Ketamine-assisted buprenorphine initiation: a pilot case series.

BACKGROUND: Many people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone. METHODS: Patients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4-8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3-6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience. RESULTS: Over a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients. CONCLUSIONS: Ketamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.

A systematic review and meta-analysis of ketamine in pediatric status epilepticus.

OBJECTIVE: Status epilepticus (SE) is a common neurological medical emergency in the pediatric population, with 10%-40% of cases progressing to refractory SE (RSE), requiring treatment with anesthetic infusions. We present a systematic review and meta-analysis of the use of ketamine for the treatment of pediatric SE and its potential advantages over other anesthetic infusions. METHODS: This review follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Electronic databases, including PubMed, Cochrane Library, Ovid, Embase, and Google Scholar, were searched with the keywords "pediatrics," "status epilepticus," and "ketamine treatment." Randomized trials, prospective and retrospective cohort studies, and case reports were considered for inclusion. RESULTS: Eighteen publications met the initial inclusion criteria. The 18 publications comprise 11 case reports, one nonconclusive clinical trial, two case series, and four retrospective cohorts. After excluding the case reports because of reporting bias, only the six case series and cohorts were included in the final analysis. There were 172 patients in the six included studies. The weighted age was 9.93 (SD = 10.29) years. The weighted maximum dose was 7.44 (SD = 9.39) mg/kg/h. SE cessation was attained in 51% (95% confidence interval = 43-59) of cases with the addition of ketamine. The heterogeneity was I2 = 0%, t2 = 0, χ2 (5) = 3.39 (p = .64). SIGNIFICANCE: Pediatric RSE is difficult to treat, resulting in increased morbidity and mortality. Without strong recommendations and evidence regarding preferred agents, this review provides evidence that ketamine may be considered in managing SE in the pediatric population.

Exploring the impact of music on response to ketamine/esketamine: A scoping review.

Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of music and ketamine-or esketamine (the S(+) enantiomer of ketamine)-in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.

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.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Review article: Efficacy of prophylactic ondansetron versus placebo or control in reducing vomiting in children undergoing ketamine procedural sedation in the emergency department: A systematic review and meta-analysis.

Ketamine is commonly used for procedural sedation anaesthesia in paediatric patients undergoing painful procedures in the ED. Ketamine's safety profile is excellent, but ketamine-associated vomiting (KAV) is common. Routine ondansetron prophylaxis could reduce KAV incidence. This literature review evaluated the efficacy of prophylactic ondansetron in reducing KAV incidence. A systematic literature review was performed on databases and trial registries on 14 January 2023 to identify randomised controlled trials. The primary outcome was reduction in KAV incidence, for any route of prophylactic ondansetron, in ED and up to 24 h post-discharge. ED length of stay, parental satisfaction and time to resumption of normal diet were secondary outcomes. Data analysis was performed using Revman 5.3. Meta-analysis was performed using random effects modelling. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Evidence quality was assessed using Grading of Recommendation, Assessment Development and Evaluation methodology. Five trials with 920 participants met the eligibility criteria. Prophylactic ondansetron resulted in a reduction in KAV incidence overall odds ratio of 0.51 (95% confidence interval: 0.36-0.73). Intravenous and intramuscular prophylactic ondansetron showed benefit whereas the effect of oral administration was unclear. There was no difference between groups for secondary outcomes overall. The quality of evidence was deemed to be low overall because of high risk of bias and imprecision in outcome measures. This review found low to moderate certainty evidence that prophylactic ondansetron reduces KAV incidence. Methodologically rigorous research, with appropriately timed prophylactic ondansetron based on the route of administration, would further elucidate prophylactic oral ondansetron's efficacy.

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.

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.

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.

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.

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.