Ketamine Procedural Sedation (Yin Et

SPECIAL K: A LITTLE GOES A LONG WAY ALI PRYNE PHARMD, BCPS VALLEY VIEW HOSPITAL, GLENWOOD SPRINGS, CO

DISCLOSURES

• Nothing to disclose OBJECTIVES

1. Compare differing doses of ketamine for indications such as sedation, analgesia, and depression. 2. Analyze recently published literature regarding ketamine and esketamine use. 3. Discuss treatment plans for safe administration and monitoring of ketamine.

BACKGROUND

• Administration of ketamine in Alaska limited to provider only • RN not able to provide deep sedation • Nursing advisory MECHANISM OF ACTION

• Produces a cataleptic-like state in which the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. • Ketamine is a noncompetitive NMDA receptor antagonist that blocks glutamate.

MECHANISM OF ACTION

• Low (subanesthetic) doses produce analgesia, and modulate central sensitization, hyperalgesia and opioid tolerance. Reduces polysynaptic spinal reflexes.

ASSESSMENT QUESTION

Select all approved routes of administration  Intranasal  Intravenous/Intraosseous  Intramuscular  Oral  Rectal  Endotracheal ADMINISTRATION

• Oral, IM, IV, IN or Rectal

Ketamine Slow infusion vs IV push (Clattenburg et. al.)

Purpose Low dose ketamine (0.3 mg/kg) IV push (IVP) vs slow infusion (SI) (over 15 min)

Methods Prospective, randomized, double blind, double dummy, placebo controlled Moderate to severe pain in ED Primary outcome = side effects only – not efficacy Psychoperceptual SE w/in 60 min of administration Used SERDSA (side effects rating scale for dissociative anesthetics) Data 59 participants, 86.2% IVP vs 70% SI; not significant 75.9% IVP vs 43.4% SI; statistically significant No difference in analgesia effect Discussion Small study, not validated scale

Conclusions Similar rate of SE, less severe w/ SI IVP = higher risk of “bothersome” SE

Considerations Limited external validity Blinded – attempted to limit bias Pharmacokinetics Onset of action: IV: 30 seconds IM: ~4 minutes IN: ~10 minutes Oral: ~30 minutes Duration: IV:~10 minutes IM: 15-25 minutes IN: Up to 60 minutes Protein binding: 27 % Metabolism: Four varying metabolites Hepatic via N-dealkylation (norketamine) - ~30 % as potent as ketamine Bioavailability: IM: 93% IN: 35-50% Oral: 20-30% Half-life: Alpha ~10-15 minutes, Beta 2.5 hours Time to peak, plasma: IM: 5-30 minutes IN: 10-15 minutes Oral: ~30 minutes Excretion: Urine 91%, feces 3% SPECIAL CONSIDERATIONS

• Psychedelic/dissociative effects • Nystagmus • Protruding tongue, exaggerated mouth movements • Hypertonia SPECIAL CONSIDERATIONS

• Head trauma/bleeds – increases ICP and intraocular pressure • Schizophrenia – even if stable on medications • Cardiac decompensation • Pharynx/larynx/bronchial abnormalities** • Bladder dysfunction • Tachycardia/arrythmias

ASSESSMENT QUESTION

• T/F: Ketamine is commercially available only as 50 mg/mL and 100 mg/mL. SAFETY CONSIDERATIONS

• ISMP high risk medication • Concentration/math errors • “Ketofol” – mix of propofol and ketamine • Generally 1:1 COMPOUNDING

Infusion • Dilute 50 or 100 mg/mL with D5W or NS to final concentration of 1-2 mg/mL • Do NOT use 10 mg/mL • Do not mix w/ barbituates (i.e. PHENobarbital, PENTobarbital) or diazepam

• Generally send full vial for IV push, intranasal or IM routes VIAL SIZES

x PATIENT CASE

A 34 y/o M is transported to the ER after a MVC. No PMH and NKDA. He had a positive LOC, airbags did not deploy, GCS of 9, and is beginning to not protect his airway. MD would like to proceed with RSI and looks to you for recommendations…

• What other information do you want to know? • Why would you advocate for/against ketamine? ADVERSE REACTIONS

• Cardiovascular: tachycardia, hypertension • CNS: dependence, hypertonia, increased ICP • Dermatologic: rash • Endocrine/metabolic: diabetes insipidus • Gastrointestinal: nausea, sialorrhea • Genitourinary: bladder dysfunction, cystitis, urgency • Neuromuscular: laryngospasm • Ophthalmic: diplopia, increased intraocular pressure, nystagmus • Respiratory: apnea, respiratory depression Ketamine Safety: PTSD (Highland et. al.)

Purpose Determine if ketamine SE increase risk for PTSD in combat casualty care. X Methods Evaluated those medically evacuated from combat (paired) PCL (PTSD checklist scores) w/in 365 days of injury, if positive and severity Ketamine >7 days before evaluation Matched cohort n(1:1, and 1:4)

Data N=1158, 107 got ketamine Primary outcome: OR=1.28 95% CI (0.48-3.47) p = .62 Secondary outcome: mean difference 1.98 95% CI (-.99 – 4.96) p = .19

Discussion Varying times between assessment, ketamine administration, and injury Low power Unknown if received in field (just at medical center post injury) Conclusions Medical and surgical care provided in service members does not appear to increase risk for PTSD

Considerations Small sample size Accounted for confounders fairly well SEDATION KETAMINE DOSING: SEDATION

• Adults • IV: 1-2 mg/kg • IM: 4-5 mg/kg, may repeat 2-5 mg/kg if needed

• Pediatrics • IV: 1-2 mg/kg • IM: 4-5 mg/kg • Intranasal: 3-6 mg/kg* • Oral: 5 mg/kg *

Ketamine Procedural Sedation (Yin et. Al.)

Purpose Optimal agent combined w/ propofol for sedation in elderly patients undergoing gastrointestinal endoscopy

Methods ketamine w/ propofol dexmedetomidine w/ propofol sufentail w/ profofol saline w/ propofol

Data See next page

Discussion Well done study (prospective, blind, large single center) No major biases

Conclusions Lower rates of bradycardia, hypoxia, and hypotension

Considerations Only studied elderly patients (60-80 years old) short procedures (<40 min) weren’t in poor physical status (per ASA classifications)

Ketamine Intubation sedation (Shahtahmasebi et. al.)

Purpose Does ketamine administration impact intubation rates in the transport of patients w/ behavioral disturbances

Methods Pre and post ketamine protocol introduction Selected patients transferred from remote areas of Australia Intubation rates and adverse event Ketamine failure = adverse event

Data N=340 patients, 129 had an intervention See next page for results AE = 18 ketamine and 50 I+V (difference of -0.43, p = <0.00001 CI -0.58 to -0.28) Discussion 92.5% were mental health/substance abuse Selection bias Conclusions Ketamine reduced intubation rates in patients w/ behavioral disturbances on transport Reduces adverse reactions, but does have risks Considerations Included all post protocol = real life May require intubation for other illness/low GCS Lower cost?

Ketamine Adjunct sedation in vented patients (Groetzinger et. al.) Purpose Ketamine use as adjunct sedation in mechanically vented patients Methods Retrospective review between 2012-2016, on continuous infusion Dosing, effect on other sedatives, total sedative use, Sedation-Agitation Scale (SAS), ADRs and hemodynamics Excluded if paralyzed or ketamine for <6 hours

Data N=91, median dose= 0.41 mg/kg/hr, duration = 2.8 days 63% reduction or discontinuation of alternative sedative 7.7% had ADR = discontinuation Increase in SAS at goal 61% vs 55% p =0.001 Discussion Descriptive report No standard protocol for dosing Selection bias (only started in 65% of patients Conclusions Acceptable adjunct sedation in critically ill patients

Considerations Attempt for light sedation 30% of adults may experience emergence reactions, only 2% in this study Ketamine Adjunct sedation (Pruskowski et. al.)

Purpose Ketamine as adjunct sedation/analgesia in trauma patients

Methods Retrospective chart review – must have sedation, not just acute pain Determine time at RASS goal and alternative sedation doses Changes 72 hours before or 72 hours after initiation Data N=36, mostly white men w/ blunt trauma Decreased opioid and propofol use Increased dexmedetomidine and ziprasidone use Did not change time at goal RASS

Discussion Trade off? Less opioid use for psychosis AE

Conclusions Ketamine infusions may not be the best choice for trauma patients

Considerations Single center, small study Did not confound for TBI, substance withdrawal or psychiatric disorders

ANALGESIA

Painless

KETAMINE DOSING: ANALGESIA

• Adults • IV: 0.2-0.8 mg/kg bolus followed by 1 mcg/kg/minute • Intranasal: acute pain 0.5-1 mg/kg

• Pediatrics • IV • IM • Intranasal

Ketamine Consensus Guidelines: Infusions for Pain (Cohen et. al.) Indications Chronic neuropathic pain, spinal cord injury, phantom limb pain, post-herpetic neuralgia, headache/migraine, cancer pain, and chronic back pain

Contraindications Angina, HTN, high risk CVD, elevated ICP, elevated intraocular pressure, liver disease, hypothyroidism, delirium, psychosis, intoxication, aspiration risk, or active substance abuse.

Dose range Minimum dose of 80 mg infused over 2 hours Chronic pain requires higher doses, longer infusions and more frequent administration

Administration requirements At a doctors office w/ training for resuscitation and monitoring hemodynamics

Rescue medications Possibly midazolam or dexmedetomidine (psychosis) No strong recommendations

Positive treatment response High refractory risk, 30% pain reduction = positive outcome Standard duration = >3 weeks outpatient and >6 weeks inpatient Ketamine Acute pain (Karlow et. al.)

Purpose Low dose ketamine use as alternative to opioids in ED

Methods Meta-analysis, doses <0.5 mg/kg Pain scale assessed w/in 60 minutes of administration 3 studies included N=261 patients

Data NRS or VAS scale Difference 0.42 95% CI = -0.70 to 1.54

Discussion Strict criteria for inclusion

Conclusions Low dose ketamine was non-inferior to opioids (morphine equivalents)

Considerations Only 3 studies reviewed DEPRESSION KETAMINE DOSING: DEPRESSION

• Adults • IV: 0.5 mg/kg twice weekly

Ketamine Depression(Sanacora et. al.)

Patient selection Major depressive disorder w/o psychotic features Avoid w/ other traditional contraindications (i.e. increased ICP)

Treatment setting/training Basic general training requirements Knowledge of emergence reactions and psychosis

Delivery IV w/ monitoring of O2, blood pressure, RR, and HR Frequent monitoring of alertness/sedation scale 1 dose per week by the second month Follow up-duration Typical response occurs after 3 treatments No standard number or duration established

Long term effects Unknown

Considerations High abuse potential ASSESSMENT QUESTION

• Esketamine is a/an: a. Prodrug of ketamine b. Metabolite of ketamine c. S-enantiomer of ketamine d. Inactive metabolite of ketamine Esketamine MECHANISM OF ACTION

• S-enantiomer of racemic ketamine • Non-selective, non competitive N-methyl-D-aspartate (NMDA) receptor antagonist • Depression - unknown

PHARMACOKINETICS

Protein binding: 43 – 45 %

Metabolism: metabolized to active metabolite noresketamine via CYP450, CYP2B6, CYP3A4 and some CYP2C9/CYP2C19

Bioavailability: ~50%

Half-life: 7-12 hours, noresketamine ~8 hours

Time to peak, plasma: 20-40 minutes

Excretion: Urine <1% unchanged ADMINISTRATION

• Intranasal only • MD office DEPRESSION ESKETAMINE DOSING: DEPRESSION

• Adults • Intranasal (induction): 56 mg twice weekly, may increase up to 84 mg twice weekly • Evaluate after 4 weeks for continuance • Intranasal (maintenance): At week five, continue previous dose (i.e. 56 or 84) but decrease to weekly. Evaluate every 4 weeks and decrease interval as tolerated.

Esketamine Intranasal w/ oral antidepressant treatment (Daly et. al.) Purpose Safety, efficacy and dose response of intranasal esketamine

Methods Phase 2, double blind, double dummy, randomized, placebo controlled 4 phase (screening, double blind tx 1-14 days, open label tx 15-74, post tx follow-up at 8 weeks) Treated twice weekly w/ placebo (33), 28 mg (11), 56 mg (11) or 84 mg (12) Changed in MADRS scale Data Esketamine was superior to placebo (all three doses) 28 mg = -4.2 [2.09] p = .02, 56 mg = -6.3 [2.07] p = .001, 84 mg = -9 [2.13] p < .001 Discussion Difficult to blind d/t bitter taste of esketamine Excluded those with SI, psychosis, PTSD, OCD, or substance abuse

Conclusions Promising tx for MDD in specific patient population

Considerations Funded by Janssen, makers of esketamine Esketamine IV w/ oral antidepressant treatment (Singh et. al.)

Purpose Efficacy and safety of esketamine IV as adjunct to oral antidepressant medications

Methods Multicenter, randomized Infusion on day 1 and day 4 of either 0.2 mg/kg or 0.4 mg/kg Matched 1:1:1, non responders who had placebo were reassigned on day 4 N=30 MADRS score reduction Data Significant improvement in MADRS score 0.2 mg/kg = -16.8 (3) p <.001, 0.4 mg/kg = -16.9 (2.61) p <.001, placebo =-3.8 (2.97)

Discussion Lower SE profile w/ 0.2 mg/kg dose (nausea, head ache and dissociation) Rapid response to administration

Conclusions Possible adjunct treatment

Considerations Small population Limited information on long term Not available in US ASSESSMENT QUESTION

Select all approved routes of administration  Intranasal  Intravenous/Intraosseous  Intramuscular  Oral  Rectal  Endotracheal ASSESSMENT QUESTION

• T/F: Ketamine is commercially available only as 50 mg/mL and 100 mg/mL. PATIENT CASE

• What other information do you want to know? • Why would you advocate for/against ketamine? ASSESSMENT QUESTION

• Esketamine is a/an: a. Prodrug of ketamine b. Metabolite of ketamine c. S-enantiomer of ketamine d. Inactive metabolite of ketamine QUESTIONS?

REFERENCES

• Alaska State Board of Nursing Advisory Opinion. Link: https://www.commerce.alaska.gov/web/portals/5/pub/nur_advisory_ketamine_administration.pdf • ISMP's List of High-Alert Medications in Acute Care Settings. Link: https://www.ismp.org/recommendations/high-alert-medications- acute-list • Ketamine. Lexi-Drugs. [updated 2019 Aug 6; cited 2019 Aug 12] In Lexicomp Online [Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. • Clattenburg E, Hailozian C, Haro D, et al. Slow infusion of low-dose ketamine reduces bothersome side effects compared to intravenous push: a double-blind, double-dummy, randomized controlled trial. Acad Emerg Med 2018;25:1048-1052. • Highland K, Soumoff A, Spinks E, et al. Ketamine administration during hospitalization is not associated with posttraumatic stress disorder outcomes in military combat casualties: a matched cohort study. Int Anesthesiol Res Soc 2019. DOI: 10.1213/ANE.0000000000004327. • Yin S, Hong J, Sha T, et al. Efficacy and tolerability of sufentani, dexmedetomidine, or ketamine added to propofol-based sedation for gastrointestinal endoscopy in elderly patients: a prospective, randomized, controlled trial. Clin Ther 2019; awaiting publication. • Shahtahmasebi R, Johnson R, Shahtahmasebi S. Impact f a ketamine sedation protocol on intubation rates and undesirable outcomes in the transport of patients with acute behavioural disturbance. Emerg Med Australas 2019;29:291-296. • Groetzinger L, Rivosecchi R, Bain W, et al. Ketamine infusion for adjunct sedation in mechanically ventilated adults. Pharmacotherapy 2018;38(2):181-188.

REFERENCES

• Pruskowski K, Harbourt K, Pajoumand M, et al. Impact of ketamine use on adjunctive analgesic and sedative medications in critically ill trauma patients. Pharmacotherapy 2017;37(12):1537-1544. • Cohen S, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American society of regional anesthesia and pain medicine, the American academy of pain medicine, and the American society of anesthesiologists. Reg Anesth Pain Med 2018;43: 00-00. • Karlow N, Schlaepfer CH, Stoll CR, et al. A systematic review and meta-analysis of ketamine as an alternative to opiods for acute pain in the emergency department. Acad Emerg Med 2018;25:1086-97. • Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 2017;74:399-405. • Bahr R, Lopez A, Rey J. Intranasal esketamine for use in treatment-resistant depression in conjunction with an oral antidepressant. Drug Forecast P&T 2019;44(6):340-347. • Daly E, Trivedi M, Janik A, et al. A randomized withdrawal, double-blind, multicenter study of esketamine nasal spray plus an oral antidepressant for relapse prevention in treatment-resistant depression. JAMA Psychiatry 2018;75(2);139-148. • Singh J, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment –resistant depression: a double-blind, double- randomization, placebo-controlled study. Biol Psychiatry 2016; 80:424-431. • Esketamine. Lexi-Drugs. [updated 2019 Aug 6; cited 2019 Aug 12] In Lexicomp Online [Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.