This study is a two centre, double-blind, randomized controlled trial. Patients will be randomly allocated to receive either 50mg/kg body weight of placebo or amoxicillin 5 days after surgery as standard prophylaxis regime.
Participating centres are the department of otolaryngology at Kilimanjaro Christian Medical Centre (KCMC) in Moshi and the department of paediatric surgery at the Arusha Lutheran Medical Centre (ALMC) in Arusha, being the only settings with established Ear, Nose and Throat (ENT) services in northern Tanzania.
All Children from 2 to 14 years of age who will undergo an elective (adeno)tonsillectomy will be approached. Elective surgery is indicated in case of recurrent chronic tonsillitis, as defined by 5 or more episodes of tonsillitis yearly for at least 2 consecutive years, or in case of obstructive sleep apnoea due to adenotonsillar hypertrophy with inadequate response to pharmacotherapy. Inclusion will be done after written informed consent. Inclusion of patients started January 2019.
Patients will be excluded from participation if they meet any of the following criteria.
The patient is scheduled for unilateral tonsillectomy, tonsillar biopsy, tonsillectomy for a known carcinoma.
The (adeno)tonsillectomy is combined with any other type of surgery.
The patient has an acute tonsillar infection or peritonsillar abscess at the time of surgery.
The patient is known to have a cardiac co-morbidity, with or without current treatment or follow-up by a cardiologist.
The patient has a condition which results in weakness or failure of the host defence mechanism, like leukemia, acquired immune deficiency syndrome or current use of immunosuppressive medication.
The patient has a syndromal disorder or a craniofacial malformation.
The patient has a reported allergy to any antibiotic, ibuprofen or paracetamol.
The patient was treated with antibiotics during or less than 1 week prior to surgery.
Patients on any other concomitant medications at the point of enrolment.
To compare the postoperative morbidity following elective (adeno)tonsillectomy in children treated with postoperative amoxicillin or a placebo in Northern Tanzania. We hypothesize that placebo is noninferior to amoxicillin in preventing postoperative morbidities following a (adeno)tonsillectomy in children in northern Tanzania.
The primary outcome is post-(adeno)tonsillectomy morbidity, however morbidity cannot be measured as a single parameter. Postoperative haemorrhage and infection are the most important postoperative complications contributing to post-(adeno)tonsillectomy morbidity. Post-(adeno)tonsillectomy infection is difficult to define since the tonsillar beds are left to heal by secondary intention after surgery in a bacterial, mucosal environment. Typical symptoms of surgical site infection are therefore absent. Clinically worsening pain and raised temperature are thus considered features of infection. For this reason, postoperative haemorrhage, raised temperature (fever) and pain are the primary outcomes in this research.
Postoperative haemorrhage as defined using two parameters (major as if warranting re‐admission, blood transfusion or return to theatre for haemostasis and minor as any recorded postoperative blood loss i.e. Spitting of blood saliva 24 hours post-operative). Fever (temperature greater than 38°C on 2 consecutive post-operative days or greater than 39°C on any postoperative day), Post-operative pain score (Wong-Baker FACES® Pain Rating Score).
Temperature will be taken daily by the research nurse while admitted and thereafter by the parent/caretaker with an axillary thermometer until the seventh postoperative day.
The Wong-Baker FACES® Pain Rating Scale will be used to assess children's pain perception postoperatively. Written permission has been granted from Wong-Baker FACES Foundation for using both the English (while in hospital) and Swahili (while at home) Wong-Baker FACES® Pain Rating Scale in this study. The consequent need for analgesics will be documented by the prescribing physician.
These includes time until normal diet is resumed, time until normal activities are resumed and adverse events (rash, vomiting, diarrhea and anaphylaxis) and microbial recolonization of the tonsillar niche.
Post-operative bleeding, fever and pain were used as primary outcomes. We calculated power for all primary outcomes and only took the outcome with the largest number of participants. Based on the latest Cochrane review, titled “Antibiotics to reduce post-tonsillectomy morbidity”, 2,5% of all patients who undergo an elective tonsillectomy have a significant postoperative haemorrhage. With this haemorrhage rate, a significance level (α) of 0.05, a power(π) of 0.80, and a non-inferiority margin of 5%, we calculated the number of patients in our intervention group. The group treated with antibiotics should include 121 patients, giving a total of 242 patients necessary for analysis. To allow for some loss to follow-up, the aim is to include 270 children.
Baseline characteristics of the subjects will be compiled at informed consent. Subjects will be randomly divided into an intervention and a control arm on the day of admission, with the aid of a computer-based randomization module in a 1:1 ratio. Stratified randomization is accomplished using gender, age group (2-4 years, 5-8 years and 9-14 years), residence (rural or urban) and research centre (KCMC or ALMC) as strata. Randomization is performed by the KCMC’s research pharmacist who will then prepare medication (either the antibiotics or a placebo capsules or solution, depending on the age of the child). Both placebo capsules as well as solutions have the same taste and appearance as the amoxicillin capsules and solution. Labelled with only the study protocol number and patients’ details the medication will be distributed by one of the research nurses. Thus, blinding all health professionals involved in the trial process.
All (adeno)tonsillectomies will be carried out under general anaesthesia with the use of orotracheal intubation. Surgery will be performed by all grades of doctors, from residents to specialists. The tonsils are removed using either routine dissection, Sluders technique or electrodissection . Which technique is chosen depends on the surgeon’s experience and preference. Previous studies have shown that the technique does not affect the outcome or the postoperative morbidity [7, 8]. In all patients the adenoid is removed using Beckmann adenoid curette.
During surgery just before dissection of the tonsils, a swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the tonsillar surface for culture and sensitivity. After the operation is completed, one dissected tonsil will be submerged in iodopovidone for around 30 seconds. Subsequently the tonsil will be rinsed using sterilized normal saline and divided into two parts with a new sterile blade. Another swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the core of the tonsil.
For patients operated at KCMC both swabs will be maintained at a temperature between 2 and 8 degrees Celsius dispatched within 30 minutes to the microbiology research laboratory. Samples from ALMC will be stored at a temperature between 2 and 8 degrees Celsius and transported on the same day to the microbiology research laboratory. At the microbiology research laboratory all swabs will be incubated at 37 degrees Celsius for 24 hours. After incubation is completed, subcultures from growing microorganism will be prepared on agar plates. The isolated bacteria will then be gram stained and microscopically investigated. Only pathogenic organisms will be worked up, no workups for normal flora will be done. Microbiological workup will entirely adhere to the Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing. Antibiotic sensitivity testing will be done for all pathogenic, cultured microorganisms using the disc diffusion test . Discs of the most common antibiotics will be used.
After surgery all patients will be kept at the ward for at least one night. Based on their clinical condition patients will be discharged. On the ward, patients will receive their labelled medication with either 50 milligrams per kilogram amoxicillin or the placebo. Medication will be taken eight hourly for five consecutive days. Parents and caretakers are given instructions about the importance of continuing the medication after discharge from the hospital.
All patients will be given paracetamol three times a day and ibuprofen twice a day based on their weight for 10 days. Any additional analgesics or other treatment will be started whenever necessary at the discretion of the treating physician.
During discharge, a questionnaire will be provided to persons legally responsible for the participating child. It will be filled out daily and will be presented to the investigator at follow-up visits. The questionnaire is translated, adopted and modified from the standardized Linden et al post tonsillectomy follow-up questionnaire.
On day 7, the wound bed and the general health status will be inspected by the study doctor at the department of otolaryngology at KCMC and ALMC respectively. On day 14, a third swab (Copan ESwab, Copan Italia SPA, Brescia Italy) of the surgical site will be taken and sent to the microbiology research laboratory for culture and sensitivity analysis, as described above. During both visits detailed information will be obtained by the study doctor. The entire process from patients allocation up to follow-up is displayed in figure 1 and well described on SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) in figure 2.
Continuous variables will be presented as means and standard deviation or median and interquartile range (IQR) if not normally distributed. Categorical data will be presented as a number with percentage. All analysis will be done according to an intention-to-treat protocol.
Differences between the observed risks of events (for primary outcomes bleeding, and fever) between placebo and antibiotics group will be calculated along with their 95% confidence intervals. Absolute risks will also be presented as it is important to be aware of the underlying risk of events. Differences in pain score between the two treatment arms will be calculated as mean differences with 95% CIs, using Student’s tests. Secondary outcomes will be analysed using Chi squared tests for categorical data (return to normal activities and microbial recolonization) or Wilcoxon rank sum tests (days to return to normal diet) for continuous data. P-values < 0.05 will be considered statistically significant. All data will be coded to maximize confidentiality. Collected data will be entered into a database and analysed using IBM® SPSS® Statistics version 24.
Data and safety monitoring
Data and safety monitoring will be done by the independent data and safety monitoring committee of Kilimanjaro Christian Research Institute (KCRI). They will perform interim analyses every six months as long as patient inclusion and data collection is ongoing.
Ethics approval and consent to participate
This clinical trial has been approved by the Kilimanjaro Christian Medical College Research Ethics and Review Committee (CRERC), the Tanzanian Food and Drug Authority (TFDA) and the Tanzanian National Institute for Medical Research (NIMR). Prior to randomization, written informed consent will be obtained from the parents/caretakers of each participant.