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Rapid agitation control with ketamine in the emergency department (RACKED): a randomized controlled trial… Barbic, David; Andolfatto, Gary; Grunau, Brian; Scheuermeyer, Frank X; MacEwan, William; Honer, William G; Wong, Hubert; Barbic, Skye P Nov 26, 2018

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STUDY PROTOCOL Open AccessRapid agitation control with ketamine inthe emergency department (RACKED): arandomized controlled trial protocolDavid Barbic1,6* , Gary Andolfatto2, Brian Grunau1,6, Frank X. Scheuermeyer1,6, William MacEwan3, William G. Honer3,Hubert Wong4,6 and Skye P. Barbic5,6AbstractBackground: The rapid control of patients presenting to the emergency department (ED) with psychomotoragitation 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 andsafe behavioral control. A prospective, randomized controlled trial is required to measure the potential superiorityof 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 acombination 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 administeredand assessments will be completed. A follow-up safety visit will occur on day 3. The primary objective of this study is tocompare IM ketamine to a combination of IM midazolam and haloperidol with regards to the time required for adequatebehavioral control, in minutes, in patients presenting to the ED with psychomotor agitation and violent behavior, asmeasured 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 acombination of midazolam and haloperidol for the sedation of patients presenting to the ED with psychomotor agitationand violent behavior. To our knowledge, this study is the first randomized controlled trial to compare ketamine to currentstandard care for this indication. We have attempted to address numerous logistical issues with the design of this studyincluding 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.Keywords: Ketamine, Agitation, Midazolam, Haloperidol, Randomized controlled trial, Emergency medicineBackgroundThe rapid control of patients presenting to the emer-gency department (ED) with psychomotor agitation andpotentially violent behavior is paramount for the safetyof patients and ED staff. Mental health crises, substancemisuse, hypoxia, dementia, and metabolic or central ner-vous system disease processes are common reasons foragitation and potentially aggressive behavior in patientspresenting to the ED [1]. Patients with this presentationprovide a unique challenge to ED staff whose primaryconcerns are both patient safety and determining thecause of the agitation and violent behavior. Behavioralemergencies in the ED are multifactorial, complex, andrequire prompt response from ED staff to prevent injuryof the patient, staff, and other visitors to the department.Although referred to as a “last resort,” an approach tocontrol such situations in the ED is the rapid adminis-tration of intramuscular (IM) medications. This allowsED staff to assess, stabilize, diagnose, and monitor pa-tients in a way that is safe for both patient and ED staff* Correspondence: David.barbic@ubc.ca1Department of Emergency Medicine, St Paul’s Hospital, 1081 Burrard St,Vancouver, BC V6Z 1Y6, Canada6Centre for Health Evaluation Outcome Sciences, Vancouver, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Barbic et al. Trials          (2018) 19:651 https://doi.org/10.1186/s13063-018-2992-x[1–4]. Three main classes of medications exist torestrain a patient in the ED: (1) benzodiazepines; (2) typ-ical or classical antipsychotics; and (3) atypical antipsy-chotics. Ensuring patients receive the right interventionat the right time is critical to optimize the health and re-covery outcomes of this vulnerable patient group. Emer-gency clinicians lack a clear, consensus standard of careas demonstrated by a recent systematic review on thistopic [5].Sedation of agitated and potentially violent patients inthe ED with benzodiazepines is associated with an in-creased risk of respiratory depression, oxygen desatur-ation, and the need for airway interventions [5]. The useof antipsychotic medications for the sedation of agitatedpatients is associated with dystonia, akathisia, parkinson-ism, and neuroleptic malignant syndrome [6].Ketamine is a non-competitive N-methyl-D-asparticacid receptor (NMDA) antagonist and a highly effectivedissociative anesthetic [7]. Ketamine provides rapid dis-sociative anesthesia and analgesia and has been used ex-tensively for a number of indications including low-doseanalgesia [8, 9], procedural sedation [10–12], and generalanesthesia in resource-limited settings [13]. Ketaminehas many potential benefits for IM sedation of the agi-tated and violent patient, including [14] rapid dissoci-ation to facilitate behavioral control and favorablecardiovascular stability compared to other agents usedfor sedation [15].Ketamine preserves patients’ inherent respiratorydrive, minimizing the risk of respiratory depression, oxy-gen desaturation, and other related adverse events (AEs)[11, 12, 16]. Ketamine provides analgesia for proceduresrequired in the assessment and management of these pa-tients, such as intravenous insertion and phlebotomy. Alow rate of AEs with the use of ketamine for proceduralsedation [7, 17] suggests that ketamine may be a safemedication for IM behavioral control of the agitated andviolent patient in the emergency department setting.The use of IM ketamine in the pre-hospital setting hasbeen described in several retrospective chart reviews andprospective series [3, 18–26] and has been demonstratedto provide rapid and safe behavioral control [18, 23, 24].These studies have also demonstrated favorable AE pro-files. Retrospective chart reviews and prospective caseseries from the ED indicate effective and rapid sedationwith ketamine [25, 26]. The main methodological limita-tions of these studies are their retrospective nature andthe lack of a controlled comparison group. Furthermore,a recent position statement by the American College ofEmergency Physicians highlighted the need for “high-qu-ality research…to establish the safety and efficacy ofketamine compared with other agents for the control ofthe acutely agitated patient in the ED” [27]. As a result,a prospective, randomized controlled trial is required tomeasure the potential superiority of IM ketamine com-pared to current standard care (IM benzodiazepines plusantipsychotics) for the rapid and safe control of patientspresenting to the ED with psychomotor agitation andviolent behavior.MethodsOverall study designThis will be a parallel, prospective, randomized, controlledtrial of 5 mg/kg IM ketamine compared to a combinationof 5 mg IM midazolam and 5 mg IM haloperidol.The study will enroll approximately 184 patients, ran-domized equally to two study arms. There will be onestudy visit during which study medication will be admin-istered and assessments will be completed. A follow-upsafety visit will occur on day 3. The primary objective ofthis study is to compare IM ketamine to a combinationof IM midazolam and haloperidol with regards to thetime required for adequate behavioral control, inminutes, in patients presenting to the ED with psycho-motor agitation and violence, as measured by the Rich-mond Agitation-Sedation Scale (RASS; Additional file 1).The Richmond Agitation Sedation Scale is a validated,10-level sedation scale (+ 4 “combative” to − 5 “unarou-sable”) used to quantify patient agitation [28].Primary objectiveThe primary objective of this study is to compare IMketamine to a combination of IM midazolam and halo-peridol with regards to the time required for adequatesedation, in minutes, in ED patients with psychomotoragitation and violent behavior.Secondary objectivesThe secondary objectives of this study include:1. Investigating the safety and tolerability of ketamine;2. Evaluating the percentage of participants in eacharm requiring rescue medications at 5–30 min(at 5 min intervals) after study medication(s)administration. Rescue medications are defined asbenzodiazepines, antipsychotics, or other sedativemedications prescribed by the treating emergencyphysician for the purpose of achieving behavioralcontrol;3. Evaluating the percentage of participantsexperiencing sedation outcomes in each arm asdefined by the TROOPS criteria (Additional file 1);4. Evaluate the percentage of participants in each armwith neuroleptic malignant syndrome within 24 hof enrolment, adjudicated to be due to theadministration of study medications;5. Describe the pre-hospital use of force by police inthis patient population;Barbic et al. Trials          (2018) 19:651 Page 2 of 136. Evaluate the participants’ clinical study experience;7. Evaluate the study ED nurses’ clinical studyexperience;8. Evaluate the effectiveness of blinding in the study.Selection and enrolment of participantsNumber of participantsThe study will enroll approximately 184 participants.Inclusion criteria1. Age 19–60 years inclusive;2. Patients presenting to the ED with psychomotoragitation or violent behavior (RASS score > + 3).Exclusion criteria1. Age < 19 years;2. Age > 60 years;3. Previous participation in this study;4. Women suspected or known to be pregnant orbreastfeeding;5. Previous known hypersensitivity, intolerance orallergy to ketamine, midazolam, or haloperidol ortheir components;6. Individuals who are in comatose states or havecentral nervous system (CNS) depression due toalcohol or are taking other depressant drugs;7. Individuals with severe depressive states, spasticdiseases, and with Parkinson’s disease, except in thecase of dyskinesias due to levodopa treatment;8. Senile patients with pre-existing Parkinson-likesymptoms;9. Individuals with a history of cerebrovascularaccident;10. Individuals in whom a significant elevation of bloodpressure would constitute a serious hazard, such aspatients with significant hypertension;11. Individuals with severe cardiac decompensation;12. Individuals who intend to have surgery of thepharynx, larynx, or bronchial tree unless adequatemuscle relaxants are used;13. Individuals with acute pulmonary insufficiency;14. Individuals with severe chronic obstructivepulmonary disease;15. Individuals with acute narrow angle glaucoma.Enrolment proceduresDesignated study staff in the ED will identify potentialparticipants – adult patients who present to the ED withpsychomotor agitation or violent behavior – by commu-nicating directly with the study investigator orsub-investigator. Patients will be enrolled when studystaff are available in the ED. The study will be conductedat St Paul’s Hospital ED.A waiver for informed consent has been granted bythe UBC Providence Health Care Research Ethics Board(PHC REB) for this study. In cases where a potential par-ticipant presents to the ED accompanied by a substitutedecision-maker, informed consent will be obtained fromthe substitute decision-maker.A substitute decision-maker must be either: (1) theparticipant’s spouse, child, parent sibling, grandparent,grandchild, or any anyone else related by birth or adop-tion to the individual; (2) a close friend of the partici-pant; or (3) a person immediately related to theindividual by marriage. Furthermore, the substitutedecision-maker must be aged at least 19 years, have beenin contact with the participant during the preceding12 months, have no dispute with the individual, and becapable of giving, refusing, or revoking substitute con-sent on the participant’s behalf.The substitute decision-maker must decide to giveor refuse consent in the participant’s best interests.When deciding whether it is in the participant’s bestinterests to give or refuse substitute consent, the sub-stitute decision-maker must consider the individual’scurrent wishes and known beliefs and values, whetherthe individual’s condition or wellbeing is likely to beimproved by the proposed healthcare, whether theparticipant’s condition or wellbeing is likely to im-prove without the proposed healthcare, whether thebenefit the individual is expected to obtain from theproposed healthcare is greater than the risk of harm,and whether a less restrictive or less intrusive form ofhealthcare would be as beneficial as the proposedhealthcare.Withdrawal of participantsA participant may be withdrawn from the study due tothe reasons listed below including, but not limited to:□ The participant’s or substitute decision-maker’srequest;□ Severe adverse effects, serious adverse events(SAEs), and/or other safety reasons;□ It is in the participant’s best interest according tothe Investigator’s clinical judgment;□ The Sponsor–Investigator terminates the study.All premature discontinuations and their causes mustbe documented by the Investigator on the appropriateCRF pages, e.g., final status, AEs.Participants are free to withdraw from the study at anytime and for whatever reason, specified or unspecified,and without prejudice to his or her medical care by aphysician.Barbic et al. Trials          (2018) 19:651 Page 3 of 13If a participant withdraws or is removed from thestudy for any reason before the completion of the study,the reason for, and date of, the discontinuation, and thedate of the last dose of the study medication must be re-corded in the appropriate section of the CRF.Randomization and blinding proceduresRandomizationThe study biostatistician will generate the treatmentallocations before the start of the study using a random-ized block design with varying block sizes. Each blockwill contain equal numbers of participants for each arm.The randomization schedule will be stored with thestudy medications in the Omnicell medication storagesystem in the ED. The group allocation will be concealedfrom blinded study staff by a sealed, opaque envelopewith a unique study identifier code on the exterior. Thiswill be withdrawn from the Omnicell by a designatedunblinded ED study nurse administering medications.The unblinded ED study nurse will prepare and adminis-ter study medication after opening the next sequentialenvelope in the randomization system stored with thestudy medication. Treatment allocation will be con-cealed from all other study investigators, study staff, andparticipants, following the administration of studymedications.BlindingBlinding occurs immediately following enrolment intothe study and group allocation. All participants, investi-gators, and study staff conducting study procedures willbe blinded to study group allocation. The ED nurse ad-ministering study medication will be the only unblindedindividual involved with the study. This ED nurse is notinvolved with the assessment of any study outcomes orother procedures related to the study.Study treatmentsThe study medications and doses were chosen after alengthy review of the existing literature [29] and asurvey of regional ED physicians’ preferences for sed-ation of this patient population. Midazolam and halo-peridol are medications widely used in emergencymedicine for rapid behavioral control of the agitatedand violent patient [5, 6]. These medications couldreasonably be considered “standard therapy” for thisindication by emergency physicians.Investigational product descriptionGeneric name: ketamine hydrochloride injection.Brand name: Ketalar®, DIN 00224405 (10-mL vial,500 mg/10 mL).Ketalar® is a rapid-acting, non-barbiturate generalanesthetic. It produces an anesthetic state characterizedby profound analgesia, normal pharyngeal-laryngeal re-flexes, and normal or slightly enhanced skeletal muscletone. Mild cardiac stimulation and occasionally respira-tory depression occur. The anesthetic state produced byKetalar® has been termed “dissociative anesthesia” in thatit appears to selectively interrupt association pathways ofthe brain before producing somesthetic sensory block-age. Ketalar® decreases the activity of the neocortex andsubcortical structures (thalamus) and increases the activ-ity in the limbic system and reticular substance.Dosing and administrationParticipants in the treatment arm will receive a singleintramuscular injection of 5 mg/kg Ketalar® administeredby an unblinded study nurse.Potential side effects:□ Temporary augmentation of heart rate and bloodpressure□ Hypotension, arrhythmias, bradycardia□ Respiratory depression (with IV administration only)□ Laryngospasm□ Increased salivation□ Enhanced skeletal muscle tone□ Blurred vision, nystagmus, diplopia (transient)□ Anorexia, nausea, vomiting□ Transient erythema, morbiliform rash, anaphylaxis□ Increased intraocular pressure (transient)□ Emergence reaction (hallucinations or frighteningdepersonalization)Comparative treatmentsMidazolamGeneric name: Midazolam injection, USP.Brand name: n/a; DIN 02242905 (5 mg/mL).Midazolam possesses all the pharmacological effects ofthe benzodiazepines, namely it is a sedative, hypnotic, anti-convulsant, anxiolytic, muscle relaxant and amnestic agent.In addition, midazolam enhances GABAergic inhibition, de-creases the firing rate of single neurons, decreases the cere-bral metabolic rate for oxygen, decreases cerebral bloodflow, enhances the survival time of mice in a hypoxic milieu,and induces amnesia in the passive avoidance paradigm.Midazolam binds in nanomolar concentrations to thehigh-affinity, stereospecific, benzodiazepine receptorsites in the mammalian brain. These receptor sites arefunctionally coupled to GABA recognition sites and tosites related to chloride channels. Midazolam decreasesthe cyclic GMP level in the cerebellum.Dosing and administrationThe control group will receive a single intramuscular in-jection of the combination 5 mg midazolam and 5 mghaloperidol administered by an unblinded study nurse.Barbic et al. Trials          (2018) 19:651 Page 4 of 13Potential side effects:□ Increased or decreased mean arterial pressure□ Increased or decreased pulse rate□ Decreased respiratory rate□ Apnea□ Headache□ Hiccoughs□ Nausea□ Emesis/vomitingHaloperidolGeneric name: Haloperidol injection, USPBrand name: n/a, DIN 00808652 (5 mg/mL, 1-mLampule)Haloperidol injection (IM) is a butyrophenone deriva-tive with antipsychotic properties that has been consid-ered particularly effective in the management ofhyperactivity, agitation, and mania. Haloperidol is an ef-fective neuroleptic and also possesses antiemetic proper-ties; it has a marked tendency to provoke extrapyramidaleffects and has relatively weak alpha-adrenolytic proper-ties. It may also exhibit hypothermic and anorexiant ef-fects, and potentiate the action of barbiturates, generalanesthetics, and other CNS depressant drugs.Dosing and administrationThe control group will receive a single IM injection ofthe combination 5 mg midazolam and 5 mg haloperidoladministered by a study nurse under the investigator’s orsub-investigator’s direction.Potential side effects:□ Prolongation of the QTc interval□ Orthostatic hypotension□ Extrapyramidal symptoms (e.g. dystonias, akathisia,parkinsonism, tardive dyskinesia)□ Agitation□ Drowsiness, insomnia, sedation□ Hyperprolactinemia□ Priapism□ Anticholinergic effects (e.g. dry mouth, constipation,urinary retention)□ Tachycardia, ECG abnormalities□ Neuroleptic malignant syndromeStudy products supply and accountability proceduresStudy medication will be purchased by ProvidenceHealth Care Pharmacy and stored at the study site in asecure, limited access medication storage system(Omnicell).Study medication will be organized and labelled in thehospital pharmacy and delivered to the Omnicell storagesystem per standard hospital procedures. An unblindedED study nurse will prepare and administer study medi-cation after opening the next sequential envelope in therandomization system stored with the study medication.A medication dispensing log will be used to track andmaintain accountability for the study medication. Un-used study products will be disposed of according tomanufacturers’ instructions. Study medications will behandled and stored according to instructions providedin the respective Product Monographs.The Canadian Controlled Drugs and Substances Act(CDSA) regulates controlled and targeted substancespossession, transport, and administration. The study sitemaintains a system for controlling access through facilityand station-based locked storage and an audited recon-ciliation process. The study medications used in thisstudy will be managed using this existing system.Rescue medicationsParticipants will receive rescue sedation medications at thediscretion of the treating ED study investigator. Rescuemedications are defined as benzodiazepines, antipsychotics,or other sedative medications prescribed by the treatingemergency physician for the purpose of behavioral control.Risks and precautionsRisk managementRisk minimization, management, and assessment proce-dures have been implemented in the study to minimize andassess potential risks to those who participate in this clinicalstudy with ketamine, midazolam, and haloperidol. Compo-nents include: (1) specific study entry and exclusion criteriato ensure that participants who have underlying character-istics that potentially increase their risk for an adverse out-come are excluded; and (2) protocol-specific procedures forminimizing and managing AEs, such as no patients aged >60 years or women who are known or suspected to bepregnant or breast feeding will be enrolled. Additionally, allparticipants will receive routine ED care for this patientpopulation including: (i) basic laboratory testing; (ii) elec-trocardiogram; (iii) complete physical exam by a study EDphysician; and (iv) vital signs collection and monitoringevery 5 min; and (3) overview surveillance will be done byan independent Medical Monitor.This study does not involve a Data Monitoring Com-mittee (DMC). The decision to not form a DMC for thisstudy was arrived at following external review by experi-enced emergency physician peer review, external peerreview by Health Canada, and two independent grantfunding agencies.Clinical and laboratory evaluationsClinical evaluationsThe blinded treating ED study investigator and studynurse(s) caring for the participant will be asked toBarbic et al. Trials          (2018) 19:651 Page 5 of 13assess the level of sedation of the participant and rec-ord the number of minutes required to reach a RASS< − 1 (Additional file 1), following study medicationadministration. Observation will start immediatelyafter study medication administration and every5 min until 30 min post study medication administra-tion. The participant’s outcomes will be treated ascensored after 30 min. In addition, if administrationof rescue medication is required during the 5–30 minperiod following study medication(s) administration,this information will be collected. Rescue medicationsare defined as benzodiazepines, antipsychotics, orother sedative medications prescribed by the treatingED study investigator for the purpose of achieving be-havioral control.The time required from first dose of study medica-tion(s) administration until assessment by a psychiatricnurse or psychiatrist in the ED will be collected.For each participant sedation outcomes will be collectedbased on the Tracking and Reporting Outcomes Of Pro-cedural Sedation (TROOPS) criteria form. The TROOPScriteria form is a multidisciplinary, consensus-based, stan-dardized quality improvement tool developed by the Inter-national Committee for the Advancement of ProceduralSedation. Refer to Additional file 1 and https://www.scien-cedirect.com/science/article/pii/S0007091217539471.A 100 mm visual analog scale (VAS; Additional file 1)will be utilized to measure dissociative/emergence re-action symptoms. The Barnes Akathisia Scale [30] is arating scale for the assessment of drug-related akathi-sia. (Additional file 1) Scores are in the range of 0 (nodrug-related akathisia) to 14 (severe drug-relatedakathisia). It will be used to measure the occurrenceand severity of abnormal movements. The Global Dys-tonia Severity Rating Scale (GDS) is a rating scale forthe assessment of dystonia in ten body areas withscores in the range of 0 (no dystonia) to 100 (severedystonia) (Additional file 1) [31].Neuroleptic malignant syndrome is a potential riskfactor with administration of the study medications.Clinical evaluation for neuroleptic malignant syn-drome will be conducted within 24 h following studymedication(s) administration as well as the follow-upvisit on day 3.Routine ED care will be conducted as described inTable 1: Schedule of Events.SurveysFor each participant, the blinded study investigator orother staff member will be asked to provide their per-sonal impression of which medication the participant re-ceived at 30 min following medication administration,using the Effectiveness of Study Drug Blinding Survey(Additional file 1). Only one survey will be completedfor each participant.For each participant, the blinded ED study nurse ad-ministering the study medications will be asked to assesshis/her perceptions of participant care using the StudyNurse Experience Survey (Additional file 1).Table 1 Schedule of eventsVisit typeScreening and treatment visit Follow-up visitaProcedures: Day 1 Day 3 (± 1 day)Assessment of eligibility XRandomization XStudy drugadministrationXVital signsb XComplete physicalexamXRoutine laboratorytestingcXECG XRASSb XTime to sedation XTime to psychiatricassessment (in the ED)XRescue medicationassessmentbXIncidence of sedationoutcomesXUse of physicalrestraintsXEffectiveness of StudyDrug Blinding SurveyXStudy Nurse ExperienceSurveyXParticipant ExperienceSurveyXVAS XBarnes Akathisia Scale XGDS XPre-hospital use offorceXAdverse eventcollectionX XNeuroleptic malignantsyndromeXd XReview participantinformation sheetXaVia telephone or in-personbConducted immediately after study medication administration and every5 min until 30 min, after study medication administrationcCBC, rapid metabolic panel, toxicology screendAssessed within 24 h following study medication administrationBarbic et al. Trials          (2018) 19:651 Page 6 of 13If feasible, study participants will be asked to assesstheir perception of their ED care experience using theParticipant Experience Survey (Additional file 1) beforebeing discharged from the ER.Study proceduresScreening and treatment visit proceduresDesignated study staff in the ED will identify potentialparticipants, screen patients for eligibility, and conductdata collection. Please refer to (Fig. 1).The treatment visit will occur immediately followingpre-study screening procedures.Following the patient’s assessment of eligibility, the fol-lowing procedures will be conducted by the blindedstudy staff except where noted below:□ Enrollment and randomization;□ Study medication(s) administration (by theunblinded ED study nurse);□ Routine ED care for this patient populationincluding:○ Basic laboratory testing (CBC, rapid metabolicpanel, toxicology screen)○ Electrocardiograph○ Complete physical exam, including estimatedweight○ Vital signs collection and monitoring immediatelyafter study medication administration and every5 min until 30 min after medicationadministration;□ Assessment of the level of sedation; time required toreach a RASS < − 1 (Additional file 1);□ Assessment of the time (in minutes) required fromfirst dose of study medication(s) administration untilassessment by psychiatric nurse or psychiatrist inthe ED;□ Administration of rescue medication; as required;○ Assessment of rescue medications between 5 and30 min (at 5-min intervals) of initial IM medica-tion administration. Rescue medications are de-fined as benzodiazepines, antipsychotics, or othersedative medications prescribed by the treatingemergency physician for the purpose of achievingbehavioral control;□ Use of physical restraints (including duration ofapplication);□ Incidence of sedation outcomes as defined by theTROOPS criteria (Additional file 1);STUDY PERIODEnrolment Allocation Post-allocation Close-outTIMEPOINT** -t1 0 t1 txENROLMENT:XEligibility screen XInformed consent N/AAllocation XINTERVENTIONS:KETAMINE XMIDAZOLAM & HALOPERIDOL XASSESSMENTS:Baseline Variables [Age, gender, pre-sedation RASS]XPrimary Outcome [Time to sedation]XSecondary Outcomes [Adverse events, rescue medications, sedation outcomes, NMS, prehospital use of force, participant experience, nurse experience, effectiveness of blinding]X XFig. 1 SPIRIT Flow Diagram of schedule of enrolment, interventions, and assessmentsBarbic et al. Trials          (2018) 19:651 Page 7 of 13□ Effectiveness of Study Drug Blinding Survey(Additional file 1);□ Study Nurse Experience Survey (Additional file 1);□ Participant Experience Survey (Additional file 1);□ VAS for dissociative/emergence reaction symptoms(Additional file 1);□ Barnes Akathisia Scale for occurrence and severityof abnormal movements (Additional file 1);□ GDS for occurrence and severity of dystonia(Additional file 1);□ Pre-hospital use of force (number and type(s) ofrestraint);□ Collection of AEs;□ Assessment for neuroleptic malignant syndromewithin 24 h following study medication(s)administration;□ Review of Participant Information Sheet anddiscussion with participant.All rescue medications and SAEs will be recorded aspart of regular study data collection. All AEs will befollowed up until their resolution or stabilization; referto Section 10.4.Standard ED tests and interventions for these patientswill proceed without interruption from the study. Studyparticipants will continue to receive the standard of caretreatment if presenting with agitated and violentbehavior.Follow-up visit proceduresThe follow-up visit will occur on day 3 (± 1 day) via tele-phone or in-person. The following procedures will beconducted:□ Assessment for neuroleptic malignant syndrome;□ Collection of AEs.Evaluation, recording, and reporting of adverseeventsDefinitionsAdverse eventsAn AE is any untoward medical occurrence in a patientor clinical investigation participant, administered a studymedication/intervention, which does not necessarilyhave a causal relationship with this treatment. An AEcan therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, ordisease temporally associated with the use of a medicinal(investigational) study medication/intervention, whetheror not related to the medicinal (investigational) studymedication/intervention.During the treatment and safety follow-up visits, infor-mation on AEs will be gathered and documentedaccordingly. AEs will be graded as mild, moderate,severe, or life-threatening and assessed by causality asprobably related, possibly related, unlikely to be related,or not related to the study medications.Stable chronic conditions which are present beforeclinical trial entry and do not worsen are not consideredAEs and will be accounted for in the participant’s med-ical history.Serious adverse eventsAn SAE is defined as an AE meeting one of the follow-ing criteria at any dose:□ Results in death during the period of protocol-defined surveillance;□ Is a life-threatening event (defined as a participantat immediate risk of death at the time of the event);□ Results in inpatient hospitalization or prolongationof existing hospitalization during the period ofprotocol-defined surveillance;□ Results in persistent or significant disability orincapacity (disability is defined as a substantialdisruption of a person’s ability to conduct normallife functions);□ Is a congenital anomaly or birth defect.Any other important medical event that may not resultin one of the above outcomes, may be considered a SAEwhen, based upon appropriate medical judgment, theevent may jeopardize the participant and may requiremedical or surgical intervention to prevent one of theoutcomes listed above. Examples of such medical eventsinclude allergic bronchospasm requiring intensive treat-ment in an emergency room or at home, blood dyscra-sias or convulsions that do not result in inpatienthospitalization, or the development of drug dependencyor drug abuse.It is anticipated that patients included in this study willpresent to the ED with underlying medical issues thatwill require admission to hospital for stabilization andtreatment (i.e. acute mental health crises, infections,drug overdoses, trauma). Inpatient hospitalization or ad-mission to the Intensive Care Unit (ICU) will not beconsidered a SAE when the patient’s final discharge diag-nosis from their hospital stay is attributed to theseunderlying medical conditions.We will engage a Medical Monitor (independent EDphysician not involved in the direct conduct of thestudy) to review SAEs as they occur.AE descriptions and recordingIntensityThe intensity (severity) for each AE (including SAE) willbe graded according to the Common TerminologyBarbic et al. Trials          (2018) 19:651 Page 8 of 13Criteria for Adverse Events (CTCAE) Version 4.0(https://evs.nci.nih.gov/ftp1/CTCAE/About.html).Relationship to study treatmentFor all collected AEs (including SAEs), the clinician who ex-amines and evaluates the participant will determine theAE’s causality based on temporal relationship and his/herclinical judgment. The degree of certainty about causalitywill be graded using the categories below:Definitely related: There is clear evidence to suggest acausal relationship, and other possible contributing factorscan be ruled out. The clinical event, including anabnormal laboratory test result, occurs in a plausible timerelationship to drug administration and cannot beexplained by concurrent disease or other drugs orchemicals. The response to withdrawal of the drug (de-challenge) should be clinically plausible. The event mustbe pharmacologically or phenomenologically definitive,with use of a satisfactory re-challenge procedure ifnecessary;Probably related: There is evidence to suggest a causalrelationship; the influence of other factors is unlikely. Theclinical event, including an abnormal laboratory test result,occurs within a reasonable time sequence toadministration of the drug, is unlikely to be attributed toconcurrent disease or other drugs or chemicals, andfollows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not required to ful-fill this definition;Possibly related: There is some evidence to suggest acausal relationship (e.g. the event occurred within areasonable time after administration of the trialmedication). However, the influence of other factors mayhave contributed to the event (e.g. the participant’s clinicalcondition, other concomitant events). Although anadverse drug event may rate only as “possibly related”soon after discovery, it can be flagged as requiring moreinformation and later be upgraded to “probably related” or“definitely related,” as appropriate.Unlikely: A clinical event, including an abnormallaboratory test result, whose temporal relationship todrug administration makes a causal relationshipimprobable (e.g. the event did not occur within areasonable time after administration of the trialmedication) and in which other drugs or chemicals orunderlying disease provides plausible explanations(e.g. the participant’s clinical condition, otherconcomitant treatments).Not related: The AE is completely independent of studydrug administration and/or evidence exists that theevent is definitely related to another etiology. Theremust be an alternative, definitive etiology documentedby the clinician.Reporting and evaluation of SAEs and other clinicallysignificant AEsSAEs All SAEs that occur during the course of the studymust be reported to the Sponsor-Investigator within24 h of the site becoming aware of the event. The Centrefor Health Evaluation and Outcome Sciences (CHÉOS)will be responsible for reporting expedited events toHealth Canada on behalf of the Sponsor-Investigatorwithin the required timeframe.Follow-up for adverse events All AEs (including SAEs)will be followed where possible until resolution or untilthe investigator has determined that the AE has re-solved, stabilized, or become chronic and no furtherfollow-up is required.Statistical considerationsSample size considerations/justificationThis is the first randomized double-blind controlled trialon the use of ketamine for rapid, primary behavioralcontrol in the ED. Previous work on this topic has dem-onstrated a mean time to sedation of 7 min for patientsreceiving the benzodiazepines and antipsychotics. Theprojected mean time of sedation for patients receivingketamine in this study is anticipated to be 4 min (unpub-lished data), resulting in a mean reduction of 3 min anda hazard ratio (HR) of 7/4 = 1.75. However, to ensure ad-equate power, the sample size calculation will assume alower mean reduction of 2.5 min (HR = 7/4.5 = 1.56).To achieve 80% power, assuming a HR =1.56, an alpha= 0.05, and patients are followed up to 30 min, the re-quired sample size is 166 (83 per group). Assuming a10% loss to follow up [attrition], a final sample size of184 (92 patients per group) will be required. If indeedthe true mean time to sedation for patients receivingketamine is 4 min (3 min reduction), the power of thistrial will be 94%.Datasets to be analyzedData collected during the study will be entered into adesigned database. Data will be checked by a data man-ager and any queries will be resolved with the assistanceof study staff.The finalized datasets to be analyzed will be importedinto statistical software, e.g. SAS system. All the datasetswill include a unique identifier for each patient. Thestructure of each dataset is to have one patient per rowand one variable per column.Outcome measuresPrimary endpoint: Time from first IM medication ad-ministration to adequate sedation which is defined asRASS ≤ − 1.Barbic et al. Trials          (2018) 19:651 Page 9 of 13Secondary endpoints:1. Percentage participants with adverse events in eacharm;2. Percentage of participants in each arm requiringrescue medications between 5 and 30 min (at 5-minintervals) after study medication(s) administrationby count;3. Percentage of participants in each arm experiencingsedation outcomes as defined by the TROOPScriteria;4. Percentage of participants with neurolepticmalignant syndrome events within 24 h ofenrollment of each arm;5. Percentage of participants experiencing pre-hospitaluse of force by police in this participant population,by number and type of restraint;6. Participant experience survey outcomes;7. Study Nurse Experience Survey outcomes;8. Effectiveness of Blinding Survey outcomes.Analysis of primary outcome measuresA Cox proportional hazards model will be used to assessthe difference in time to adequate sedation between thetwo arms. In the analysis, patients who do not achieveadequate sedation criteria will be censored at the end offollow-up period of 30 min. The model will adjust forthe following covariates: age; gender; and RASS beforeadministration of study medication. The hazard ratio be-tween the two arms and associated 95% confidenceinterval (CI) will be reported.Analysis will be based on an intent-to-treat basis, i.e.the patient will be included in the analysis as being ran-domized. An as-treated analysis will be also conductedas a sensitivity analysis.Analysis of secondary outcome measuresAEs will be summarized for each arm by presenting thenumber and percentage of participants having any AEs,having AEs in severity levels (graded as mild, moderate,severe, or life-threatening). The associated 95% CI of thepercentage will also be reported.Participants requiring rescue medications between 5and 30 min of initial IM medication administration ineach arm will be summarized as percentage, along withits 95% CI.The number and percentage of participants with anysedation outcomes will be summarized for each arm,along with the 95% CI of the percentage. Furthermore,the number and percentage in each type of sedation out-comes will be presented.Incidence of neuroleptic malignant syndrome within24 h of enrollment of each arm will be summarized ascount and percentage and associated 95% CI.Percentage of participants experiencing pre-hospitaluse of force by police in the cohort will be reported aswell as its 95% CI. Furthermore, the number and per-centage in each type of restraints will be presented.Participant’s clinical experience survey is a question-naire with four questions (regarding feeling on medica-tion and sedation medications) and answered as YES/NO. The number and percentage (and its 95% CI) ofpatients chosen YES (or NO) for each question will bereported.Nurse’s clinical experience survey is a questionnairewith four questions (regarding feeling on medicationand sedation medications) and answered as YES/NO.The number and percentage (and its 95% CI) of studynurse chosen YES (or NO) for each question will bereported.To evaluate the effectiveness of blindness of the study,study nurses and physicians will be asked to guess themedication (Midazolam and haloperidol or Ketamine or“don’t know”) that the participant received at the end ofthe study. A table of guess versus treatment received willbe generated for the answers from study nurses and aswell physicians. Blinding indices and associated 95% CIwill be reported.Other variables of interestParticipant demographic and clinical characteristics willbe collected and summarized as mean and standard de-viation (SD) or median and interquartile range for con-tinuous variables and count and percentage forcategorical variables as well as its 95% CI. Demographicvariables include: age and gender. Clinical variables ofinterest include: (1) RASS before IM administration; (2)a VAS to measure dissociative/emergence reaction symp-toms; 3) Barnes Akathisia Scale to measure occurrenceand severity of abnormal movements; 4) Global DystoniaScale; 5) and percentage of participants with the use ofphysical restraints and duration of application.Ethical considerationsThis study will be conducted in accordance with theICH GCP Guidelines, Tri-Council Policy statement, andthe principles in the Declaration of Helsinki. The Inves-tigator will be thoroughly familiar with the appropriateuse of the study treatment as described in the protocoland study medication Product Monographs.Informed consentA waiver for informed consent has been granted by theUBC Providence Health Care Research Ethics Board(PHC REB) for this study.Barbic et al. Trials          (2018) 19:651 Page 10 of 13ConfidentialityAll participant-related information including CRFs,evaluation forms, reports, etc. will be kept strictly confi-dential. All records will be kept in a secure, locked loca-tion and only accessible to research staff. Participantswill be identified only by means of a coded number spe-cific to each participant. All computerized databases willidentify participants by numeric codes only and will bepassword-protected.Upon request, and in the presence of the investigatoror his/her representative, participant records will bemade available to the study sponsor, monitoring groupsrepresentative of the study sponsor, representatives offunding groups, and applicable regulatory agencies forthe purpose of verification of clinical trial proceduresand/or data, as is permissible by local regulations.Participants will be assigned a unique study identifiercode to maintain confidentiality during and after the re-search study. Participants will be identified on data col-lection forms by this unique identifier.General trial conduct considerationsAdherence to protocolProtocol amendmentsAll protocol amendments will be reviewed and approvedand if applicable submitted to the applicable regulatoryagencies for prior approval or notification. The Investi-gator must sign and date the amendment before imple-mentation. All protocol amendments must also besubmitted to the ethics committee.Protocol deviationsNo deviations from this protocol will be permittedwithout the prior written approval of theSponsor-Investigator, except when the modification isneeded to eliminate an immediate hazard or hazards toparticipants. Any deviations that may affect a partici-pant’s treatment or informed consent, especially thoseincreasing potential risks, must receive prior approvalfrom the REB unless performed to remove an immedi-ate safety risk to the participants. In this case it will bereported to the REB and the Sponsor-Investigator im-mediately thereafter. Any departures from the protocolmust be documented.Study monitoringThe study site agrees to allow study monitors from theSponsor-Investigator and/or his representatives directaccess to the study records and medical records fromthose patients enrolled in the clinical study as well asdrug accountability records. Adequate monitoring spaceand time must be provided. The Sponsor-Investigatorrepresentative will perform ongoing study site monitor-ing after the first 10–15 participants have been enrolledand then at random intervals during enrolment to en-sure compliance.Protocol deviations will be monitored and recorded bythe study monitor.Record keepingSource documentsThe Investigator must maintain adequate and accuratesource documents upon which CRFs for each participantare based. They are to be separate and distinct fromCRFs except for cases in which the Sponsor-Investigatorhas pre-determined that direct data entry into specifiedpages of the participant’s CRF is appropriate. These re-cords should include detailed notes on:□ Inclusion and exclusion criteria details;□ RASS;□ AEs and concomitant medication;□ Results of relevant examinations;□ Laboratory printouts;□ Enrolment number;□ Compliance/non-compliance protocol deviationinformation.Data managementInstructions concerning the recording of study data onelectronic CRFs will be provided by the CHÉOS DataManagement Centre to assure the quality of computer-ized data for this study. The study site is responsible forsubmitting the data in a timely fashion. All data will bemaintained on secure computer servers at CHÉOS.Record retentionThe Investigator will maintain all study recordsaccording to the ICH-GCP and applicable regulatoryrequirement(s). Records will be retained for 25 years,in accordance with applicable regulatory require-ment(s). If the Sponsor-Investigator withdraws fromthe responsibility of keeping the study records, cus-tody must be transferred to a person willing to acceptthe responsibility. No destruction of medical recordsshould occur without the written approval of theSponsor-Investigator.All data will be destroyed by trained IT professionalsafter 25 years.Discussion sectionWe present the protocol for a novel study to determinewhether ketamine is a rapid and safe option, comparedto a combination of midazolam and haloperidol, for thesedation of patients presenting to the ED with agitationand violent behavior. To our knowledge, this study is thefirst randomized controlled trial to compare ketamine tocurrent standard care for this indication.Barbic et al. Trials          (2018) 19:651 Page 11 of 13We have attempted to address numerous logistical is-sues with the design of this study. Patients presenting tothe ED with psychomotor agitation and violent behaviorlack the capacity to provide informed consent for re-search purposes and the lack the ability for the informedrefusal of medical care. As a result, we have obtained awaiver of informed consent from our institutional Re-search Ethics board. In cases where a potential partici-pant presents to the ED accompanied by an appropriatesubstitute decision-maker, informed consent will be ob-tained from the appropriate substitute decision-maker.We feel that this strikes a fine balance between the eth-ical principles of respect for patient autonomy andnon-maleficence, and safely conducting research on apressing issue of patient safety in a marginalized groupof patients lacking the capacity to provide informed con-sent or informed refusal of care.The pharmacodynamic effects of ketamine for proced-ural sedation provide a unique challenge for the conductof this study. Prior work has demonstrated that ocularnystagmus is a key physical exam finding that can distin-guish between patients receiving ketamine compared tomidazolam [32]. To maintain adequate blinding of thedata collectors and outcome assessors for this study,they will remain behind opaque dividers in the clinicalcare space in the ED to prevent them from observingpotential ocular nystagmus in the intervention group, orthe lack of nystagmus in the control group.Timely participant enrolment of eligible patients canbe a challenge with any randomized controlled trial. Thisis a single-center study and our required sample size is184 patients. To ensure adequate and timely patientenrolment, we will endeavor to have study staff mem-bers present in the ED approximately 16 h per day,each day of the week. Our site sees approximatelythree potentially eligible patients each day and we an-ticipate being able to reliably enroll approximately onepatient per day, allowing for complete enrolment inapproximately 6–8 months. However, it is possible thatpatient enrolment may not occur as efficiently as an-ticipated. We will consider expanding this from asingle-center to multi-center study if the enrolment ofpatients is suboptimal at approximately eight monthsinto the trial.Another anticipated challenge of this trial is that this amarginalized and high-risk population with high rates ofsubstance use, mental health challenges, and socialmarginalization, including homelessness. This patientpopulation may not be compliant with all study require-ments. We hypothesize that the rate of completion ofthe Patient Experience Survey will be low. Further, weanticipate that compliance rates will be very low for thefollow-up visit at approximately three days after theindex visit.This study is being supported and monitored by theCentre for Health Evaluation and Outcome Science(CHEOS) at St Paul’s Hospital, Vancouver, Canada.CHEOS has extensive expertise and experience in theconduct of clinical trials, data monitoring and manage-ment, data analysis, and regulatory compliance in theareas of HIV, substance use, and marginalized popula-tions. We are confident that this support capacity willallow for active monitoring of data quality and com-pleteness, regulatory compliance, and the rapid assess-ment of AEs and SAEs (Additional file 2).Trial statusThe protocol reported here is version 2.2, dated 18 De-cember 2017. Trial enrolment began on 11 June 2018and is anticipated to finish on 30 June 2019.Additional fileAdditional file 1: Richmond Agitation Sedation Scale (RASS). TROOPSCriteria. Effectiveness of Study Blinding Survey. Study Nurse ExperienceSurvey. Participant Experience Survey. Visual Analog Scale for EmergenceReactions. Barnes Akathisia Scale. Global Dystonia Severity Rating Scale.(DOCX 400 kb)Additional file 2: SPIRIT 2013 Checklist: Recommended items to addressin a clinical trial protocol and related documents*. (DOC 121 kb)AbbreviationsAE: Adverse event; CDSA: Controlled Drug and Substance Act; CRF: Casereport form; ED: Emergency department; GDS: Global Dystonia SeverityRating Scale; ICH GCP: International Conference on Harmonisation GoodClinical Practice; IM: Intramuscular; NMDA: N-methyl-D-aspartate;RASS: Richmond Agitation-Sedation Scale; REB: Research Ethics Board;SAE: Serious adverse event; TROOPS: Tracking and Reporting Outcomes ofProcedural Sedation; VAS: Visual analog scaleAcknowledgementsThe authors would like to thank Ms. Leslie Love and Ms. Dana Nohynek fromCHEOS for their guidance and support, and the Pharmacy department at StPaul’s Hospital for their assistance. The authors would also like to thank theSt Paul’s Emergency Associates for their support during the developmentand conduct of this study.FundingThis study has received peer-reviewed, competitive grant funding from the Emer-gency Advancement Fund (Canadian Association of Emergency Physicians) andthe Vancouver Coastal Health Research Institute Innovation and TranslationResearch Awards. Neither of the study sponsors had a role in the design of thestudy, collection and analysis of data, interpretation of results, or manuscriptpreparation.Availability of data and materialsData are available upon request due to privacy or other restrictions.Authors’ contributionsDB, GA, and FXS conceived the idea for this study. All authors (DB, GA, BG,FXS, WH, WM, SB, HW) were involved in the design and conduct of thisstudy. All authors have seen, read, and approved this manuscript.Ethics approval and consent to participateEthical approval for this study has been obtained from the University ofBritish Columbia, Providence Health Care Research Institute Research EthicsBoard (H17–00571).Barbic et al. Trials          (2018) 19:651 Page 12 of 13Consent for publicationAll authors have given consent for publication. Consent for publication frompatients is not applicable as this is a protocol.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Emergency Medicine, St Paul’s Hospital, 1081 Burrard St,Vancouver, BC V6Z 1Y6, Canada. 2Department of Emergency Medicine, Lion’sGate Hospital, 231 15th St E, North Vancouver, BC, Canada. 3Department ofPsychiatry, University of British Columbia, Vancouver, BC, Canada. 4School ofPublic Health and Epidemiology, University of British Columbia, Vancouver,BC, Canada. 5Department of Occupational Science and OccupationalTherapy, Vancouver, BC, Canada. 6Centre for Health Evaluation OutcomeSciences, Vancouver, BC, Canada.Received: 30 April 2018 Accepted: 16 October 2018References1. Vilke GM, DeBard ML, Chan TC, Ho JD, Dawes DM, Hall C, et al. ExcitedDelirium Syndrome (ExDS): defining based on a review of the literature.JEM. 2012;43(5):897–905.2. Calver LA, Downes MA, Page CB, Bryant JL, Isbister GK. The impact of astandardised intramuscular sedation protocol for acute behaviouraldisturbance in the emergency department. BMC Emerg Med. 2010;10(1):14.3. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA.Randomized controlled trial of intramuscular droperidol versus midazolamfor violence and acute behavioral disturbance: the DORM study. Ann EmergMed. 2010;56(4):392–401 e1.4. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DCM.Intravenous droperidol or olanzapine as an adjunct to midazolam for theacutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61(1):72–81.5. Korczak V, Kirby A, Gunja N. Chemical agents for the sedation ofagitated patients in the ED: a systematic review. Am J Emerg Med.2016;34(12):2426–31.6. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207–22.7. Sih K, Campbell SG, Tallon JM, Magee K, Zed PJ. Ketamine in adultemergency medicine: controversies and recent advances. AnnPharmacother. 2011;45(12):1525–34.8. Motov S, Mai M, Pushkar I, Likourezos A, Drapkin J, Yasavolian M, et al. Aprospective randomized, double-dummy trial comparing intravenous pushdose of low dose ketamine to short infusion of low dose ketamine fortreatment of moderate to severe pain in the emergency department. Am JEmerg Med. 2017;35(8):1095–100.9. Andolfatto G, Willman E, Joo D, Miller P, Wong W-B, Koehn M, et al.Intranasal ketamine for analgesia in the emergency department: aprospective observational series. Miner J, editor. Acad Emerg Med. 2013;20(10):1050–4.10. Chudnofsky CR, Weber JE, Stoyanoff PJ, Colone PD, Wilkerson MD, HallinenDL, et al. A combination of midazolam and ketamine for proceduralsedation and analgesia in adult emergency department patients. 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Cole JB, Moore JC, Nystrom PC, Orozco BS, Stellpflug SJ, Kornas RL, et al. Aprospective study of ketamine versus haloperidol for severe prehospitalagitation. Clin Toxicol. 2016;54(7):556–62.21. Cong ML, Humble I. A Ketamine Protocol and Intubation Rates forPsychiatric Air Medical Retrieval. Air M J. 2015;34(6):357–9.22. Iwanicki JL, Barrett W, Saghafi O, Buchanan J, Heard KJ, Lavonas EJ, McVaneyK.Prehospital ketamine for excited delirium in the setting of acute drugintoxication.23. Le Cong M, Gynther B, Hunter E, Schuller P. Ketamine sedation for patientswith acute agitation and psychiatric illness requiring aeromedical retrieval:Table 1. Emerg Med J. 2012;29(4):335–7.24. Scheppke K, Braghiroli J, Shalaby M, Chait R. Prehospital Use of IM Ketaminefor Sedation of Violent and Agitated Patients. West J Emerg Med. 2014;15(7):736–41.25. Hopper AB, Vilke GM, Castillo EM, Campillo A, Davie T, Wilson MP. Ketamineuse for acute agitation in the emergency department. 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Norambuena C, Yanez J, Flores V, Puentes P, Carrasco P, Villena R. Oralketamine and midazolam for pediatric burn patients: a prospective,randomized, double-blind study. J Pediatr Surg. 2013;48(3):629–34.Barbic et al. Trials          (2018) 19:651 Page 13 of 13

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