ENA Subdissociative Ketamine for Analgesia in Adults 2016

Emergency Department use

of Subdissociative-dose

Ketamine for Treatment of

Acute Pain

LAUREN STANLEY, MD FACEP

ASSISTANT MEDICAL DIRECTOR

BOONE COUNTY EMERGENCY MEDICINE

Objectives

By the end of this presentation, participants will be able to:

Understand pharmacology of subdissociative-dose ketamine

Identify target patient populations for use of subdissociative /

analgesic-dose ketamine

Understand the “nuts and bolts” of administering analgesic-dose

ketamine (including dosing, monitoring recommendations, adverse

reactions and their management)

Evaluate and address staff and patient perception of treatment

Why are novel pain medications needed?

Pain is most common presenting complaint to the

Emergency Department

…and we give A LOT of pain medications.

But we aren’t always great at it!

1. Pain may be under-treated

Under treatment of pain

“Pain in the Emergency Department: Results of the Pain

and Emergency Medicine Initiative (PEMI) Multicenter

Study”

- Only 60% of patients received analgesics

- lengthy delays (median, 90 minutes; range, 0 to 962 minutes)

- 74% of patients were discharged in moderate to severe pain.



2. …or over-treated, leading to adverse effects

(especially opioids)



2. …or over-treated, leading to adverse effects

(especially opioids)

Acute effects: respiratory depression, hypoxia,

bradycardia, hypotension

Long-term effects including opioid dependence/abuse,

opioid-induced hyperalgesia (OIH)

Opioid-Induced Hyperalgesia

= state of increased pain sensitization

caused by exposure to opioids

Related to abnormalities in glutamate system,

NMDA receptor upgrading

Allodynia

Morphine can INCREASE the pain

Opioid epidemic Pain control

The History of Ketamine

Synthesized in 1962 in attempt to find safer anesthetic

alternative to PCP

because of PCP’s effects of hallucinations,

mania, seizures

First used on soldiers in WWII and Vietnam War

So, how does subdissociative-dose

ketamine work?

subdissociative dissociative

0.1-0.4mg/kg IV 1-2mg/kg IV

PAIN CONTROL SEDATION

Mechanism of ketamine action

Primarily acts as NMDA receptor antagonist

- Belongs to family of receptors that

mediate excitatory nerve transmission

in the brain

- Plays role in cellular mechanism

for learning, memory


Open NMDA channel allows Ca2+ ions to flow into the neuron

NMDA receptor antagonism

Blocks flow of Ca2+ ions into neuron

Blocked ability to process information

sensory less, analgesia, amnesia, state of DISSOCIATION

Strong pain stimuli activate NMDA receptors and produce

hyperexcitability of neurons

Increased sensitization, “wind up pain”,

pain memory

Thus, Ketamine fights hyperalgesia and “wind up” pain

Ketamine disrupts many downstream, longer-lasting cellular

processes such as gene expression, protein regulation


Also acts on opioid, GABA, cholinergic receptors

sympathetic nervous system

Antidepressant effects (serotonin activation)

Increases endogenous inhibition of pain sensation

Increases release of dopamine, norepinephrine; prevents uptake

What patient populations might benefit

from subdissociative-dose ketamine?

(almost) ANYONE!!!

Target population 1: chronic opioid users

Many have developed significant opioid tolerance and opioid-

induced hyperalgesia, making traditionally used medications (such as fentanyl, morphine, hydromorphone) ineffective.

Using high or frequent doses of opioids may also be unsafe

because of progressive respiratory depression and cardiovascular effects (such as hypotension) despite lack of

pain control

Target population 2: patients at risk for adverse

effects of opioids

The elderly

Patients at risk for hypoventilation

- For example, patients with acute intoxication who are already at risk

for respiratory depression

Hemodynamically unstable patients

- Trauma, Burn

Target population 3: refractory pain despite

“typical” meds

How does it compare to morphine?

Intravenous Subdissociative-Dose Ketamine Versus Morphine

for Analgesia in the Emergency Department: A Randomized

Controlled Trial

[Ann Emerg Med. 2015;66:222–229.]

90 patients enrolled, 18-55 years old

Musculoskeletal, flank, back, abdominal pain

Morphine 0.1mg/kg or Ketamine 0.3mg/kg IV

Ketamine > morphine at 15 minutes, but

no significant difference in pain scores

at 30 minutes

Baseline pain scores: 8.6 versus 8.5

30min: 4.1 versus 3.9

No significant difference in adverse

effects

- Ketamine patients reported increased

minor adverse effects at 15 minutes

15min 30min 120min

“Conclusion: Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED.”

Bottom line…

Ketamine is

SAFE + EFFECTIVE

So, how do we do give ketamine

for acute pain?

So, how do we do give ketamine for acute

pain?

Patient preparation:

Cardiac and continuous SpO2 monitor

Pre-ketamine vital signs (within 10 minutes of giving drug)

Then repeated q15minutes until patient back at baseline mental status

DOSING

0.1 – 0.4 mg/kg IV,

with maximum bolus of 40mg

average initial dose 10-20mg

Onset of action: 30 seconds – 1 min

Peak effect: 1-5 minutes

Duration of action: 20-30 minutes

DOSING

Or…

administer in 100mL 0.9% normal saline,

infused over 10 minutes

DOSING

Drip can be started after initial bolus:

0.1 – 0.3 mg/kg/hr IV

to prepare: ketamine 100 mg in 100 mL of 0.9% NS to

make a 1mg/mL drip

Adverse effects of subdissociative-

dose ketamine

…aka what could go wrong?

Adverse effects of subdissociative-dose

ketamine: Cardiovascular

Arrhythmia (tachycardia most common)

Hypertension


ketamine: Psychiatric

Agitation, delirium, confusion

Hallucinations


ketamine: Others

Transient hypertonia and/or tonic clonic movements

Transient laryngospasm

Increased salivation and respiratory secretions

Apnea, respiratory depression

Nausea, vomiting

Increase in ICP (Intracranial Pressure) or intraocular

pressure

Cardiovascular: bradycardia, hypotension


ketamine

Adverse effects are much less common than with DISSOCIATIVE-dose ketamine

(ie for procedural sedation)

Subdissociative Dissociative

Adverse effects of subdissociative dose

ketamine:

What do I do if these

happen???


ketamine: Management

Supportive care measures!

Managing adverse effects of ketamine:

supportive care measures

For acute agitation, hallucinations:

maintain calm, quiet environment, with

dim lighting if possible

use benzo’s (lorazepam = Ativan;

midazolam = Versed; etc)



For respiratory adverse reactions

reposition head/airway

apply supplemental oxygen as

needed for hypoxia

use suction for airway secretions

bag-valve-mask assisted ventilation (or

advanced airway techniques) as needed



For nausea/vomiting: ondansetron 4-8mg

IV if not otherwise contraindicated



For hypotension: 500-1000mL 0.9% NS IV

bolus if not otherwise contraindicated

So, who SHOULDN’T receive

subdissociative-dose ketamine?

Absolute contraindications:

1. Allergy to ketamine

2. Age <3 months

3. Suspicion of acute primary psychotic condition such

as schizophrenia

Relative Contraindications:

Conditions in which elevated blood pressure would be

hazardous

- Acute angina

- Acute heart failure



hazardous

- Acute angina


Elevated intraocular pressure (such as acute

glaucoma)



hazardous

- Acute angina


Elevated intraocular pressure

Patients with known or suspected

upper airway obstruction


Conditions in which elevated blood pressure would be hazardous

- Acute angina


Elevated intraocular pressure (such as acute glaucoma)

Patients with known or suspected upper airway obstruction

Cases in which elevated intracranial pressure is suspected (such as obstructive hydrocephalus) - CONTROVERSIAL


Conditions in which elevated blood pressure would be hazardous

- Acute angina


Elevated intraocular pressure

Patients with known or suspected

upper airway obstruction

Elevated ICP

Acute thyrotoxicosis

Use caution with…

Mild-moderate hypertension, tachycardia

Neurotic traits

Acute alcohol intoxication

Patient and Staff Perception of Treatment

Patient Perception

It works!

Decreased time to pain control

Adverse effects should be discussed prior to giving the

medication

Staff Perception: Initial

“It’s too much work!”

“It makes patients crazy.”

“Drug-seekers love it.”

Staff Perception: After using it


We do vital signs and put patients on monitors anyway!






Agitation/delirium are less common than with dissociative-dose ketamine

Adverse effects (agitation) are easily managed with lorazepam






Good! Their pain is treated effectively and they are ready to be discharged safely, more quickly than if traditional meds (opioids) were given.

Introducing a new

Medication/Treatment

Early adopters The Majority Late adopters

Staff Perception: Overall

SUMMARY

Subdissociative-dose ketamine is a safe alternative to

traditionally used pain medications in the Emergency

Department, especially for:

1. Patients with chronic pain and on chronic opioids

2. Patients in whom opioids would be unsafe

- Hypoventilation risk

- Hypotensive

3. Patients with refractory pain (kidney stones, headaches, etc)

SUMMARY

Ketamine primarily works as an NMDA receptor

antagonist, but has activity at multiple other receptors

as well

SUMMARY

The main adverse effects include:

- Tachycardia

- Hypertension

- Agitation

- Delirium

- Laryngospasm

- Increased airway secretions

SUMMARY

Due to cardiovascular and respiratory effects, patients should be

on cardiac and SpO2 monitor throughout treatment

Adverse effects can be managed by supportive care (especially

benzo’s!)

Since implementation of protocol for subdissociative-dose

ketamine at our hospital, patient and staff perception has been

positive

Where to find our protocol

www.ena.org

Document share

Thank you!

Questions?

[email protected]

CITATIONS

1. Todd, K. H., Ducharme, J., Choiniere, M., Crandall, C. S., Fosnocht, D. E., Homel, P., Tanabe, P., & PEMI Study Group. (2007). Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. The journal of pain, 8(6), 460-466.

2. Smith, R. J., Rhodes, K., Paciotti, B., Kelly, S., Perrone, J., & Meisel, Z. F. (2015). Patient perspectives of acute pain management in the era of the opioid epidemic. Annals of emergency medicine, 66(3), 246-252.

3. Cordell, William H., et al. "The high prevalence of pain in emergency medical care." The American journal of emergency medicine 20.3 (2002): 165-169.

4. Martin, J. S., and R. Spirig. "Pain prevalence and patient preferences concerning pain management in the emergency department." Pflege 19.6 (2006): 326-334.

5. Safe use of opioids in hospitals. Sentinel Event Alert 2012:1-5.

6. Sleigh, Jamie, et al. "Ketamine–More mechanisms of action than just NMDA blockade." Trends in Anaesthesia and Critical Care 4.2 (2014): 76-81.

7. Hocking, Graham, and Michael J. Cousins. "Ketamine in chronic pain management: an evidence-based review." Anesthesia & Analgesia 97.6 (2003): 1730-1739.

CITATIONS

8. Motov, S., Rockoff, B., Cohen, V., Pushkar, I., Likourezos, A., McKay, C., & Fromm, C. (2015). Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: a randomized controlled trial. Annals of emergency medicine, 66(3), 222-229.

9. Miller, J. P., Schauer, S. G., Ganem, V. J., & Bebarta, V. S. (2015). Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. The American journal of emergency medicine, 33(3), 402-408.

10. Richards, J. R., & Rockford, R. E. (2013). Low-dose ketamine analgesia: patient and physician experience in the ED. The American journal of emergency medicine, 31(2), 390-394.

11. Sin, B., Ternas, T., & Motov, S. M. (2015). The use of subdissociative‐dose ketamine for acute pain in the emergency department. Academic Emergency Medicine, 22(3), 251-257. (review article)

12. Lee M, Silverman SM, et al. A comprehensive rview of opioid-induced hyperalgesia. Pain Physician, 14(2):145.

CITATIONS

13. Ahern, T. L., Herring, A. A., Anderson, E. S., Madia, V. A., Fahimi, J., & Frazee, B. W. (2015). The

first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. The American journal of emergency medicine, 33(2), 197-201. 14. Ahern, T. L., Herring, A. A., Stone, M. B., & Frazee, B. W. (2013). Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. The American

journal of emergency medicine, 31(5), 847-851. 15. 15. Zeiler, F. A., Teitelbaum, J., West, M., & Gillman, L. M. (2014). The ketamine effect on ICP in traumatic brain injury. Neurocritical care, 21(1), 163-173.

Subdissociative Ketamine for Analgesia in Adults: Proposed protocol for use

Indication: acute pain (traumatic or non-traumatic) in patients >16 years of age

Mechanism of action: primarily acts as NMDA receptor antagonist.

- Also acts on multiple other receptors including opioid, GABA, cholinergic; sympathetic nervous

system

- Increases endogenous inhibition of pain sensation

- Prevents hyperalgesia and “pain wind up”

Target patient populations:

- Patients with severe pain refractory to other analgesics (including opioids such as morphine,

hydromorphone, fentanyl; anti-inflammatory medications, such as toradol; acetaminophen).

May be used as adjunct to these other medications, or as solo agent.

- Patients with chronic pain, especially those who are opioid-tolerant

o Many patients on chronic opioids have developed significant opioid tolerance and

opioid-induced hyperalgesia, making traditionally used medications (such as fentanyl

morphine, hydromorphone) ineffective.

o Using high or frequent doses of opioids may also be unsafe because of progressive

respiratory depression and cardiovascular effects (such as hypotension) despite lack of

pain control

- Patients at risk for compromised airway patency, hypoventilation, or hemodynamic instability if

given opioid medications

o Ketamine causes minimal central respiratory depression, so is safer for use in patients at

risk for hypoventilation

o Ketamine’s cardiovascular effects are usually stimulatory (ie, hypertension instead of

hypotension), so safer for use in patients at risk for hypotension

Contraindications:

- Absolute:

o Previous allergy to ketamine

o Age < 3 months

o suspicion of acute psychotic condition including schizophrenia

- Relative:

o Cases in which elevated intracranial pressure is suspected (such as hydrocephalus)

o Elevated intraocular pressure (such as acute glaucoma)

o condition in which elevated blood pressure would be hazardous (such as acute angina,

acute heart failure)

o Use with caution in patients with acute alcohol intoxication

o Acute thyrotoxicosis

o Patients with known or suspected upper airway obstruction

Monitoring requirements for administration

- Continuous Cardiac and oxygen saturation monitoring established before administration

- Baseline vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation) documented

within 10 minutes prior to medication administration; then repeat vital signs every 15 minutes

after medication administration, until patient returns to pretreatment level of awareness and

verbalization

- Baseline and post-medication pain scores as per nursing protocol

- Notify physician/provider if: o heart rate <60 or >110 o systolic blood pressure <90 or >180 o respiratory rate <10 o development of hallucinations or acute agitation or combativeness

Dose: 0.1 – 0.4 mg/kg IV, with maximum bolus of 40mg (average dose 10-20mg)

- Alternatively, 2mg/kg IM

- When given IV: administer over at least 1 minute; alternatively, may administer as IVP with

100mL 0.9% normal saline, infused over 10 minutes

- Following initial bolus, may be used as continuous infusion: 10-20mg/hr IV (to prepare: ketamine

100 mg in 100 mL of 0.9% NS to make a 1mg/mL drip)

Possible adverse reactions:

- Arrhythmia (tachycardia most common)

- Hypertension (hypotension less common)

- Recovery agitation, delirium, confusion

- Hallucinations

- Transient hypertonia and/or tonic clonic movements

- Transient laryngospasm

- Apnea, respiratory depression

- Nausea, vomiting

- Increased salivation and respiratory secretions

- Note: adverse reactions occur more commonly when medication is used at dissociative doses

Reversal agent: none

Management of adverse reactions: supportive care

- For respiratory adverse reactions: reposition head/airway, apply supplemental oxygen as

needed for hypoxia, use suction for airway secretions, use bag-valve-mask assisted ventilation

(or advanced airway techniques) as needed

- For acute agitation, hallucinations: maintain calm, quiet environment, with dim lighting if

possible; see adjunctive medications below

- For nausea/vomiting: ondansetron 4-8mg IVP if not otherwise contraindicated

- For hypotension: 500-1000mL 0.9% NS IV bolus if not otherwise contraindicated

Adjunctive medications:

- benzodiazepines for agitation, hallucinations

o lorazepam 0.02 – 0.04 mg/kg IV (maximum dose 2mg IV)

o midazolam 0.01 – 0.05 mg/kg (average dose 0.5 – 4mg)

o consider co-administration of benzodiazepine with ketamine

o or, benzodiazepine can be administered in a PRN fashion (PRN agitation, hallucinations)

- consider giving hydromorphone 0.5-1mg IV for persistent pain

Selected articles with relevant data

Ahern TL, Herring AA, Stone MB, et al. “Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain,” Amer J Emerg Med, 2013;31(5):847-51. Ahern TL, Herring AA, Anderson ES, et al, “The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED,” Amer J Emerg Med, 2015;33(2):197-201. Sleigh J, Harvey M, Voss L, et al, “Ketamine: More mechanisms of action than just NMDA blockade, Trends in Anesthesia and Critical Care 2014;4:76-81 Green SM, Roback MG, Kennedy RM, et al, "Clinical Practice Guideline for Emergency Department

Ketamine Dissociative Sedation: 2011 Update," Ann Emerg Med, 2011;57(5):449-61.

Hocking G and Cousins MJ, "Ketamine in Chronic Pain Management: An Evidence-Based Review,"

Anesth Analg, 2003, 97(6):1730-9.

Kurdi MS, Theerth KA, Deva RS, “Ketamine: Current applications in anesthesia, pain, and critical care,”

Anesth Essays Res. 2014;8(3):283-90.

Motov S, Rockoff B, Cohen V, et al, “Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial.” Ann Emerg Med. 2015 Mar 26 (EPub ahead of print) Shankar R, Wilson JA, Colvin L, “Non-opioid-based adjuvant analgesia in perioperative care,” Cont Edu Anaesth Crit Care & Pain, 2013;13(5):152-157.

(May 2015)

http://www.sciencedirect.com/science/article/pii/S0735675714008006

http://www.sciencedirect.com/science/article/pii/S0735675714008006

http://www.ncbi.nlm.nih.gov/pubmed/25886322

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ENA Subdissociative Ketamine for Analgesia in Adults 2016