The use of probiotics in preventing post-operative antibiotic-associated diarrhea in children following appendicectomy.

Background Appendicitis is one of the most common surgical emergencies in children. The incidence is estimated at 25 per 10,000 (age 10-17), 1-2 per 10,000 (age <4) with approximately 250-300 appendicectomies performed at Monash Children’s Hospital (MCH) every year. Antibiotics are paramount for the management of appendicitis and are commonly given for 24-48 hours post-operatively in children with simple (non-perforated appendicitis). However, in children with perforated/complicated appendicitis (25-30% of cases), antibiotics are required for a minimum of 5 to 7 days post-operatively. Antibiotics alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD) [1]. The frequency of AAD is estimated to be between 11% and 30% for children on antibiotics for a variety of medical conditions [2]. There is no specific data available in the literature regarding the incidence of AAD in children following appendicitis. At MCH we estimate that about 25% (75-80 patients per year) of children exposed to a prolonged course of antibiotics following appendicectomy develop AAD in the form of persisting abnormal bowel motions and intestinal symptoms (gas/flatulence, abdominal bloating and pain), causing delay in return to school and normal activities. Current evidence from the Cochrane Database of Systematic Reviews suggests that incidence of AAD in children receiving probiotics can be reduced from 19% to 8% particularly with the use of Lactobacilli spp [3]. A study focusing on AAD in children following appendicitis has never been conducted. However, a small trial in children on prophylactic antibiotics following hypospadias surgery has documented that the use of probiotics (L. rhamnosus) significantly reduces the incidence and duration of postoperative AAD and postoperative complications [4]. Furthermore, there is evidence that appendicitis results from a fundamental disturbance in the appendiceal microbiota with overgrowth of Fusobacterium and other oral pathogens [5]. It is conceivable therefore that the use of antibiotics, especially if prolonged, together with the abnormal overgrowth of pathogens, will contribute to AAD following appendicitis. We hypothesise that the use of probiotics following appendicectomy might lead to a reduction of AAD incidence with a quicker recovery, reduction in post-operative complications, hospital readmission and healthcare costs. Methods This will be a randomised, double-blind, placebo-controlled trial assessing the effects of probiotics (commercially available combined probiotic strains: Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus) in preventing post-operative AAD in children following appendicectomy at MCH. Patients will be randomly allocated to the intervention group or placebo group by weighted minimisation for age, gender, intraoperative findings (simple appendicitis, perforated appendicitis with localised peritonitis and perforated appendicitis with diffuse peritonitis) and estimated duration of antibiotic therapy. Probiotics will be administered for one month on resumption of normal oral intake after appendicectomy. An epidemiological study will also be conducted to clarify the incidence of post-appendicectomy AAD. Population As no data is available in the literature, the sample size estimation is based on the results from the Cochrane Database Systematic Review by Goldenberg et al. aiming at 60% reduction in the incidence of AAD [3]. Two-hundred and sixty-six children (133 in each arm) aged 4-15 years with no significant associated co-morbidities (ASA 1-2) undergoing laparoscopic appendicectomy will be included. The study is powered on a 90% chance of detecting a difference at the 5% significance level (1-α= 0.9, β= 0.05) with a reduction of AAD from 25% to 10%.   Outcome measures The following outcomes will be measured in the post-operative period using validated questionnaires: - Nausea and vomiting - Gas/flatulence, abdominal bloating and pain - Taste disturbance/Low appetite - Constipation/diarrhea/ stools consistency (using the Bristol stool chart) - Stool analysis in children with AAD - Incidence of post-operative complications (days of pyrexia, intra-abdominal abscess formation) - Time to return to normal activities Data analysis Results will be analysed after data extraction with dedicated statistical software. Data will be expressed as mean ± SD, median (range), interquartile range (IQR), count number, or percentages, as indicated. The D’Agostino and Pearson normality test will be used to evaluate the normal distribution of continuous variables. Unpaired Student’s t, Mann–Whitney U, Chi-squares, or Fischer’s exact test will be used where appropriate to identify differences between the two groups for continuous or categorical variables. Multiple regression anal