Ketamine

TIVA – A Multi-Modal Approach Doris Pavia , CRNA

Objectives

• • • • Define the mechanism of the drug action of Ketamine Define the side effects of Ketamine and the concerns in the veteran population State the uses of Ketamine as part of multi modal therapy State the uses of Ketamine as treatment for Complex Regional Pain Syndrome

Ketamine

Ketamine

• • • Special K Club Drug Date Rape

Ketamine

• • • Phencyclidine Derivative Dissociative Anesthesia Acts Centrally and Peripherally

Site of Action

Mechanism of Action

NMDA Receptor • • • Ketamine is a noncompetitive antagonist Acts at the NMDA receptors in the dorsal horn of the spinal cord Ketamine binds to the NMDA receptors, preventing the channel from opening

Mechanism of Action

• Depresses the transmission of impulses in the medial medullary reticular formation

Mechanism of Action

• • • • • Inhibits the production of nitric oxide Acts on opioid receptors: Mu, Delta, and Kappa Acts as a noradrenergic and serotonergic uptake inhibitor Blocks voltage-sensitive calcium channels Depresses sodium channels

Mechanism of Action

• • • Inhibits the reuptake of catecholamines Inhibits neuronal uptake and increased serotonergic activity Induce catacholamine release and stimulates Beta 2 adrenergic receptors

Side Effects

Central Nervous System: -Delirium -Dizziness -Euphoria -Diplopia -Short term memory loss Psychotomimetic Phenomenon – mimics the symptoms of psychosis Emergence Delirium: visual, auditory, and confusional illusions

Side Effects

Central Nervous System, Continued: -Potent Cerebral Vasodilator -Increased Cerebral Metabolism Cardiovascular: -Direct Myocardial Depressant -Indirectly Stimulates the Cardiovascular System

Side Effects

Respiratory: -No change in ventilatory response to CO2 -Bronchial smooth muscle relaxant -Increased salivary and tracheobronchial secretions

•

Veterans

Post-Traumatic Stress Disorder – Exposure to a Traumatic Event – Intrusive Recollections Criterion – Avoidance Criterion – Negative Cognitions and Mood Criterion – Alterations in Arousal or Reactivity Criterion – Duration Criterion – Functional Significance Criterion – Exclusion Criterion

Ketamine

Ketamine

Dosing of Ketamine for Adults IV: 0.25 - 1 mg/kg IM: 2-3 mg/kg Dosing of Ketamine for Children IV: 0.25 – 1 mg/kg IM: 2-3 mg/kg PO: 6-10 mg/kg

Ketamine

• • Onset of Action: IV: < 30 seconds IM: 3-4 minutes • • • Peak Effects: IV: 1 minute IM: 5-20 minutes PO: 30 minutes

Ketamine

• • Metabolism: Hepatic Norketamine is an active metabolite – 20% to 30% as potent as Ketamine – Contributes to prolonged effects • Excretion: Renal

TIVA - Multimodal Therapy

• • • Benzodiazepines – most effective in preventing emergence delirium – Midazolam > Diazepam (stoelting 2006) Propofol – sedative-hypnotic Opioids – potentiates analgesia

TIVA – Multimodal Therapy

Mixed with propofol: Propofol:ketamine (10:1)-Propofol 200mg with ketamine 20mg Propofol:ketamine (25:1)-Propofol 500mg with ketamine 20mg *50mg total for the case: 20mg in the first bottle, 10mg in each following bottle x 3 *50mg total for the case: 20mg IV bolus after induction, 10mg every hour x 3

Complex Regional Pain Syndrome

Reflex Sympathetic Dystrophy Characterized by: -Preceding noxious event -Continuing pain disproportionate to the inciting event -Edema and changes in blood flow -Exclusion of other existing conditions that could account for the degree of pain and dysfunction

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

Central Sensitization – -Reduced firing threshold of the A delta and C fibers. -Ongoing release of neurotransmitters and peptide neuromodulators. -Through multiple cascades, magnesium is then blocked from the NMDA receptors.

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome

• http://rsdhealthcare.or

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Complex Regional Pain Syndrome

VAPHS: Pretreatment: Perphenazine 8mg PO Dexmedetomidine 40mcg slow IV push Midazolam 4mg IV titrated Glycopyrrolate 0.2mg IV x 1-2 doses Lidocaine 100mg IV x 1 Dexamethasone 4mg IV

Complex Regional Pain Syndrome

Ketamine Infusion – 500mg in 250ml of NSS Start Ketamine at 125-150mg/hr, run over 3.5-4 hours Propofol Infusion – 25mcg/kg/min (separate) Esmolol Infusion - 10-25 mcg/kg/min, as tolerated Ondansetron 4mg IV, towards the end of the ketamine infusion

Complex Regional Pain Syndrome

1 st patient: 28 yr old male Initial injury: fractured right ankle in May 2007 2 mos later – severe pain radiating up leg, cast removed Oct 2007 – Removal of hardware Worsening symptoms, up leg to hip “Deep, sharp, burning and numb” Rating pain at rest: 7/10 pain with movement:10/10

Complex Regional Pain Syndrome

Patient was irritable, unable to sleep, unable to work Symptoms: - worse with cold, weight bearing, walking, sudden movements, and bumps -relieved with heat -intermittant swelling -color changes in right foot/ankle: purple to black, cold to touch

Complex Regional Pain Syndrome

Initial Treatment in Pain Clinic: Percocet progressed to Oxycontin & Percocet Changed to Methadone & Percocet Optimal Pain Control: Fentanyl patches Actiq 600 mcg ~ 3 times/day -allows patient to walk and play with kids

Complex Regional Pain Syndrome

Discharged, referred to civilian Pain clinic, no Actiq available. Placed on: Methadone Lyrica Dilaudid NSAIDS Antineuropathic pain drugs Physical therapy and acupuncture Lumbar sympathetic block – made pain worse Ankle block – no relief

Complex Regional Pain Syndrome

2/2009: Pain Consult at VAPHS: Morphine 30mg PO Q 4 Hr Fentanyl Patch 75mcg Q 72 Hr Patient was irritable and tearful Right ankle joint severely limited ROM, due to pain, severe tenderness.

MRI: Chronic changes due to surgeries, no obvious cause for pain Referred to Tampa Pain Rehabilitation

Complex Regional Pain Syndrome

Moved care to Pittsburgh in May 2013 Pain @ rest Pain w/ move Ketamine Propofol MS Contin Fentanyl Patch Symptoms

5/13

2/10 4/10 400 mg 200mg 30mg x 2 100mcg Improved ADLs

11/13 12/13

6/10* 8/10* 400mg 200mg 30mg x 2 100mcg 4-5 good wks 4 hrs of sleep 8/10* 9/10* 400mg 100mg 30mg x 3 50mcg Decreased fentanyl patch * Patient states that the high scores are due to the cold weather

1/14

8/10* 9/10* 400mg 100mg 30mg x 3 50 mcg Only 1-2 flare-ups/day

Complex Regional Pain Syndrome

2 nd Patient: 38 yr old male History of 3 ankle stabilization surgeries: 2008 – Brostrom Procedure 4/2009 – Crisman-Snook Procedure 7/2009 – Hardware removal Walter Reed, ketamine treatments, Ketamine coma

Complex Regional Pain Syndrome

The distribution of pain is from below the left knee to all the toes and involves all surfaces. Feels like a broken, dull ache, sharp, electrical, on fire pain. Scars are allodynic and with weight bearing, rates pain 10/10 The spread of pain is up the proximal leg to the waist to upper right leg. It has improved with the ketamine infusions.

Complex Regional Pain Syndrome

3/5-10/12: Ketamine coma: Ketamine started at 100mg/hr with versed 5mg/hr. Ketamine goal of 550mg/hr reached on 3/9, versed was 18mg/hr with PRN boluses; Extubated on 3/10. Ventilator associated pneumonia and MRSA

Complex Regional Pain Syndrome

He reports that since the ketamine coma (3/2012), he no longer has the spread of pain. Does continue to report flare-ups. He does receive the ketamine infusions approximately every 2 months to help control his pain

Complex Regional Pain Syndrome

• • • • 4/2012: in the elevator he states that he bumped his affected foot. He received a ketamine infusion along with a sciatic block.

The nerve block replicated a new injury.

His CRPS relapsed. He received infusions on 6/12, and 8/12.

Due to his continued pain and many conversations with the pain physicians, the patient decided to have a BKA.

Complex Regional Pain Syndrome

• He was to have the BKA on 9/30/2013 at Cleveland Clinic. In collaboration with the orthopedic surgeons, the patient received a Ketamine infusion in PGH on 9/24, had the BKA on 9/30 and he was to have a follow-up infusion on 10/4 after his surgery. However, he incurred a staph infection, requiring additional surgery.

Complex Regional Pain Syndrome

• • • Patient did experience relief from his CRPS symptoms with the BKA until January 6 th , when the symptoms returned.

He has started back up on his ketamine infusion.

He is pleased with his decision to have the BKA, as he does not worry about guarding his foot and he is more functional.

Complex Regional Pain Syndrome

• • International Research Foundation for RSD/CRPS: www.rsdfoundation.org

RSDSA – Reflex Sympathetic Dystrophy Syndrome Association: www.rsds.org

References

• • • • • A, & Curran, H. Valerie. (2012). Ketamine use: a review. Addiction, 107(1), 27-38. doi: 10.1111/j.1360-0443.2011.03576.x

Azari, PanLindsay David R. Briones DeanClarke CollinBuchheit ThomasPyati Srinivas. (2012). Efficacy and Safety of Ketamine in Patients with Complex Regional Pain Syndrome. CNS Drugs, 26(3), 215-228. Correll, G. E., Maleki, J., Gracely, E. J., Muir, J. J., & Harbut, R. E. (2004). Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Medicine, 5(3), 263-275. Dowben, Jonathan S. Grant Joan S. Keltner Norman L. (2013). Biological Perspectives Biological Perspectives: Ketamine as an Alternative Treatment for Treatment-Resistant Depression. Perspectives in Psychiatric Care, 49(1), 2-4. doi: 10.1111/ppc.12006

Kiefer, Ralph-ThomasRohr PeterPloppa AnnetteAltemeyer Karl-HeinzSchwartzman Robert Jay. (2007). Complete Recovery From Intractable Complex Regional Pain Syndrome, CRPS-Type I, Following Anesthetic Ketamine and Midazolam. Pain Practice, 7(2), 147-150. doi: 10.1111/j.1533-2500.2007.00123.x

References

• • • • • McGhee, Laura L., Maani, Christopher V., Garza, Thomas H., Gaylord, Kathryn M., & Black, Ian H. (2008). The correlation between ketamine and posttraumatic stress disorder in burned service members. The Journal Of Trauma, 64(2 Suppl), S195. doi: 10.1097/TA.0b013e318160ba1d

Stoelting, Robert K., Hillier, Simon. (2006). Pharmacology & Physiology in Anesthetic Practice. Philadelphia: Lippincott Williams & Wilkins.

Stone, J. MDietrich CEdden RMehta M. ADe Simoni SReed L. JKrystal J. HNutt DBarker G. J. (2012). Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Molecular Psychiatry, 17(7), 664-665. doi: 10.1038/mp.2011.171

Thomas, Michael C., Jennett-Reznek, Alison M., & Patanwala, Asad E. (2011). Combination of ketamine and propofol versus either agent alone for procedural sedation in the emergency department. American Journal of Health-System Pharmacy, 68(23), 2248-2256. doi: 10.2146/ajhp110136 Womble, Arthur L. (2013). Effects of ketamine on major depressive disorder in a patient with posttraumatic stress disorder. AANA Journal, 81(2), 118-119.