. Secondary outcomes included the need for rescue medications and serious adverse events. RESULTS: Between June 30, 2018, and March 13, 2020, we screened 308 patients and enrolled 80. The median time to sedation was 14.7 minutes for midazolam and haloperidol versus 5.8 minutes for ketamine (difference 8.8 minutes [95% confidence interval (CI) 3.0 to 14.5]). Adjusted Cox proportional model analysis favored the ketamine arm (hazard ratio 2.43, 95% CI 1.43 to 4.12). Five (12.5%) patients in the ketamine arm and 2 (5.0%) patients in the midazolam and haloperidol arm experienced serious adverse events (difference 7.5% [95% CI -4.8% to 19.8%]). CONCLUSION: In ED patients with severe agitation, intramuscular ketamine provided significantly shorter time to adequate sedation than a combination of intramuscular midazolam and haloperidol.

Impact of young age on outcomes of emergency department procedural sedation.

OBJECTIVES: Relatively little is known about outcomes of procedural sedation in very young children. Our objective was to examine the association between procedural sedation in young children (≤ 2 years) and the incidence of sedation-related adverse events. METHODS: This is a secondary analysis of a prospective cohort study of children 0 to 18 years undergoing parenteral procedural sedation in six Canadian pediatric emergency departments (ED). The primary risk factor was age ≤ 2 years. Secondary risk factors were sex, procedure type, pre-procedure and sedation medications. The outcomes examined were: serious adverse events (SAE), significant interventions, oxygen desaturation and vomiting. RESULTS: Of the 6295 patients included, 946 (15%) were ≤2 years. Children 13-24 months comprised 90% of the young age group. Children ≤ 2 years were sedated most commonly for laceration repair (n = 450; 47.6%), while orthopedic reduction was most common in children > 2 (n = 3983; 74.5%). Ketamine was the most common medication in both groups, but was used more frequently in children ≤ 2 years (80.9% vs 58.9%; p < 0.001). There was no difference in the odds of SAE (OR 0.83, 95% Confidence Interval (CI) 0.4 to 1.9), significant intervention (OR 0.82, 95% CI 0.4 to 1.7) or oxygen desaturation (OR 0.95, 95% CI 0.7 to 1.3) between age groups, however children ≤ 2 years vomited less frequently (OR 0.24, 95% CI 0.1 to 0.6). CONCLUSIONS: Young age, specifically between 13 and 24 months, was not associated with a significant difference in the incidence of adverse events.

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?"

Maintaining an adequate level of sedation and analgesia plays a key role in the management of traumatic brain injury (TBI). To date, it is unclear which drug or combination of drugs is most effective in achieving these goals. Ketamine is an agent with attractive pharmacological and pharmacokinetics characteristics. Current evidence shows that ketamine does not increase and may instead decrease intracranial pressure, and its safety profile makes it a reliable tool in the prehospital environment. In this point of view, we discuss different aspects of the use of ketamine in the acute phase of TBI, with its potential benefits and pitfalls.

Description of Adverse Events in a Cohort of Dance Festival Attendees with Stimulant-Induced Severe Agitation Treated with Dissociative-Dose Ketamine.

BACKGROUND: Emergency clinicians often treat severe agitation resulting from intoxicants, psychiatric illness, and other CNS or systemic diseases. Recreational drugs-especially stimulants-are frequently used by attendees of electronic dance music festivals (EDMFs), and festivalgoers may become dangerously agitated and pose an immediate threat to themselves and others. Although benzodiazepines and antipsychotics are classically used to treat severe agitation, these medications are burdened by safety concerns including respiratory depression and cardiac arrhythmias. The effects of ketamine when used to treat severe agitation in an exclusive cohort of patients with psychostimulant drug-induced toxicity (PDIT) has not previously been reported, and existing literature describes a widely variant safety profile when ketamine is used for sedation of the agitated patient. OBJECTIVE: To describe ketamine's adverse event profile when used to treat patients with severe agitation resulting from PDIT. METHODS: This is a retrospective, observational study enrolling consecutive patients who presented for medical attention at a large outdoor EDMF over a period of eight days on two consecutive weekends in the summer of 2017. The EDMF had an estimated attendance of 40,000 per weekend. A medical tent was set up on-site; patients were managed by a team of EMS providers, nurses and emergency physicians. Medications used, adverse events and the need for repeat dosing were abstracted from prehospital care reports. RESULTS: Over the course of eight days, 1081 of 1186 patients who were evaluated in the medical tent had a recorded chief complaint. 274 of these patients (25.3%) had a chief complaint of altered mental status. In patients presenting with AMS, 68 patients (24.8%) had severe agitation that was treated with dissociative-dose (≥4 mg/kg) intramuscular ketamine. The mean initial dose of ketamine was 308 mg. There were four serious adverse events (5.9%): Two patients (2.9%) had copious hypersalivation treated with atropine, one patient (1.5%) had transient apnea requiring assisted ventilation, and one patient (1.5%) was intubated and transported to the hospital. 42 patients (61.8%) required redosing of calming medications. All patients who received ketamine except the single patient who was intubated and transported were observed in the medical tent until resolution of symptoms and discharged back to the festival. CONCLUSION: In this cohort of festival attendees who developed stimulant-induced severe agitation and were treated with dissociative-dose ketamine, serious adverse events occurred in 5.9% of patients including one patient who was intubated.

Safety and Efficacy of the Combination of Propofol and Ketamine for Procedural Sedation/Anesthesia in the Pediatric Population: A Systematic Review and Meta-analysis.

BACKGROUND: Drugs such as propofol and ketamine are used alone or in combination to provide sedation for medical procedures in children. The purpose of this systematic review was to compare the safety and effectiveness of propofol and ketamine to other drug regimens. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Web of Science, and the grey literature (meta-Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar) for randomized controlled studies comparing intravenous propofol and ketamine to any other single or combination drug regimen administered to children undergoing diagnostic or therapeutic procedures. Meta-analyses were performed for primary (hemodynamic and respiratory adverse events) and secondary outcomes using RevMan 5.3. We assessed the risk of bias and the certainty (quality) evidence for all outcomes using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-nine studies were included for analysis. Based on low-to-moderate quality evidence, we concluded that the use of propofol and ketamine may result in a slight-to-small reduction in the risk of hypotension, bradycardia, and apnea, and a slight increase in the risk of tachycardia, hypertension, and other respiratory adverse events, such as cough or laryngospasm. The ratio of propofol to ketamine and comparator drug regimen subgroups effects were important for desaturation and some secondary outcomes. CONCLUSIONS: The use of propofol and ketamine had a minimal effect on the incidence of adverse events and other secondary outcomes. Large-scale studies are required to more accurately estimate adverse event rates and the effects of propofol and ketamine on patient-important outcomes.

Comparison of the efficacy of ketamine- propofol versus sodium thiopental-fentanyl in sedation: a randomised clinical trial.

BACKGROUND: Many sedative regimens have been studied with controversial efficiencies. This study tried to assess the desirable and adverse effects of sodium thiopental-fentanyl (TF) with ketamine-propofol (KP) for procedural sedation and analgesia in the emergency department. METHODS: After signing written consent, patients were enrolled in this randomised double-blind trial to receive either KP or TF to reach the desired sedation level. The respiratory and haemodynamic complications, nausea and vomiting, recovery agitation, patient recall and satisfaction, provider satisfaction and recovery time were compared. RESULTS: Of the participants, 47 in the KP group and 49 in the TF group were enrolled. The mean and SD scores were 6.91±1.93 and 8.34±1.25 for patients' satisfaction and 7.55±1.54 and 8.65±1.00 for satisfaction of physicians performing the procedures in TF and KP groups, respectively (p=0.000). Moreover, 39 (79.59%) and 18 (38.29%) of patients declared that they had recalled the procedures in the TF and KP groups, respectively (p=0.000). Transient hypoxia was reported in 2.1% and 8.1% in the KP and TF groups leading to perform 4.2% vs 8.1% airway manoeuvres, respectively, without the need for endotracheal intubation or further admission. CONCLUSIONS: KP and TF combinations were effectively comparable although KP resulted in higher patient and provider satisfaction. This study did not detect a difference regarding adverse respiratory or haemodynamic effects. It is estimated that the TF combination can be potent and efficacious with possible low adverse events in procedural sedation.

Efficacy of ketamine for initial control of acute agitation in the emergency department: A randomized study.

BACKGROUND: Clinicians often encounter agitated patients, and current treatment options include benzodiazepines and antipsychotics. Ketamine rapidly induces dissociation, maintains cardiovascular stability, spontaneous respirations, and airway reflexes. There are no prospective, randomized studies comparing ketamine to other agents in the initial management of acute agitation in the Emergency Department (ED). OBJECTIVE: Determine the efficacy and safety of ketamine compared to parenteral haloperidol plus lorazepam for initial control of acute agitation. METHODS: This study was a prospective, single-institution, randomized, open-label, real world, standard of care pilot study. Adult patients with combative agitation were randomized to ketamine (4 mg/kg IM or 1 mg/kg IV) or haloperidol/lorazepam (haloperidol 5-10 mg IM or IV + lorazepam 1-2 mg IM or IV). The primary outcome was sedation within 5 min, and secondary outcomes included sedation within 15 min, time to sedation, and safety. RESULTS: Ninety three patients were enrolled from January 15, 2018 to October 10, 2018. Significantly more patients who received ketamine compared to haloperidol/lorazepam were sedated within 5 min (22% vs 0%, p = 0.001) and 15 min (66% vs 7%, p < 0.001). The median time to sedation in patients who received ketamine compared to haloperidol/lorazepam was 15 vs 36 min respectively (p < 0.001). Patients who received ketamine experienced a significant, but transient tachycardia (p = 0.01) and hypertension (p = 0.01). CONCLUSION: In patients with combative agitation, ketamine was significantly more effective than haloperidol/lorazepam for initial control of acute agitation, and was not associated with any significant adverse effects.

Negative results for ketamine use in severe acute bronchospasm: a randomised controlled trial.

BACKGROUND: Ketamine has bronchodilation properties. The aim of the single-centre, evaluator-blinded, randomised clinical trial study was to evaluate whether continuous infusion of ketamine is associated with improvement in respiratory mechanics correlated with bronchospasm relief, as compared with continuous infusion of fentanyl. METHODS: Adult patients submitted to invasive mechanical ventilation were included if they had an acute severe bronchospasm, due to status asthmaticus or COPD exacerbation. They were randomised to ketamine or a standard IV analgesia with fentanyl, both in bolus and continuous infusion. Measurements of respiratory mechanics (airway resistance - Rsmax, dynamic compliance - Cdyn and intrinsic PEEP - PEEPi) both at baseline and 3 and 24 h after randomisation were performed. The main outcome of this study was to evaluate the improvement of Rsmax in 3 h of continuous infusion of the study drugs. RESULTS: Ketamine use was not associated with greater reduction in Rsmax when compared with fentanyl, either after 3 h (0 cm H2O L-1 s-1 ± 6 vs. -3 cm H2O L-1 s-1 ± 7.7, respectively; P = 0.16) or after 24 h (-3 cm H2O L-1 s-1 ± 17 vs. -3.5 cm H2O L-1 s-1 ± 13.7, respectively; P = 0.73). Patients randomized to the ketamine group did not have better improvements in delta PEEPi as compared with fentanyl in 3 h (P = 0.77) or in 24 h (P = 0.72). CONCLUSIONS: In this study, ketamine use was not associated with improvement in ventilatory variables associated with bronchospasm.

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Anaesthetic management for hiatal hernia repair in a child with Bartter's syndrome: A case report.

Bartter syndrome is a rare disorder characterized by reduced sodium chloride transport in the distal nephrons of the kidney. Its clinical features are renal salt wasting, hypokalemic metabolic alkalosis, elevated renin and aldosterone levels with normal or low blood pressure, polyuria, hypercalciuria and malnutrition. The pathophysiologic and biochemical changes in these patients should be kept in mind when considering anaesthetic management. This case report describes our management in a nineteen months old, 3.6 kg weight male child with Bartter's syndrome who underwent elective repair of hiatal hernia and gastrostomy.