Low-dose Ketamine vs Morphine for Vaso-occlusive Crisis in Sicklers (KEM-VOC)

Low-dose Ketamine Versus Morphine for Severe Painful Sickle Cell Crises in Children at Mulago Hospital: A Randomised Controlled Trial

This clinical trial will inform of the role of Low dose ketamine in the acute treatment of severe painful sickle cell crisis in children in a day-case sickle cell centre. The primary aim is to determine whether Low dose ketamine is non inferior to morphine in the management of acute painful sickle cell crises. The specific objectives will be to determine the maximal change in NRS pain score following administration of ketamine and to examine the safety profile of ketamine compared to morphine in this population.

The investigators hypothesize that low dose ketamine will result in similar effective pain control as morphine alone and will not be associated with an increase in adverse events.

Study Overview

• Status: Completed
• Conditions: Acute Pain; Sickle Cell Crisis
• Intervention / Treatment: Drug: Low dose ketamine; Drug: Morphine

Detailed Description

Acute pain episodes associated with sickle cell disease (SCD) are very difficult to manage effectively. Opioid, phobia, tolerance, availability and side effects have been major roadblocks in our ability to provide these patients with adequate pain relief.

Ketamine is cheap, widely safe, readily available drug in low-middle income setting, with analgesic effects at sub-anesthetic doses and has a wide range of use including surgery (opioid sparing drug), burns (change of dressing ) and cancer related pain. However literature concerning its use in sickle cell crises is still limited in our setting.

This is a double-blinded, randomized control, study comparing low-dose ketamine (LDK) to morphine for acute pain control in children with sickle cell crises. A sample of 240 children will be enrolled from a population of patients with Sickle Cell Anemia aged 7-18 who present to the Mulago Referral Hospital Sickle Cell Clinic with acute painful Vaso-occlusive Crisis (VOC). To take part in the study, a patient must have a pain score of 7 and above as assessment by the treating physician in addition to the patient meeting all other study criteria.

After enrollment, the consented patient's weight in kg will be determined at the holding area with a standardized calibrated weighing scale (SECA - From National Medical Stores, Uganda) before transfer to the treatment room.

Baseline clinical parameters which include pulse rate, respiratory rate, blood pressure, temperature, oxygen saturation, level of consciousness, Numerical Rating Scale (NRS) Pain score (with 0 being no pain and 10 being the worst pain possible) and sites of VOC pain will be noted.

This will be followed by placement of a peripheral intravenous cannula, G22-G20 (this is part of standard care) with subsequent fluid load of 15mls per kg of crystalloid, repeated if required. Other non analgesic therapies will be prescribed by the primary care provider and started concurrently.

The recruited patients will then be randomized and allocated to receive Ketamine at 1mg/kg (study drug) or morphine at 0.1mg/kg (active control) through an intravenous infusion using a syringe pump(Agilia, Fresenius Kabi) over 10 minutes.

The vital signs and NRS and Ramsay sedation scores (RSS) will be reassessed and recorded at 5, 10 and 20 minutes after the end of the drug infusion. However, patient monitoring will be continuous. At 20 minutes, patients with NRS of 5 and more will be given a second dose without crossing over. Monitoring will be continued as above. If the NRS is less than 5, they will continue to be reassessed every 20 minutes (vital signs, NRS, RSS and adverse events) until either inpatient admission to the ward or up to 120 minutes after which they will be cared for by the ward team..

If they require a third dose of pain medication at any time during the study, this will be deemed as treatment failure and the treating pediatrician will be contacted to provide further pain control.

Any Ketamine (even for morphine) side effects as listed in the risks and safety section will monitored for among the study subjects and will treated by the study team.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda, 256
    • Sickle Cell clinic, Mulago Hospital Complex

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children aged 7-18 years
• sickle cell anemia patient with severe acute painful crisis
• Parental consent and child assent where applicable

Exclusion Criteria:

• Oxygen saturations below 90% on initial assessment
• Altered conscious and mental state that hinders communication
• Current enrollment in another clinical trial involving an investigational drug.
• History of a stroke
• Hypertension,
• Increased intracranial pressure.
• Glaucoma,
• Failed/ Difficult IV access

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose ketamine; Low dose ketamine 1mg/kg given as an IV infusion via syringe pump over 10 minutes. Maximum of 2 doses to be given during study period that will last 2 hours.	Drug: Low dose ketamine; Children in this arm shall receive a slow infusion of ketamine at a sub-anesthetic dose and monitored for pain, vital signs and side effects for 2 hours. Records will be taken at 5, 10, 20, 40, 60, 80, 100 and 120min.; Other Names: Ketamine hydrochrolide 50mg/ml,Nirma Pharmaceuticals (India)
Active Comparator: Morphine; Morphine 0.1mg/kg given as an IV infusion via a syringe pump over 10 minutes. Maximum of 2 doses to be given during the study period that will last 2 hours.	Drug: Morphine; Children in this arm shall receive intravenous infusion of morphine at analgesic dose and then monitored for pain, vital signs and side effects for 2 hours. Records will be taken at 5, 10, 20, 40, 60, 80, 100 and 120min.; Other Names: Morphine sulphate 10mg/ml, Martindale Pharmaceuticals (UK)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Change in NRS Pain Scores as a Percentage of Baseline NRS Pain Score.	Our primary outcome measurement was the maximum change on the verbal NRS pain scale compared with their initial score (baseline). The NRS was used to measure a patient's subjective level of pain on a scale from 0 (representing no pain at all) to 10 (the worst pain imaginable) using whole numbers. The NRS score was documented just prior to the administration of the study drug (time zero). After infusion of the study drug was complete, NRS scores were documented at 5, 10, 20, and then every 20 minutes thereafter up to 120 minutes. We stopped recording NRS scores prior to 120 minutes if the patient requested a third dose of the study drug, withdrew consent or developed a severe adverse effect.	5, 10, 20,25,30, 40,45,50 60, 80, 100, 120 minutes post drug adminstration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Maximal Analgesic Effect and Duration of Action of Ketamine	Following dosage with study medication, the amount of time taken to demonstrate the maximal change in the patient's NRS pain score. Maximal change in NRS pain score is to be defined as the largest change from patient's baseline pain score. Duration of maximal change is how long the patient's pain score remained at this level.	5, 10, 20, 40, 60, 80, 100, 120 minutes post drug administration
Incidence of Side Effects, Including Outlying Vital Signs	The patient will be assessed for vital signs (blood pressure, heart rate, respiratory rate, oxygen saturation), Ramsay Sedation Scale (RSS) score at 5,10,20 minutes following medication administration and then every 20 minutes until a total of 120 minutes from the first dose of study medication. outlying vital signs recorded.( systolic Blood pressure less than 90mmHg or greater than 150mmHg, Heart rate less than 50bpm or greater than 150bpm, oxygen saturation below 90%, respiratory rate below 9breaths/minute or greater than 40breaths/minute and RSS of 1 or greater than 3) The RSS was used to asses the level of agitation or sedation caused by the intervention .the scale ranges from 1(anxious/agitated) to 6( no response to stimulus-deep sedation) with 2 being the optimal (cooperative, oriented and tranquil).A checklist for side effects like airway problems, allergic reactions, salivation, dysphoria,nystagmus, respiratory/cardiac arrest, awakening hallucinations, nausea/vomiting was used	5, 10, 20, 40, 60, 80, 100, 120 minutes post drug administration
Incidence of Treatment Failure by Treatment Group.	Requiring more than two doses of the study medication provided for adequate pain control	120 minutes

Collaborators and Investigators

• Sponsor: Makerere University
• Investigators: Principal Investigator: Felix A. Lubega, MBChB, Makerere University, College of Health Sciences, Department of Anesthesia and Critical Care; Study Chair: Tonny S. Luggya, MMed, Makerere University, College of Health Sciences, Department of Anaesthesia and Critical care; Study Director: Deogratias Munube, MMed, Makerere University, College of Health Sciences, Department of Child Health and Pediatrics; Study Director: Fred Bulamba, MBChB, Makerere University, College of Health Sciences, Department of Anaesthesia and Critical care; Study Director: Mithrika S De Silva, MD, University of Sydney, Department of Peadiatrics

Publications and helpful links

General Publications

• Marcus RJ, Victoria BA, Rushman SC, Thompson JP. Comparison of ketamine and morphine for analgesia after tonsillectomy in children. Br J Anaesth. 2000 Jun;84(6):739-42. doi: 10.1093/oxfordjournals.bja.a013585.
• Lubega FA, DeSilva MS, Munube D, Nkwine R, Tumukunde J, Agaba PK, Nabukenya MT, Bulamba F, Luggya TS. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: a randomized controlled trial. Scand J Pain. 2018 Jan 26;18(1):19-27. doi: 10.1515/sjpain-2017-0140.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: April 22, 2015
• First Submitted That Met QC Criteria: May 5, 2015
• First Posted (Estimate): May 6, 2015

Study Record Updates

• Last Update Posted (Estimate): August 3, 2016
• Last Update Submitted That Met QC Criteria: June 22, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Opioid; Narcotics; Ketamine; Morphine
• Other Study ID Numbers: 2013/HD07/606U

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No