2.4 Intervention and assessment
All enrolled children were first administered supervised mouthwash with 5 ml drinking water, as oral swish for 30 seconds followed by spitting and without swallowing. This exercise was carried out to assess the adequacy of the mouthwash technique by the patient. Those children who were not able to follow commands or not able to carry out the mouthwash procedure adequately were planned not to be administered the mouthwash, and not to be included for analysis. However, all the enrolled children were able to follow the instructions adequately.
Children randomized to the intervention group received ketamine mouthwash (prepared as 4 mg of ketamine in 1 ml solution by diluting marketed formulation of ketamine in an appropriate pharmaceutical diluent) at a dose of 0.25 ml/kg body weight mouthwash solution (i.e., ketamine 1 mg/kg body weight), with the maximum dose set as 40 mg ketamine, i.e., 10 ml mouthwash solution. The children in the control group received placebo mouthwash (containing the same diluent that was used to prepare the ketamine mouthwash solution), at a dose of 0.25 ml/ kg body weight, with maximum dose set as 10 ml. The mouthwash was administered in a supervised manner as an oral swish for 30 seconds, followed by spit. In the case of the patient swallowing the solution accidentally, he/she was planned to be closely monitored for vitals and any adverse effects of ketamine.
Based on a study by Bredlau et al17, oral ketamine doses ranging from 0.25–1.5 mg/kg/dose three times a day for two weeks was found to be safe in children. Hence, the intervention dose in this study, even if accidentally swallowed, was to be considered safe, with the requirement of only close monitoring for 4 hours. But such a patient was decided not to be considered for analysis, because of a possible effect of systemic absorption of ketamine on OM pain. However, none of the enrolled children swallowed the mouthwash solution.
A 6-point Wong-Baker faces pain rating scale (0-5) was used for assessing oral mucositis pain. The patients were assessed for OM pain score and adverse events at baseline, every 15 minutes in the first hour, and hourly thereafter for the next 3 hours (total 4 hours).
The patients were instructed not to take any analgesic medication until one hour after the mouthwash administration. The patients were assessed for pain score, and if required, oral paracetamol (intravenous in case of inability to take the oral drug) was given at a dose of 15 mg/kg. If the patient still complained of pain one hour after administration of paracetamol, oral tramadol (IV in case of inability to take the oral drug) was planned to be administered at a dose of 1 mg/kg/dose (maximum 40 mg). If the patient complained of intolerable pain within the first hour of administration of the mouthwash, the patient was planned to be given analgesics as described above, with no further monitoring as per the study protocol and exclusion from analysis. However, no patient required rescue analgesic medication before completion of 60 minutes.
Outcome assessment
The primary objective of the study was to determine the mean reduction of OM pain (on a numeric of a 6-point scale) in children on cancer chemotherapy at 1-hour after administration of ketamine mouthwash, as compared to placebo. Secondary outcomes included a reduction in the requirement of other topical and systemic analgesics and the determination of adverse events associated with the use of ketamine mouthwash.
2.6 Sample Size
Based on the study by Shillingburg et al13,assuming a mean pain score reduction of 3-points in the intervention group and 2-points in control, with a standard deviation (SD) of 1, level of confidence 95%, and power 90%, a sample size of 44 patients (22 in each arm) was determined and targeted for accrual, based on the two-sample t-test with an equal-variance assumption. Because of the short follow-up period (4-hour), no additional patients were targeted for enrolment.