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.

Clinical Practice Guideline for Emergency Department Procedural Sedation With Propofol: 2018 Update.

We update an evidence-based clinical practice guideline for the administration of propofol for emergency department procedural sedation. Both the unique considerations of using this drug in the pediatric population and the substantial new research warrant revision of the 2007 advisory. We discuss the indications, contraindications, personnel requirements, monitoring, dosing, coadministered medications, and adverse events for propofol sedation.

Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults.

STUDY OBJECTIVE: We compare intranasal ketamine with intranasal placebo in providing pain reduction at 30 minutes when added to usual paramedic care with nitrous oxide. METHODS: This was a randomized double-blind study of out-of-hospital patients with acute pain who reported a verbal numeric rating scale (VNRS) pain score greater than or equal to 5. Exclusion criteria were younger than 18 years, known ketamine intolerance, nontraumatic chest pain, altered mental status, pregnancy, and nasal occlusion. Patients received usual paramedic care and were randomized to receive either intranasal ketamine or intranasal saline solution at 0.75 mg/kg. The primary outcome was the proportion of patients with VNRS score reduction greater than or equal to 2 at 30 minutes. Secondary outcomes were pain reduction at 15 minutes, patient-reported comfort, satisfaction scores, nitrous oxide consumption, and incidence of adverse events. RESULTS: One hundred twenty subjects were enrolled. Seventy-six percent of intranasal ketamine patients versus 41% of placebo patients reported a greater than or equal to 2-point VNRS reduction at 30 minutes (difference 35%; 95% confidence interval 17% to 51%). Median VNRS reduction at 15 minutes was 2.0 and 1.0 and at 30 minutes was 3.0 and 1.0 for ketamine and placebo, respectively. Improved comfort at 15 and 30 minutes was reported for 75% versus 57% and 61% versus 46% of ketamine and placebo patients, respectively. Sixty-two percent of patients (95% confidence interval 49% to 73%) versus 20% (95% confidence interval 12% to 32%) reported adverse events with ketamine and placebo, respectively. Adverse events were minor, with no patients requiring physical or medical intervention. CONCLUSION: Added to nitrous oxide, intranasal ketamine provides clinically significant pain reduction and improved comfort compared with intranasal placebo, with more minor adverse events.

The Canadian Community Utilization of Stroke Prevention Study in Atrial Fibrillation in the Emergency Department (C-CUSP ED).

STUDY OBJECTIVE: Lack of oral anticoagulation prescription in the emergency department (ED) has been identified as a care gap in atrial fibrillation patients. This study seeks to determine whether the use of a tool kit for emergency physicians with a follow-up community-based atrial fibrillation clinic resulted in greater oral anticoagulation prescription at ED discharge than usual care. METHODS: This was a before-after study in 5 Canadian EDs in 3 cities. Patients who presented to the ED with atrial fibrillation were eligible for inclusion. The before phase (1) was retrospective; 2 after phases (2 and 3) were prospective: phase 2 used an oral anticoagulation prescription tool for emergency physicians and patient education materials, whereas phase 3 used the same prescription tool, patient materials, atrial fibrillation educational session, and follow-up in an atrial fibrillation clinic. Each phase was 1 year long. The primary outcome was the rate of new oral anticoagulation prescription at ED discharge for patients who were oral anticoagulation eligible and not receiving oral anticoagulation at presentation. RESULTS: A total of 631 patients were included. Mean age was 69 years (SD 14 years), 47.4% were women, and 69.6% of patients had a CHADS2 score greater than or equal to 1. The rate of new oral anticoagulation prescription in phase 1 was 15.8% compared with 54.1% and 47.2%, in phases 2 and 3, respectively. After multivariable adjustment, the odds ratio for new oral anticoagulation prescription was 8.03 (95% confidence interval 3.52 to 18.29) for phase 3 versus 1. The 6-month rate of oral anticoagulation use was numerically but not significantly higher in phase 3 compared with phase 2 (71.6% versus 79.4%; adjusted odds ratio 2.30; 95% confidence interval 0.89 to 5.96). The rate of major bleeding at 6 months was 0%, 0.8%, and 1% in phases 1, 2, and 3, respectively. CONCLUSION: An oral anticoagulation prescription tool was associated with an increase in new oral anticoagulation prescription in the ED, irrespective of whether an atrial fibrillation clinic follow-up was scheduled. The use of an atrial fibrillation clinic was associated with a trend to a higher rate of oral anticoagulation at 6-month follow-up.

Characteristics of and Predictors for Apnea and Clinical Interventions During Procedural Sedation.

STUDY OBJECTIVE: We describe the characteristics of and predictors for apnea and clinical interventions during emergency department (ED) procedural sedation. METHODS: High-resolution data were collected prospectively, using a convenience sample of ED patients undergoing propofol or ketofol sedation. End tidal CO2 (etco2), respiratory rate, pulse rate, and SpO2 were electronically recorded in 1-second intervals. Procedure times, drug delivery, and interventions were electronically annotated. Kaplan-Meier curves were used to describe the onset of clinical interventions as a function of sedation time. The onset of apnea (15 consecutive seconds with carbon dioxide ≤10 mm Hg) and clinical interventions were estimated with a series of Cox proportional hazards survival models, with time to first apnea or clinical intervention as the dependent variable. Finally, we tested the association between apnea and clinical intervention. RESULTS: Three hundred twelve patients were analyzed (53% male patients). Apnea was preceded by etco2 less than 30 mm Hg or greater than 50 mm Hg at 30, 60, and 90 seconds before its onset. Clinical interventions were predicted by apnea, SpO2, and propofol use. Increasing age predicted both apnea and interventions. Apnea was not predicted by respiratory rate or SpO2. Apnea occurred in half of the patients and clinical interventions in a quarter of them. Clinical intervention was not predicted by abnormal respiratory rate or abnormal etco2 level. The majority of clinical interventions (85%) were minor, with no cases of assisted ventilation, intubation, or complications. CONCLUSION: Alterations in etco2 predicted apnea along a specific time course. Alterations in SpO2, apnea, and propofol use predicted clinical interventions. Increasing age predicted both apnea and clinical intervention.

Factors associated with frequent buprenorphine / naloxone initiation in a national survey of Canadian emergency physicians.

OBJECTIVE: To identify individual and site-related factors associated with frequent emergency department (ED) buprenorphine/naloxone (BUP) initiation. BUP initiation, an effective opioid use disorder (OUD) intervention, varies widely across Canadian EDs. METHODS: We surveyed emergency physicians in 6 Canadian provinces from 2018 to 2019 using bilingual paper and web-based questionnaires. Survey domains included BUP-related practice, demographics, attitudes toward BUP, and site characteristics. We defined frequent BUP initiation (the primary outcome) as at least once per month, high OUD prevalence as at least one OUD patient per shift, and high OUD resources as at least 3 out of the following 5 resources: BUP initiation pathways, BUP in ED, peer navigators, accessible addiction specialists, and accessible follow-up clinics. We excluded responses from sites with <50% participation (to minimize non-responder bias) and those missing the primary outcome. We used univariate analysis to identify associations between frequent BUP initiation and factors of interest, stratifying by OUD prevalence. RESULTS: We excluded 3 responses for missing BUP initiation frequency and 9 for low response rate at one ED. Of the remaining 649 respondents from 34 EDs, 374 (58%) practiced in metropolitan areas, 384 (59%) reported high OUD prevalence, 312 (48%) had high OUD resources, and 161 (25%) initiated BUP frequently. Age, gender, board certification and years in practice were not associated with frequent BUP initiation. Site-specific factors were associated with frequent BUP initiation (high OUD resources [OR 6.91], high OUD prevalence [OR 4.45], and metropolitan location [OR 2.39],) as were individual attitudinal factors (willingness, confidence, and responsibility to initiate BUP.) Similar associations persisted in the high OUD prevalence subgroup. CONCLUSIONS: Individual attitudinal and site-specific factors were associated with frequent BUP initiation. Training to increase physician confidence and increasing OUD resources could increase BUP initiation and benefit ED patients with OUD.

The use of ketamine as a neuroprotective agent following cardiac arrest: A scoping review of current literature.

AIMS: The objective of this article is to summarize the state of the literature surrounding the use of ketamine as a neuroprotective agent following cardiac arrest. METHODS: Five electronic databases were used to search for studies related to the use of ketamine for neuroprotection following cardiac arrest. This search was performed once in May 2020, and an updated search was conducted in May 2021 and March 2022. RESULTS: All searches combined retrieved 181 results; no clinical trials were identified. As such, the authors were limited to writing a scoping review of the literature rather than a systematic review. CONCLUSIONS: The current state of the literature describes the mechanism of action of ketamine as a neuroprotective agent through its action as an NMDA antagonist. There is evidence of its efficacy as a neuroprotective agent in preclinical models of cardiac arrest. Current published clinical work supports the use of ketamine ameliorating neurologic outcomes in other conditions such as epilepsy, traumatic brain injury, and depression. The current state of the literature is reflective of the notion that the use of ketamine following cardiac arrest may result in improved neurologic outcomes. Future research directions should focus on the use of ketamine as a possible clinical intervention following cardiac arrest.

Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial.

STUDY OBJECTIVE: We determine whether a 1:1 mixture of ketamine and propofol (ketofol) for emergency department (ED) procedural sedation results in a 13% or more absolute reduction in adverse respiratory events compared with propofol alone. METHODS: Participants were randomized to receive either ketofol or propofol in a double-blind fashion. Inclusion criteria were aged 14 years or older and American Society of Anesthesiology class 1 to 3 status. The primary outcome was the number and proportion of patients experiencing an adverse respiratory event as defined by the Quebec Criteria. Secondary outcomes were sedation consistency, efficacy, and time; induction time; and adverse events. RESULTS: A total of 284 patients were enrolled, 142 per group. Forty-three (30%) patients experienced an adverse respiratory event in the ketofol group compared with 46 (32%) in the propofol group (difference 2%; 95% confidence interval -9% to 13%; P=.80). Three ketofol patients and 1 propofol patient received bag-valve-mask ventilation. Sixty-five (46%) patients receiving ketofol and 93 (65%) patients receiving propofol required repeated medication dosing or progressed to a Ramsay Sedation Score of 4 or less during their procedure (difference 19%; 95% confidence interval 8% to 31%; P=.001). Six patients receiving ketofol were treated for recovery agitation. Other secondary outcomes were similar between the groups. Patients and staff were highly satisfied with both agents. CONCLUSION: Ketofol for ED procedural sedation does not result in a reduced incidence of adverse respiratory events compared with propofol alone. Induction time, efficacy, and sedation time were similar; however, sedation depth appeared to be more consistent with ketofol.

A cross-sectional survey on buprenorphine-naloxone practice and attitudes in 22 Canadian emergency physician groups: a cross-sectional survey.

BACKGROUND: Buprenorphine-naloxone (BUP) initiation in emergency departments improves follow-up and survival among patients with opioid use disorder. We aimed to assess self-reported BUP-related practices and attitudes among emergency physicians. METHODS: We designed a cross-sectional physician survey by adapting a validated questionnaire on opioid harm reduction practices, attitudes and barriers. We recruited physician leads from 6 Canadian provinces to administer surveys to the staff physicians in their emergency department groups between December 2018 and November 2019. We included academic and community non-locum emergency department staff physicians. We excluded responses from emergency department groups with response rates less than 50% to minimize nonresponse bias. Primary (BUP prescribing practices) and secondary (willingness and attitudes) outcomes were analyzed using descriptive statistics. RESULTS: After excluding 1 group for low response (9/26 physicians), 652 of 798 (81.7%) physicians responded from 22 groups serving 34 emergency departments. Among respondents, 64.1% (95% confidence interval [CI] 60.4%-67.8%, emergency department group range 7.1%-100.0%) had prescribed BUP at least once in their career, 38.4% had prescribed it for home initiation and 24.8% prescribed it at least once a month. Overall, 68.9% (95% CI 65.3%-72.4%, emergency department group range 24.1%-97.6%) were willing to administer BUP, 64.2% felt it was a major responsibility and 37.1% felt they understood people who use drugs. Respondents most frequently rated lack of adequate training (58.2%) and lack of time (55.2%) as very important barriers to BUP initiation. INTERPRETATION: Two-thirds of the emergency physicians surveyed prescribed BUP, although only one-quarter did so regularly and one-third prescribed it for home initiation; wide variation between emergency department groups existed. Strategies to increase BUP initiation must address physicians' lack of time and training for BUP initiation and improve their understanding of people who use drugs.

Development of the Canadian COVID-19 Emergency Department Rapid Response Network population-based registry: a methodology study.

BACKGROUND: Emergency physicians lack high-quality evidence for many diagnostic and treatment decisions made for patients with suspected or confirmed coronavirus disease 2019 (COVID-19). Our objective is to describe the methods used to collect and ensure the data quality of a multicentre registry of patients presenting to the emergency department with suspected or confirmed COVID-19. METHODS: This methodology study describes a population-based registry that has been enrolling consecutive patients presenting to the emergency department with suspected or confirmed COVID-19 since Mar. 1, 2020. Most data are collected from retrospective chart review. Phone follow-up with patients at 30 days captures the World Health Organization clinical improvement scale and contextual, social and cultural variables. Phone follow-up also captures patient-reported quality of life using the Veterans Rand 12-Item Health Survey at 30 days, 60 days, 6 months and 12 months. Fifty participating emergency departments from 8 provinces in Canada currently enrol patients into the registry. INTERPRETATION: Data from the registry of the Canadian COVID-19 Emergency Department Rapid Response Network will be used to derive and validate clinical decision rules to inform clinical decision-making, describe the natural history of the disease, evaluate COVID-19 diagnostic tests and establish the real-world effectiveness of treatments and vaccines, including in populations that are excluded or underrepresented in clinical trials. This registry has the potential to generate scientific evidence to inform our pandemic response, and to serve as a model for the rapid implementation of population-based data collection protocols for future public health emergencies. TRIAL REGISTRATION: Clinicaltrials.gov, no. NCT04702945.

A Multicenter Randomized Trial to Evaluate a Chemical-first or Electrical-first Cardioversion Strategy for Patients With Uncomplicated Acute Atrial Fibrillation.

BACKGROUND: Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both chemical-first and electrical-first strategies have been advocated, there are no comparative effectiveness data to guide clinicians. METHODS: At six urban Canadian centers, ED patients ages 18 to 75 with uncomplicated symptomatic AF of less than 48 hours and CHADS2 score of 0 or 1 were randomized using concealed allocation in a 1:1 ratio to one of the following strategies: 1) chemical cardioversion with procainamide infusion, followed by electrical countershock if unsuccessful; or 2) electrical cardioversion, followed by procainamide infusion if unsuccessful. The primary outcome was the proportion of patients discharged within 4 hours of arrival. Secondary outcomes included ED length-of-stay (LOS); prespecified ED-based adverse events; and 30-day ED revisits, hospitalizations, strokes, deaths, and quality of life (QoL). RESULTS: Eighty-four patients were analyzed: 41 in the chemical-first group and 43 in the electrical-first group. Groups were balanced in terms of age, sex, vital signs, and CHADS2 scores. All patients were discharged home, with 83 (99%) in sinus rhythm. In the chemical-first group, 13 of 41 patients (32%) were discharged within 4 hours compared to 29 of 43 patients (67%) in the electrical-first group (p = 0.001). In the chemical-first group, the median ED LOS was 5.1 hours (interquartile range [IQR] = 3.5 to 5.9 hours) compared to 3.5 hours (IQR = 2.4 to 4.6 hours) in the electrical-first group, for a median difference of 1.2 hours (95% confidence interval = 0.4 to 2.0 hours, p < 0.001). No patients experienced stroke or death. All other outcomes, including adverse events, ED revisits, and QoL, were similar. CONCLUSION: In uncomplicated ED AF patients managed with rhythm control, chemical-first and electrical-first strategies both appear to be successful and well tolerated; however, an electrical-first strategy results in a significantly shorter ED LOS.

Rapid agitation control with ketamine in the emergency department (RACKED): a randomized controlled trial protocol.

BACKGROUND: The rapid control of patients presenting to the emergency department (ED) with psychomotor agitation and violent behavior is paramount for the safety of patients and ED staff. The use of intramuscular (IM) ketamine in the pre-hospital and ED settings has demonstrated promising preliminary results to provide rapid and safe behavioral control. A prospective, randomized controlled trial is required to measure the potential superiority of IM ketamine compared to current standard care (IM benzodiazepines plus antipsychotics). METHODS: This will be a parallel, prospective, randomized, controlled trial of 5 mg/kg IM ketamine compared to a combination of 5 mg IM midazolam and 5 mg IM haloperidol. The study will enroll approximately 184 patients, randomized equally to two study arms. There will be one study visit during which study medication will be administered and assessments will be completed. A follow-up safety visit will occur on day 3. The primary objective of this study is to compare IM ketamine to a combination of IM midazolam and haloperidol with regards to the time required for adequate behavioral control, in minutes, in patients presenting to the ED with psychomotor agitation and violent behavior, as measured by the Richmond Agitation-Sedation Scale (RASS). DISCUSSION: We present a novel study to determine whether ketamine is a rapid and safe option, compared to a combination of midazolam and haloperidol for the sedation of patients presenting to the ED with psychomotor agitation and violent behavior. To our knowledge, this study is the first randomized controlled trial to compare ketamine to current standard care for this indication. We have attempted to address numerous logistical issues with the design of this study including a waiver of consent, ensuring adequate blinding of outcome assessors, patient enrolment, and data monitoring. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03375671 . Registered on 18 December 2017.

A prospective evaluation of "ketofol" (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department.

STUDY OBJECTIVE: We evaluate the effectiveness and consider the safety of intravenous ketamine/propofol combination ("ketofol") in the same syringe for procedural sedation and analgesia in the emergency department (ED). METHODS: A prospective case series of consecutive ketofol procedural sedation and analgesia events in the ED of a trauma-receiving community teaching hospital from July 2005 to February 2006 was studied. Patients of all ages, with any comorbid conditions, were included. Ketofol (1:1 mixture of ketamine 10 mg/mL and propofol 10 mg/mL) was administered intravenously at the discretion of the treating physician by using titrated aliquots. The presence or absence of adverse events was documented, as were procedural success, recovery time, and physician, nurse, and patient satisfaction. Physiologic data were recorded with established hospital procedural sedation and analgesia guidelines. RESULTS: One hundred fourteen procedural sedation and analgesia events using ketofol were performed for primarily orthopedic procedures. The median dose of medication administered was ketamine at 0.75 mg/kg and propofol at 0.75 mg/kg (range 0.2 to 2.05 mg/kg each of propofol and ketamine; interquartile range [IQR] 0.6 to 1.0 mg/kg). Procedures were successfully performed without adjunctive sedatives in 110 (96.5%) patients. Three patients (2.6%; 95% confidence interval [CI] 0.6% to 7.5%) had transient hypoxia; of these, 1 (0.9%; 95% CI 0.02% to 4.8%) required bag-valve-mask ventilation. Four patients (3.5%; 95% CI 1.0% to 8.7%) required repositioning for airway malalignment, 4 patients (3.5%; 95% CI 1.0% to 8.7%) required adjunctive medication for sedation, and 3 patients (2.6%; 95% CI 0.6% to 7.5%) had mild unpleasant emergence, of whom 1 (0.9%; 95% CI 0.02% to 4.8%) received midazolam. No patient had hypotension or vomiting or received endotracheal intubation. Median recovery time was 15 minutes (range 5 to 45 minutes; IQR 12 to 19 minutes). Median physician, nurse, and patient satisfaction scores were 10 on a 1-to-10 scale. CONCLUSION: Ketofol procedural sedation and analgesia is effective and appears to be safe for painful procedures in the ED. Few adverse events occurred and were either self-limited or responded to minimal interventions. Recoveries were rapid, and staff and patients were highly satisfied.

Statistical analysis of the age dependence of the normal capnogram.

The age dependence of the time-based capnogram from normal, healthy subjects has not been quantitatively characterized. The existence of age dependence would impact the development and operation of automated quantitative capnographic tools. Here, we quantitatively assess the relationship between normal capnogram shape and age. Capnograms were collected from healthy subjects, and physiologically-based features (exhalation duration, end-tidal CO2 and time spent at this value, normalized time spent at end-tidal CO2, end-exhalation slope, and instantaneous respiratory rate) were computationally extracted. The mean values of the individual features over 30 exhalations were linearly regressed against subject age, accounting for inter-feature correlation. After data collection, 154 of 178 subjects were eligible for analysis, with an age range of 3-78 years (mean age 39, std. dev. 20 years). The Bonferroni-corrected joint 95% confidence intervals (CIs) of the regression line slopes contained the origin for five of six features (the remaining CI was only slightly offset from the origin). The associated individual r2 values for the regressions were all below 0.07. We conclude that age is not a significant explanatory factor in describing variations in the shape of the normal capnogram. This finding could be exploited in the design of automated methods for quantitative capnogram analysis across a range of ages.