1. Ketamine Use in a Patient with Sickle Cell Crisis Refractory to Opiate Therapy
Vatché Demirjian, PharmD
PGY2 Drug Information Resident
Rutgers University

2. Conflict of Interest Consultant for Haymarket Medical Education
No other conflicts to disclose

3. Objectives
Explain the epidemiology and pathophysiology of sickle cell crisis
Develop a medication regimen that could be used to help treat patients in sickle cell crisis who may be refractory to opiates

4. Case History and Physical Admitted June 6, 2016
29 year old African American male
Multiple ED admissions due to sickle cell crisis
Avascular necrosis
Extensive surgical history (including hip replacements)
Requires a blood transfusion every three weeks
Pain score 10

5. Case Outpatient Medications Hydromorphone 8 mg PO Q3 hrs PRN
Morphine Extended Release 100 mg PO BID
Diclofenac 100 mg PO BID
Deferasirox 1000 mg PO QD
Hydroxyurea 500 mg PO QD
Folic acid 1 mg QD
Lactulose PRN
Pain score 10

6. Table 1. Sickle Cell Genotypes
Sickle Cell Disease
HbAS HbSS
Inherited disorder (HbSS)
70,000 to 100,000 patients in the United States
Disease modifying treatments
Hydroxurea
Blood Transfusions
Most children survive into adulthood
Sickle Cells have short half lives
Complications: fever related to infection, acute kidney injury, acute anemia, stroke
Carrier
Table 1. Sickle Cell Genotypes
Genotype
Hb (g/dL)
HbS (%) SS
6-9
>90 AS
Normal
<40%
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):

7. Sickle Cell Crisis Vaso-Occlusive Crisis (VOC) Tissue ischemia
Musculoskeletal pain
Variable intensity
Sharp
Stabbing
Throbbing
Unpredictable
Leading cause of emergency room visits and admissions
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):

8. Pharmacological Options
Our Patient
Day 42 – Pain and Palliative Care following
Methadone 15 mg TID
Total daily IV dose of hydromorphone
___ _mg
Possible Opioid Induced Hyperalgesia?
Mild to Moderate Pain
Acetaminophen
NSAIDS
Moderate – Severe
Opiates (morphine sulfate, hydromorphone, fentanyl)
Adjuvant Therapies for
Neuropathic pain
Anxiety
Constipation
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. JAMA. 2014;312(10):
Uprety D, Baber A, Foy M. Annals Hematol (5):

9. Assessment 1
VOC is a severe complication of sickle cell disease. Which of the following are characteristics of VOC?
Tissue ischemia
Predictable
Vary in intensity
I only
I and II
I and III
II and III
I, II and III

10. Literature Analysis

11. Medline
MeSH Terms: - (1) Anemia, Sickle Cell [Complications, Drug therapy, Therapy] - (2) Ketamine [Administration & Dosage, Therapeutic Use] - (1) and (2) Relevant Results: 2

12. Medline
The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease.
J Pain Symptom Manag
Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature.
Ann. Hematol
MeSH Terms: - (1) Anemia, Sickle Cell [Complications, Drug therapy, Therapy] - (2) Ketamine [Administration & Dosage, Therapeutic Use] - (1) and (2) Relevant Results: 2

13. Study 1 – Uprety et al.
31 y/o AA male presented to emergency department with chest tightness, significant joint pain, and headache for 1 week
Medications:
Methadone 80 mg PO TID
Oxycodone 120 mg PO q 3 hours as needed for pain control.
Pain score was still 10/10 despite increase in opioids
Day 30: Pain and Palliative Care team – opioid induced hyperalgesia
Administered ketamine
Result: Ketamine Day 7, pain score decreased significantly ranging to 4-6 out of 10
Uprety D, Baber A, Foy M. Ann Hematol (5):

14. Morphine IV requirement
Study 2 – Tawfiq QA et al.
Retrospective chart review
Patients who were not responding to morphine
Ketamine/midazolam added to patients refractory to opioids.
Day
Morphine IV requirement
145.6 mg +/ mg 1
112 mg +/ mg
p = 0.007
Tawfic QA, Faris AS, Kausalya R. J Pain Symptom Manag (2):

15. Study 2 – Tawfiq QA et al. Regimen:
Ketamine bolus 0.25 mg/kg
Ketamine infusion mg/kg/hr
Midazolam bolus 1 mg
Midazolam infusion mg/hr
Conclusion: Low dose ketamine might be effective in lowering opiate requirements in addition to providing pain relief.
Tawfic QA, Faris AS, Kausalya R. J Pain Symptom Manag (2):

16. Ketamine
FDA Indications: General anesthesia, procedural sedation, rapid sequence intubation
Mechanism of Action: Nonbarbituate anesthetic and analgesic agent. Used in outpatient and inpatient surgical procedures
Adverse effects: Respiratory depression, cardiovascular effects, emergence reactions
Ketalar ® [Package insert]. JHP Pharmaceuticals, LLC. Rochester, MI [Updated 2012 March; Cited 2017 Feb 023].
Ketamine (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 2/28/2017).

17. Ketamine ADME Outcome Absorption (Onset) 20-40 seconds Distribution
Protein Binding 47%
Volume of Distribution 2 to 3 L/kg
Metabolism
Liver (extensive)
Metabolite: Norketamine (active)
Elimination
12 to 17 mL/minute/kg
Ketalar ® [Package insert]. JHP Pharmaceuticals, LLC. Rochester, MI [Updated 2012 March; Cited 2017 Feb 023].
Ketamine (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 2/28/2017).

18. Assessment
When administering ketamine IV infusion for analgesia, it is important to add _____________ in an effort to decrease the risk of ketamine induced __________.
Norepinephrine; hypoperfusion
Benzodiazepines; emergence reactions
Benzodiazepines; respiratory depression
BiPAP; emergence reactions

19. Consultation with Physician
Original Question: Is ketamine a potential medication therapy for a patient in sickle cell crisis?
Current Regimen:
Hydromorphone 1 mg/hr and clinician bolus 4 mg IV Q 3 hr PRN
Methadone PO Q8 hrs (25 mg at 8 am and 4 pm) and 30 mg PO at 10 pm
Dexamethasone 4 mg PO Q12
Indomethacin 25 mg PO TID
Pregabalin 100 mg PO Q8

20. Consultation with Physician
Original Question: Is ketamine a potential medication therapy for a patient in sickle cell crisis?
Our Recommendation
Yes
Ketamine bolus 0.25 mg/kg
Ketamine infusion mg/kg/hr
Midazolam bolus 1 mg
Midazolam infusion mg/hr
Duration maximum 7 days, then decrease by 25% Q 24 hours.

21. Total Daily Dose of IV Hydromorphone
Outcome
Ketamine
(0.25mg/kg/hr)
Day
Total Daily Dose of IV Hydromorphone
(last 24 hours)
Pain Score
(Ketamine bolus 0.25mg/kg x 1)
124 mg 10 7
85 mg 5
62.7 mg 4 12
45 mg 14
Ketamine Stopped
28 mg

22. Conclusion
Ketamine is a potential therapeutic option for patients in sickle cell crisis who are refractory to opiates.
Bolus plus continuous infusion is reasonable
Add benzodiazepine for reduction in emergence reactions

23. References
Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014; 47(2):
Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014; 93(5):
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014; 312(10):