Clinical trial NCT03296345: Adjuvant Low-dose Ketamine in Pediatric Sickle Cell Vaso-occlusive Crisis
Official title: Adjuvant Low-dose Ketamine in Pediatric Sickle Cell Vaso-occlusive Crisis (AKTSS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Vaso-Occlusive Crisis
Keywords: Ketamine
Sickle Cell Disease
Vaso-Occlusive Episode
Lead sponsor: UCSF Benioff Children's Hospital Oakland
Sponsor class: OTHER
First posted: 2017-09-28
Enrollment: 62
Sex: ALL
Minimum age (years): 10
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Acute vaso-occlusive episodes (VOEs) in sickle cell disease (SCD) are primarily managed with opioids. Tolerance and hyperalgesia to opioids develops due to N-methyl-D-aspartate (NMDA)-receptor mediated activation of the nociceptive system, and as a receptor antagonist, ketamine mitigates this. Intravenous (IV) ketamine has demonstrated efficacy in reducing post-operative, chronic, and cancer-related pain in pediatrics, as well as in reducing time to pain control in the emergency department (ED) in adults. Limited studies suggest efficacy in adult opioid-refractory SCD patients. This study is investigating the safety and tolerability of adjuvant low-dose IV ketamine bolus for pediatric SCD VOE in the ED, as well as its efficacy in improving pain control and reducing hospitalization.

Detailed description: In this cohort study, all consenting pediatric sickle-cell patients between 10 and 25 years old who were cared for at UCSF Benioff Children's Hospital Oakland (UCSFBCHO) presenting to the emergency department for VOC were enrolled in the study. Patients were compared to themselves in a time series, pre and post exposure to the study intervention (low-dose ketamine bolus at 0.2 mg/kg x 1 prior to second dose of IV opiate). The pediatric FACES pain scale was used to measure pain scales at pre-designated time points in the ED per standard nursing protocol (FACES for younger kids, visual analog scale in adolescents/young adults). Opiate usage was summed in the ED, converted to mg/kg/hour of morphine equivalents (since different opioids agents were given to different patients based on individual historical efficacy, and since length of stay in the emergency room could affect total morphine equivalents received), and compared between the pre and post-intervention groups. In addition, length of stay, time to 50% pain control, presentation and discharge pain scores, and likelihood of discharge from the ED were compared. Data was be collected via chart review in the UCSFBCHO system by study investigators. Pre-intervention data from the past three patient encounters (e.g., the mean of the mg/kg/hour of morphine equivalents used in the last three patient encounters prior to receipt of ketamine) was compared to the post intervention data. In addition, a survey, which is attached, was given to patients/families at the time of the drug administration to attempt to discern if patients subjectively experienced improvement in their pain and if they experienced any negative side effects due to the drug administration. Monitoring for adverse events was recorded for each patient encounter.

Eligibility criteria: Inclusion Criteria:

* All English-speaking, sickle cell patients who receive their care at UCSFBCHO in the Department of Hematology who are 8-to-25-years-old presenting to the emergency department for VOC were asked to enroll.

Exclusion Criteria:

* Prior adverse reaction to ketamine
* Patients were asked during the consent process if they have ever received ketamine, and if so, if they had any serious adverse reaction, such as difficulty breathing, dysphoria, hallucinations, or allergic reaction. If they have, ketamine was not given to these patients.
* Patients who have received ketamine and experienced nausea or vomiting will be asked if they wish to receive the medication. If they do not, they did not receive ketamine.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: 18 months
Secondary outcomes:
measure: Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED
timeFrame: Up to one year prior and after LDK administration on day 1 of the study in the ED
measure: Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED
timeFrame: Up to one year prior and on presentation to the ED after LDK administration
measure: Effect of Low-dose Ketamine on Discharge Rates From the ED
timeFrame: Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group
measure: Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey
timeFrame: after LDK administration on day 1 of the study in the ED
measure: Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital
timeFrame: At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration)
measure: Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED
timeFrame: Up to one year prior to and after LDK administration on day 1 of the study in the ED
measure: Effect of Low-dose Ketamine on Time to 50% Pain Reduction
timeFrame: Up to one year prior to and after LDK administration on day 1 of the study in the ED
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital and Research Center Oakland
state: California
Study officials:
affiliation: Children's Hospital and Research Center of Oakland
name: Jonathan B Cooper-Sood, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013 Aug;23(8):684-9. doi: 10.1111/pan.12172. Epub 2013 Apr 9.
citation: Tawfic QA, Faris AS, Eipe N. Sickle cell pain management: are we missing the role of pronociception and neuropathic pain? Paediatr Anaesth. 2013 Nov;23(11):1104-5. doi: 10.1111/pan.12269. No abstract available.
citation: Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013 Jun;27(2):150-4. doi: 10.3109/15360288.2013.788599. Epub 2013 May 21.
citation: Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010 Feb;26(2):163-7. doi: 10.1097/AJP.0b013e3181b511ab.
citation: Riha H, Aaronson P, Schmidt A. Evaluation of analgesic effects of ketamine through sub-dissociative dosing in the ED. Am J Emerg Med. 2015 Jun;33(6):847-9. doi: 10.1016/j.ajem.2015.03.045. Epub 2015 Mar 25. No abstract available.
citation: Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193-202. doi: 10.1111/acem.12510.
citation: Drake AB, Milne WK, Carpenter CR. Hot Off the Press: Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med. 2015 Jul;22(7):887-9. doi: 10.1111/acem.12705. Epub 2015 Jun 30. No abstract available.
citation: Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402-8. doi: 10.1016/j.ajem.2014.12.058. Epub 2015 Jan 7.
citation: 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 May;93(5):769-71. doi: 10.1007/s00277-013-1954-3. Epub 2013 Nov 15.
citation: 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 Feb;47(2):334-40. doi: 10.1016/j.jpainsymman.2013.03.012. Epub 2013 Jul 12.
citation: Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201. doi: 10.1016/j.ajem.2014.11.010. Epub 2014 Nov 15.