Sub-dissociative Intranasal Ketamine for Pediatric Sickle Cell Pain Crises

Sickle Cell Disease Clinical Trial

Official title:

Comparison of Sub-dissociative Intranasal Ketamine Plus Standard Pain Therapy Versus Standard Pain Therapy in the Treatment of Pediatric Sickle Cell Disease Vasoocclusive Crises in Resource-limited Settings: a Multi-centered, Randomized, Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02573714
• Other study ID #: IRB2015-07
• Secondary ID: MNH/IRB/I/2015/1
• Status: Recruiting
• Phase: N/A
• Start date: December 2015
• Est. completion date: July 2019

Study information

• Verified date: March 2019
• Source: Cameroon Baptist Convention Health
• Contact: James R Young, MD
• Phone: 704-578-5078
• Email: james.young[@]carolinashealthcare.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if the use of ketamine, sniffed in the nose, is a safe and effective way to help reduce pain in pediatric sickle cell patients with pain crises in resource-limited settings.

Description:

This is a randomized, placebo-controlled, drug trial using sub-dissociative intranasal ketamine as an adjunct to standard pharmacotherapy for the management of pediatric sickle cell disease vasoocclusive pain crises in resource-poor settings. Pediatric patients will be enrolled at a teaching and referral hospital in West Africa. Patients will be randomly assigned to the treatment arm - standard therapy plus sub-dissociative intranasal ketamine (1 mg/kg) given at time zero) or the control arm - standard therapy plus intranasal normal saline (volume-matched to treatment arm), and patients will evaluated at standard intervals to assess for pain scores and vital signs (0 minutes, 30 minutes, 60 minutes, and 120 minutes). Pain will be assessed using the Faces Pain Scale - Revised (FPS-R). Patients will also be observed for any potential side effects or adverse events. All patients will be contacted 2-3 weeks post intranasal medication administration for over-the-phone follow-up using a portion of the PedsQL-SCD questionnaire, to assess for basic quality of life related to pain management and treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: July 2019
• Est. primary completion date: July 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 16 Years

Eligibility

Inclusion Criteria:

• Sickle cell disease (SCD)

• Vasoocclusive pain crisis

• Requiring analgesia

Exclusion Criteria:

• Anatomic variations of nose precluding intranasal medication administration

• Ketamine allergy

• Non-verbal

• Obtunded

• Pregnant

• Other acute SCD complications:

• Acute chest syndrome

• Sepsis

• Stroke

• Splenic sequestration

• Pulmonary embolism

• Acute osteomyelitis

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Ketamine
Intranasal ketamine (concentration: 50 mg/ml, dose: 1 mg/kg) will be given at time zero. Intranasal administration will be performed by placing the needleless syringe gently into the nares with the patient sitting upright. Volumes of = 0.75ml will be nasally inhaled in a single nare, while volumes > 0.75ml will be divided between both nares. Patients who are unable to inhale the medication nasally will receive drip administration of the same volume while recumbent on the bed.
• Normal Saline
Intranasal normal saline (placebo: volume-matched with intranasal ketamine) will be given at time zero. Intranasal administration will be performed by placing the needleless syringe gently into the nares with the patient sitting upright. Volumes of = 0.75ml will be nasally inhaled in a single nare, while volumes > 0.75ml will be divided between both nares. Patients who are unable to inhale the medication nasally will receive drip administration of the same volume while recumbent on the bed.

Other:
• Standard Pain Therapy
Typical management strategy for pediatric sickle cell disease vasoocclusive crises including acetaminophen/paracetamol, ibuprofen, oral opioids, and injectable opioids depending on pain severity.
• Pediatric Quality of Life - Sickle Cell Disease Module
Standardized quality of life assessment performed 2-3 weeks post intranasal medication administration to evaluate pain management and severity of symptoms after discharge from the hospital.
• Faces Pain Scale - Revised
All patients will answer the FPS-R at 0 minutes (immediately prior to receiving intranasal medication), 30 minutes, 60 minutes, and 120 minutes to assess current pain status.

Locations

Country	Name	City	State
Cameroon	Mbingo Baptist Hospital	Bamenda	Northwest Province
Tanzania	Muhimbili National Hospital	Dar es Salam

Sponsors (3)

Lead Sponsor	Collaborator
Cameroon Baptist Convention Health	Carolinas Medical Center, Muhimbili National Hospital

Countries where clinical trial is conducted

Cameroon,  Tanzania, 

References & Publications (44)

Alli NA, Patel M, Alli HD, Bassa F, Coetzee MJ, Davidson A, Essop MR, Lakha A, Louw VJ, Novitzky N, Philip V, Poole JE, Wainwright RD. Recommendations for the management of sickle cell disease in South Africa. S Afr Med J. 2014 Nov;104(11):743-51. Review. — View Citation

Aloni MN, Nkee L. Challenge of managing sickle cell disease in a pediatric population living in kinshasa, democratic republic of congo: a sickle cell center experience. Hemoglobin. 2014;38(3):196-200. doi: 10.3109/03630269.2014.896810. Epub 2014 Mar 26. — View Citation

Ambe JP, Mava Y, Chama R, Farouq G, Machoko Y. Clinical features of sickle cell anaemia in northern nigerian children. West Afr J Med. 2012 Apr-Jun;31(2):81-5. — View Citation

American Pain Society (1999a) Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. American Pain Society, Glenview, IL.

Andolfatto G, Willman E, Joo D, Miller P, Wong WB, Koehn M, Dobson R, Angus E, Moadebi S. Intranasal ketamine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013 Oct;20(10):1050-4. doi: 10.1111/acem.12229. — View Citation

Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia. 2011 Apr;52(4):788-93. doi: 10.1111/j.1528-1167.2010.02949.x. Epub 2011 Jan 28. — View Citation

Borland M, Jacobs I, King B, O'Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007 Mar;49(3):335-40. Epub 2006 Oct 25. — View Citation

Chien YW, Su KSE, Chang SF, Chapter 1: Anatomy and Physiology of the Nose. Nasal Systemic Drug Delivery, 1989. Dekker, New York: p. 1-26.

Diallo D, Tchernia G. Sickle cell disease in Africa. Curr Opin Hematol. 2002 Mar;9(2):111-6. Review. — View Citation

Donnelly RF. Stability of diluted ketamine packaged in glass vials. Can J Hosp Pharm. 2013 May;66(3):198. — View Citation

Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg. 1997 May;84(5):1086-90. — View Citation

GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117-71. doi: 10.1016/S0140-6736(14)61682-2. Epub 2014 Dec 18. — View Citation

Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, Pegelow CH, Vichinsky E. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood. 1995 Jul 15;86(2):776-83. Review. — View Citation

Govoni MM. Mandatory education and credentialing for dental assistants: is it the answer to the manpower crisis? Dent Assist. 1990 Jul-Aug;59(4):9-12. — View Citation

Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med. 2015 Mar;65(3):248-254.e1. doi: 10.1016/j.annemergmed.2014.09.024. Epub 2014 Nov 18. — View Citation

Green SM, Clem KJ, Rothrock SG. Ketamine safety profile in the developing world: survey of practitioners. Acad Emerg Med. 1996 Jun;3(6):598-604. — View Citation

Green SM, Roback MG, Krauss B, Brown L, McGlone RG, Agrawal D, McKee M, Weiss M, Pitetti RD, Hostetler MA, Wathen JE, Treston G, Garcia Pena BM, Gerber AC, Losek JD; Emergency Department Ketamine Meta-Analysis Study Group. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009 Aug;54(2):158-68.e1-4. doi: 10.1016/j.annemergmed.2008.12.011. Epub 2009 Feb 7. — View Citation

Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008 Jan;18(1):36-42. — View Citation

Johansson J, Sjöberg J, Nordgren M, Sandström E, Sjöberg F, Zetterström H. Prehospital analgesia using nasal administration of S-ketamine--a case series. Scand J Trauma Resusc Emerg Med. 2013 May 14;21:38. doi: 10.1186/1757-7241-21-38. — View Citation

Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998 Nov;87(5):1186-93. Review. — View Citation

Makani J, Ofori-Acquah SF, Nnodu O, Wonkam A, Ohene-Frempong K. Sickle cell disease: new opportunities and challenges in Africa. ScientificWorldJournal. 2013;2013:193252. doi: 10.1155/2013/193252. Epub 2013 Sep 19. Review. — View Citation

Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996 Aug;77(2):203-7. — View Citation

Nesher N, Ekstein MP, Paz Y, Marouani N, Chazan S, Weinbroum AA. Morphine with adjuvant ketamine vs higher dose of morphine alone for immediate postthoracotomy analgesia. Chest. 2009 Jul;136(1):245-252. doi: 10.1378/chest.08-0246. Epub 2008 Aug 27. — View Citation

Nielsen BN, Friis SM, Rømsing J, Schmiegelow K, Anderson BJ, Ferreirós N, Labocha S, Henneberg SW. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014 Feb;24(2):170-80. doi: 10.1111/pan.12268. Epub 2013 Oct 1. — View Citation

Ogun GO, Ebili H, Kotila TR. Autopsy findings and pattern of mortality in Nigerian sickle cell disease patients. Pan Afr Med J. 2014 May 8;18:30. doi: 10.11604/pamj.2014.18.30.4043. eCollection 2014. — View Citation

Olabode JO, Shokunbi WA. Types of crises in sickle cell disease patients presenting at the haematology day care unit (HDCU), University College Hospital (UCH), Ibadan. West Afr J Med. 2006 Oct-Dec;25(4):284-8. — View Citation

Palermo TM, Riley CA, Mitchell BA. Daily functioning and quality of life in children with sickle cell disease pain: relationship with family and neighborhood socioeconomic distress. J Pain. 2008 Sep;9(9):833-40. doi: 10.1016/j.jpain.2008.04.002. Epub 2008 Jun 12. — View Citation

Pandey RK, Bahetwar SK, Saksena AK, Chandra G. A comparative evaluation of drops versus atomized administration of intranasal ketamine for the procedural sedation of young uncooperative pediatric dental patients: a prospective crossover trial. J Clin Pediatr Dent. 2011 Fall;36(1):79-84. — View Citation

PedsQL Sickle Cell Disease Module, Version 3.0. 1998 JW Varni, Ph.D. (http://www.proqolid.org/instruments/pediatric_quality_of_life_inventory_sickle_cell_disease_module_pedsql_sickle_cell_disease_module)

Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 2013;10(7):e1001484. doi: 10.1371/journal.pmed.1001484. Epub 2013 Jul 16. — View Citation

Pires A, Fortuna A, Alves G, Falcão A. Intranasal drug delivery: how, why and what for? J Pharm Pharm Sci. 2009;12(3):288-311. Review. — View Citation

Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-6. — View Citation

Quinn CT, Shull EP, Ahmad N, Lee NJ, Rogers ZR, Buchanan GR. Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia. Blood. 2007 Jan 1;109(1):40-5. Epub 2006 Aug 29. — View Citation

Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989 Mar;36(2):186-97. Review. — View Citation

Smith DC, Mader TJ, Smithline HA. Low dose intravenous ketamine as an analgesic: a pilot study using an experimental model of acute pain. Am J Emerg Med. 2001 Oct;19(6):531-2. — View Citation

Tayebati SK, Nwankwo IE, Amenta F. Intranasal drug delivery to the central nervous system: present status and future outlook. Curr Pharm Des. 2013;19(3):510-26. Review. — View Citation

Tsze DS, Steele DW, Machan JT, Akhlaghi F, Linakis JG. Intranasal ketamine for procedural sedation in pediatric laceration repair: a preliminary report. Pediatr Emerg Care. 2012 Aug;28(8):767-70. — View Citation

Walker SE, Law S, DeAngelis C. Stability and compatibility of hydromorphone and ketamine in normal saline. Can J Hosp Pharm. 2001;54(3):191-199.

White JM, Ryan CF. Pharmacological properties of ketamine. Drug Alcohol Rev. 1996 Jun;15(2):145-55. — View Citation

Who.int,. "WHO | WHO Model Lists Of Essential Medicines." N.p., 2015. Web. 20 July 2015.

Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics. 2010 Sep;126(3):532-7. doi: 10.1542/peds.2010-0616. Epub 2010 Aug 9. Review. — View Citation

World Health Organisation, "Sickle cell anaemia. Agenda item 11.4," in 59th World Health Assembly, 27 May 2006, World Health Organisation, Geneva, Switzerland, 2006.

Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, Aoyama T, Yamamura Y, Yamada Y, Iga T. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003 Jan;24(1):37-43. — View Citation

Yeaman F, Oakley E, Meek R, Graudins A. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas. 2013 Apr;25(2):161-7. doi: 10.1111/1742-6723.12059. Epub 2013 Mar 20. — View Citation

* Note: There are 44 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events	Adverse events include: bad taste is mouth, drowsiness, dizziness, itchy nose, nausea, dysphoria, and other novel subjective negative experiences	Time of initial intranasal drug administration to 2 hours post intranasal drug administration
Other	Serious Adverse Events	Serious adverse events include: apnea, assisted ventilation, bradypnea, cyanosis, dissociation, emergence reaction, hypotension, laryngospasm, myoclonus, seizure, and vomiting	Time of initial intranasal drug administration to 2 hours post intranasal drug administration
Primary	Change from Baseline (time zero) in FPS-R scores between treatment groups	Measure of differences of change of FPS-R scores from baseline to 30 minutes, 60 minutes, and 120 minutes compared between treatment arms	Baseline (time zero, indicated by injection of intranasal medication), 30 minutes, 60 minutes, and 120 minutes
Secondary	Hospital length of stay	Hospital length of stay recorded from time zero to time of discharge documented by the study clinician will be a secondary outcome measure.	through study completion, an average of 3 days
Secondary	Quality of life assessment (PedsQL-SCD Module scores)	PedsQL-SCD Module scores obtained by study clinicians using over-the-phone interviews between two-three weeks post intervention will be a secondary outcome measure.	Time of first intranasal administration to 3 weeks post intranasal intervention.
Secondary	Analgesia use - paracetamol	Individual evaluation of total paracetamol use per kilogram body weight	Time of initial intranasal drug administration to 2 hours post intranasal drug administration
Secondary	Analgesia use - ibuprofen	Individual evaluation of total ibuprofen use per kilogram body weight	Time of initial intranasal drug administration to 2 hours post intranasal drug administration
Secondary	Analgesia use - opioids	Individual evaluation of total opioid use expressed as morphine equivalents per body weight.	Time of initial intranasal drug administration to 2 hours post intranasal drug administration