Utilization of Ketamine for Pain, Excited Delirium, and Procedural

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#FSHP2018 Disclosure Utilization of Ketamine for Pain, Excited • I do not have (nor does any immediate family member have): 1. a vested interest in or affiliation with any corporate Delirium, and Procedural Sedation in organization offering financial support or grant monies for this the Emergent Setting continuing education activity 2.any affiliation with an organization whose philosophy could Daniel Yousef, Pharm.D. potentially bias my presentation Emergency Medicine Clinical Specialist Residency Program Director, PGY-2 Emergency Medicine Jackson Memorial Hospital

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Objectives Ketamine Mechanism of Action • Describe the use of ketamine for acute pain in the emergency • Dissociative anesthetic department • Structurally similar to phencyclidine (PCP) • Review the use of ketamine for excited delirium in the pre-hospital setting and emergency department • Unique because it provides sedation and analgesia • Discuss the role of ketamine in procedural sedation and rapid • Exerts sedative and analgesic action primarily through NMDA sequence intubation antagonism • Select an appropriate dosing regimen for ketamine based on route • Also has affinity for opioid receptors and indication for use • Identify challenges regarding ketamine administration by non- physicians

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Ketamine Kinetics Ketamine Contraindications • Onset of action • Package insert states not to give in anyone whom a significant • Intravenous: 45-60 seconds increase in blood pressure constitutes a serious hazard • Intramuscular: 3-5 minutes • Absolute contraindications: • Acute chest pain • Duration of action • Acute global eye injury • Intravenous: 5-15 minutes • Schizophrenia • Intramuscular: 30-45 minutes • Infants and children less than 3 months old • Relative contraindications: • Procedures that will stimulate posterior pharynx • Consider not giving to patients with chronic cardiovascular disease such as heart failure, ischemic heart failure • Glaucoma

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Ketamine Side Effects Ketamine Dosing and Administration • Neurologic: for Pain • Dizziness, confusion, hallucinations, nystagmus, blurred vision • Cardiovascular: • Primarily looked at for acute pain but can also be considered for • Hypotension and hypertension chronic pain in patients who do not want opioids • Tachycardia and bradycardia • Idea is to give a sub-dissociative dose of ketamine • Pulmonary: • Laryngospasm • Dose ranges from 0.1 to 0.3 mg/kg • Hypersalivation • Recommend a dose of 0.3 mg/kg • Gastrointestinal • Suggest mixing dose in 50 mL of normal saline and administering • Nausea/vomiting over 20 minutes • One study in pediatrics found reduced vomiting in patients given ondansetron before ketamine Ann Emerg Med. 2008;52:30-34

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Ketamine Literature for Pain Ketamine for Excited Delirium • Lots of studies ranging from ketamine vs. opioids to ketamine with opioids and need for rescue opioid therapy • Overall literature suggests ketamine will decrease opioid use and in some situations can manage pain just as effectively as opioids alone • Meta-analysis looking at literature published in 2016 • ACEP policy statement • Safe to give using same procedures as opioids • Does not require intensive monitoring • List a wide variety of potential uses

PLoS ONE 11(10): e0165461. https://doi.org/10.1371/journal.pone.0165461 http://www.acepnow.com/article/acep-policy-low-dose-ketamine/

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Excited Delirium Syndrome EMS Use of Ketamine • “Syndrome of uncertain etiology characterized by delirium, agitation, and hyperadrenergic autonomic dysfunction.” Violent patients can be a danger to • Stimulant abuse or other drugs account for majority of cases EMS staff just as much as the ER staff • Bath salts/synthetic cathinones include methylone, ethylone, and alpha-PVP (Flakka) Patients can be difficult to restrain and keep restrained in moving vehicle • Mortality has been reported to be as high as 8% • Causes of death include hyperthermia and cardiovascular collapse EMS has less staff to restrain a patient • Ketamine has become a popular option due to its quick action and side effect profile • Does not lower seizure threshold • Does not impair heat dissipation J Emerg Med. 2012;43(5):897-905.

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Pre-Hospital Ketamine for Delirium Excited Delirium in the ER • Midazolam along with all other benzodiazepines has a slower onset • If no IV access has been established give 3-4 mg/kg IM when given IM • Can be given into deltoid, buttocks, or thigh • Many EMS protocols give 10 mg of midazolam IM • Recommend using the 100 mg/mL concentration for IM and • Anecdotally in acutely agitated patients on sympathomimetic medications the 10 mg/mL concentration for IV onset of action is too slow and often does not work • Good idea to label the drawer in the automated machine for the 100 mg/mL • Effective ketamine dose reported in literature ranges from concentration “IM use only” and adding a pop-up as well 3-5 mg/kg IM • Physicians are typically used to the 10 mg/mL concentration and may draw up the wrong volume in other indications without proper warnings • I recommend 4 mg/kg IM of total body weight and cap off at 500 mg • Doses less than 200 mg have been associated with treatment failure • When IV access is available recommend starting with 0.5 mg/kg and repeating another 0.5 mg/kg in 2-5 minutes • Paramedics are allowed to give so long as the medical director • Not much literature on IV ketamine for excited delirium has written a protocol allowing for its use

Ann Emerg Med. 2016;67:581-587. • Can a nurse administer ketamine in this situation?

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Florida Nursing Stance on Ketamine The Joint Commission Statement • Florida nursing board view is based on intent “Individuals who are privileged to administer sedation must be • Intent is different from indication able to rescue patients at whatever level of sedation or • Ketamine is considered an anesthetic and can only be anesthesia is achieved either intentionally or unintentionally, e.g., administered by a person credentialed in anesthesia when the patient slips from moderate into deep sedation or from deep sedation into full anesthesia.” • If intention is to produce an anesthetic state a registered nurse should not administer the medication • For excited delirium it is being given for agitation and we allow our nurses to give ketamine • Currently our institution is re-evaluating this stance

https://www.jointcommission.org/standards_information/jcfaqdetails.aspx?StandardsFAQId=1639&StandardsFAQChapterId=74&Pr • We do not allow ketamine to be given by a nurse for procedural ogramId=0&ChapterId=0&IsFeatured=False&IsNew=False&Keyword=&print=y sedation #FSHP2018 15 #FSHP2018 16

Cardiovascular Effects of Ketamine Ketamine for Procedural Sedation • Ketamine both enhances and diminishes epinephrine induced arrhythmias • Can cause both bradycardia and tachycardia, hypertension and hypotension • Ketamine induced cardiac vasospasm can lead to severe hypertension and myocardial infarction or sudden cardiac death

• We do not routinely recommend treating ketamine induced hypertension or tachycardia with anti-hypertensives • Treat ketamine induced hypertension and tachycardia with midazolam when feasible

Clin Ther. 1980;3:28-32. #FSHP2018 17 #FSHP2018 18

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Depth of Sedation Making the Case for Ketamine

Minimal Sedation (Anxiolysis) is a drug-induced state during which patients • Ketamine is a favorable choice for procedural sedation for its respond normally to verbal commands. respiratory safety profile • Allows for sedation and analgesia without suppressing the Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced respiratory drive depression of consciousness during which patients respond purposefully • Opioids should not be used during the case, can be given before or after to verbal commands, either alone or accompanied by light tactile stimulation. • Few cases in literature of laryngospasm, or patients being intubated due to over sedation Deep Sedation/Analgesia is a drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully • Main concern is with emergence phenomenon following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired

As defined by American Society of Anesthesiologists (ASA) #FSHP2018 19 #FSHP2018 20

Emergence Phenomenon Preventing bad delirium

• While the medication is active patient is having delirium or • To avoid bad delirium do not dissociation due to confusion between imaginary and real stimuli administer ketamine alone • This reaction is not emergence phenomenon but is very common • Incidence is as high as 10-20% for • Avoid this by telling patient to focus on happy thoughts monotherapy • Administer with propofol (Ketofol) • Give a benzo such as lorazepam or diazepam 30 minutes before procedure • Prefer to give ketamine and propofol (Ketofol) • Real emergence phenomenon happens after the medication • Give in separate syringes • Administration order based on effects subsides and patient has a momentary confusion from their patient’s vitals dream state • Hypotensive patients start with ketamine, and hypertensive patients • Incidence in literature is less with pediatrics, but changes with age get propofol first • Not recommend to pre-treat pediatric patients with benzodiazepines Am J Emerg Med. 2008;26:985–1028. Ann Emerg Med. 2004;460-71.

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Dosing Ketamine for Procedural Dealing with the Unexpected Sedation • If patients develop hypersalivation • Ketamine monotherapy 1 mg/kg IV • Try airway suctioning • Nebulize ipratropium • Repeat doses of ketamine 0.5 mg/kg IV as needed • Last resort before intubation, try atropine 0.5 mg IV • Ketamine with propofol 0.5-0.75 mg/kg IV • Patients who develop laryngospasm will most likely end up • Repeat doses of each at 0.5 mg/kg IV as needed intubated • Do not mix ketamine and propofol in same syringe • Happens so rarely we do not have a good idea of the incidence • Lose ability to administer the best agent based on patient’s vital signs • Use the 10 mg/mL concentration of ketamine

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Safety First Waveform Capnography

• Ketamine for procedural sedation requires 2 physicians, one to perform the procedure and one to monitor the anesthesia • Emergency Medicine residents are not credentialed in deep sedation and can only perform the procedure • Recommend two consents one for the procedure and one for the sedation • Capnography monitoring should be done on all patients requiring deep sedation • Used as a trending tool for patients who might be experiencing respiratory depression • Look at wave form for depth of breath and rate for hypoventilation

https://www.zoll.com/medical-products/defibrillators/r-series/capnogram/

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Ketamine for Rapid Sequence Dosing and Advantage of Ketamine Intubation in RSI

• Ketamine dosing range is 1-2 mg/kg IV • Suggest giving 1.5-2 mg/kg IV • Giving 1 mg/kg for procedures and excited delirium, so we should give more for RSI • Ketamine does cause bronchodilation • Dose that produces this effect is unknown • Good choice in status asthmatics cases • Ketamine has anti-epileptic properties can be a good choice in status epilepticus cases

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Ketamine in High Intracranial Sudden Cardiac Death with Pressure Cases Ketamine • Ketamine thought to raise ICP by vasoconstriction, increase • Ketamine primarily increases blood pressure and heart rate through cerebral blood flow, and increasing cerebral oxygen consumption indirect stimulation of catecholamines • CPP=MAP-ICP • Ketamine has negative inotropic effects • Early studies show ketamine increases ICP • Ketamine may cause severe hypotension and arrest in patients with impaired cardiac contractility along with diminished • Newer studies show ketamine is safe in patients with elevated ICP catecholamine states • Consider using another agent unless patient is hypotensive • Should be extra careful with ketamine in cardiac disease when giving 2 mg/kg for RSI • Do not recommend lowering the dose to 0.5 mg/kg in shock states

Emergency Medicine Australasia. 2006;8:37–44. J Int Care Med. 2012;28(6):375-379. #FSHP2018 29 #FSHP2018 30

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Ketamine for Delayed Sequence Future Uses of Ketamine in the Intubation (DSI) Emergent Setting •Hypoxia can cause delirium causing patients to rip off • Look for the use of ketamine for suicidal ideation non-rebreather masks or Bi-PAP masks •Administering ketamine can calm patients down while maintaining • Role for ketamine in calming patients before CT scans in ER, their respiratory drive so pre-oxygenation can occur without bag-mask although future studies are unlikely ventilation • Ketamine for alcohol withdrawal •Think of ketamine as procedural sedation where the procedure is preoxygenation •Sometimes patients improve so well intubation can be avoided

J Emerg Med. 2010;40(6):661-667.

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References #FSHP2018

• Langston WT, Wathen JE, Roback MG, et al. Effect of Ondansetron on the Incidence of Vomiting Associated With Ketamine Sedation in Children: A Double-Blind, Randomized, Placebo-Controlled Trial. Ann Emerg Med. 2008;52:30-34. • Vilke G, DeBard M, Chan T, et al. Excited Delirium Syndrome (ExDS): defining based on a review of the literature. J Emerg Med. 2012;43(5):897-905. Utilization of Ketamine for Pain, Excited • Hick J, Ho J. Ketamine chemical restraint to facilitate rescue of a combative “jumper”. Prehosp Emerg Care. 2005;9(1):85-89. • Isbister G, Calver L, Downes M, Page C. Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2016;67(5):581-587.e1 Delirium, and Procedural Sedation in • Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med. (2008) 26, 985–1028 • Zsigmond EK, Kothary SP, Kumar SM, Kelsch RC. Counteraction of circulatory side effects of ketamine by pretreatment with diazepam. Clin Ther. 1980;3:28-32. the Emergent Setting • Green SM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation in children. Ann Emerg Med. 2004;460-71. Daniel Yousef, Pharm.D. • Newton A, Fitton L. Intravenous ketamine for adult procedural sedation in the emergency department: a prospective cohort study. Emerg Med J. 2008;25:498–501. • Sehdev RS, Symmond AD, Kindal S. Ketamine for rapid sequence induction in patients with head injury in the emergency department. Emergency Medicine Clinical Specialist Emergency Medicine Australasia. 2006;8: 37–44. • Dewhirst E, Frazier JW, Leder M, et al. Cardiac Arrest Following Ketamine Administration for Rapid Sequence Intubation. J Int Care Med. Residency Program Director, PGY-2 Emergency Medicine 2012;28(6):375-379. • Weingart SD. Preoxygenation, reoxygenation, and delayed sequence intubation in the emergency department. J Emerg Med. Jackson Memorial Hospital 2010;40(6):661-667.

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