Appendectomy Versus Non-Operative Treatment For Acute Non-Perforated Appendicitis in Children
Condition: Appendicitis
MeSH terms: Appendicitis
Study type: Interventional

Summary: 
      Rationale and Aim: The standard treatment for acute appendicitis in children is appendectomy.
      An increasing body of evidence from the adult literature suggests that acute appendicitis may
      be treated effectively with antibiotics alone, avoiding the need for surgery. The aim of this
      study is to investigate the effectiveness of non-operative treatment of acute appendicitis in
      children.

      Study design: Pragmatic, parallel-group, unmasked, non-inferiority multicentre randomized
      controlled trial (RCT).

      Patient allocation: Children will be randomly allocated (age 5-16 years) with a diagnosis of
      acute appendicitis to either laparoscopic appendectomy or treatment with antibiotics.
      Randomization will be performed using stratification to ensure equal distribution between
      groups of presenting clinical and demographic features that may influence outcome including
      gender, duration of symptoms and center.

      Interventions: One group of children will undergo laparoscopic appendectomy that is the
      current standard treatment for children with acute appendicitis. The other group will be
      treated with intravenous antibiotics. A treatment pathway specifically designed for this
      study will be used.

      Primary Outcome: To be meaningful to parents of, and clinicians treating, children with acute
      appendicitis, the primary outcome is treatment failure defined as: (i) any additional
      intervention related to appendicitis requiring general anesthesia within 1 year of
      randomization (including recurrence of appendicitis after non-operative treatment, which we
      will treat with appendectomy) or (ii) negative appendectomy. Secondary outcomes are: (i)
      complications; (ii) time to discharge following randomization; (iii) number and duration of
      hospital admissions.

      Sample size and data analysis: The proposed RCT has a 20% non-inferiority margin to test the
      null hypothesis that treatment with antibiotics is inferior to appendectomy. Based on data
      from collaborating centers and a pilot study that we have performed, we expect recruitment of
      978 children in total (90% power) over 19 months allowing for drop out. Follow-up will be for
      12 months.
    

Detailed description: 
      Background Acute appendicitis is the commonest surgical emergency in children. The lifetime
      risk of developing appendicitis is 7-8%, with a peak incidence in the teenage years.The
      associated financial burden of treating appendicitis is very large.

      For over 100 years, surgical removal of the appendix has been deemed necessary to effectively
      treat acute appendicitis. Appendectomy remains the cornerstone of treatment for acute
      appendicitis, with the exception of phlegmon or appendix mass. However, in recent years this
      surgical dogma has been challenged and there is a growing literature to suggest that
      antibiotics without surgery may be an effective treatment for acute appendicitis in adults
      and more recently in children. However this non-operative management of acute appendicitis
      remains controversial and unproven due to the lack of large prospective randomized controlled
      trials.

      Although appendectomy is generally a simple procedure, it requires general anesthesia and is
      an abdominal operation with inherent risks and potential complications. Complications related
      to surgery or anesthesia events occur in over 10% of children within 30 days of appendectomy.
      Although a non-operative approach may avoid these risks and reduce complication rate, this
      would not be a viable alternative to surgery unless it is equally effective at curing acute
      appendicitis.

      The existing literature relating to the efficacy of non-operative treatment of acute
      appendicitis in predominantly from adult patients. Several trials and systematic reviews have
      been reported. A most recent meta-analysis concluded that there were benefits to
      non-operative treatment including fewer complications, better pain control, and shorter sick
      leave but that the combined failure and recurrence rate in patients treated non-operatively
      made this approach less effective overall.

      In children, the literature is limited. The most significant studies are: Abes et al [6] who
      described successful, non-operative treatment in 15 of 16 children who had a very short
      duration of illness, and minimal diagnostic criteria on imaging; Armstrong et al [7] who
      reported a 75% success rate in 12 children treated non-operatively along with a matched
      comparison group undergoing surgery; two RCTs from the USA that compared appendectomy with
      antibiotic treatment for children with perforated appendicitis [8,9] (a different patient
      group from the one which we intend to study); a single centre, preference-based,
      non-randomized study comparing laparoscopic appendectomy with antibiotic treatment [10] that
      reported interim results only.

      In preparation for this multi center RCT, investigators have performed a pilot RCT at one of
      the participating centers (Karolinska Institute, Stockholm) [11]. Successfully demonstrated
      feasibility of recruitment to a RCT and safety of non-operative treatment of children with
      acute appendicitis.

      Based on these observations, and in response to parents who are now asking whether their
      child with acute appendicitis really needs an operation, this randomized controlled trial
      comparing appendectomy with non-operative treatment in children with acute appendicitis will
      be done. The principal research question is: Can children with acute uncomplicated
      (non-perforated) appendicitis be treated without appendectomy?

      Rationale for the Trial This trial has the potential to significantly alter clinical practice
      for one of the most common acute health conditions in children. A finding of non-inferiority
      of treatment with antibiotics compared to appendectomy would be transformative for the
      healthcare of children with acute appendicitis in Canada and abroad, including low- and
      middle-income countries. Reducing the need for surgery in the treatment of childhood
      appendicitis represents the potential for cost savings for the healthcare system, and will
      enable improved access for children with non-emergent conditions who are awaiting surgery.

      Methods/Design Research question Can children with acute non-perforated appendicitis be
      treated with antibiotics, rather than appendectomy?

      Trial design The APPY trial has been designed as a pragmatic, parallel-group, unmasked,
      non-inferiority multicentre, international randomized controlled trial. The protocol has been
      developed in accordance with the SPIRIT guideline and the trial will be conducted and
      reported according to the CONSORT statement.

      Participants Children (5-16 years of age) with suspected acute uncomplicated appendicitis
      will be enrolled from up to 16 hospitals across Europe and North America. All centers are
      specialist Pediatric Surgery Referral Centers with trained Specialist Pediatric Surgeons and
      Pediatric Surgery Training Programs. All children with suspected acute non-perforated
      appendicitis will be assessed by the on-call surgeon who will determine eligibility for the
      study. This will be based on a clinical and/or ultrasound diagnosis of acute non-perforated
      appendicitis. The patient and child will be informed of the trial and invited to participate.

      Randomization After signed informed consent, a standardized data set will be collected from
      all participants at all participating institutions. Patients enrolled in the study will be
      randomized to groups (1:1 ratio) using an online stratified randomization tool, allowing
      instant assignment to treatment group 24 hours per day with concealment of allocation.
      Allocation to groups will be stratified taking into account factors that may affect outcome
      of treatment: 1) Sex: Male; Female; 2) Duration of symptoms <48hrs; >48hrs; and 3) Center.

      Interventions Patients will be allocated to non-operative antibiotic treatment or
      appendectomy.

      Non-operative treatment group: Participants allocated to non-operative treatment will be
      treated according to a treatment pathway standardized across all centers comprising
      intravenous fluid treatment, a minimum of 12 hours of intravenous antibiotics, a minimum
      period of 12 hours taking clear fluid only, and regular clinical review.

      During the next clinical rounds, or alternatively approximately 12 hours after randomization,
      a review of clinical symptoms will be conducted to detect symptoms and signs of significant
      clinical deterioration including, but not limited to, increased fever, increased tachycardia,
      and increased pain or tenderness. If the patient is doing well, they may be advanced to
      regular diet and be assessed for discharge during the same work day, depending on their
      clinical progression. If they are stable without deterioration but not improved to the point
      of discharge they will continue with non-operative management. A patient who has not improved
      after 48 hours of non-operative management will undergo appendectomy. All decisions will be
      made by the treating physicians and care team with consideration of the input of parents and
      child where appropriate.

      Children in whom non-operative treatment is successful will receive a minimum of 12 hours
      intravenous antibiotics and then be switched to oral antibiotics once they have shown
      clinical improvement. They will be discharged home once they meet a standardized set of
      criteria to be used in all centers: vital signs (including temperature) within normal limits,
      tolerating a light diet orally, adequate oral pain relief and mobile. They will receive a
      total course of 10 days of antibiotics (intravenous and oral) following randomization.

      Children within the non-operative treatment group will remain under the care of an attending
      pediatric surgeon who retains overall responsibility for their care. If a child's clinical
      condition deteriorates at any time, they will undergo laparoscopic appendectomy, and will
      receive post-operative care identical to that of children in the appendectomy treatment group
      (see below), and any other care that might be dictated by sound clinical judgement.

      The choice of antibiotics will vary between center and will be the antibiotic regimen that is
      current standard of care in that center. This is due to (i) varying antibiotic regimes among
      participating centers at present influenced by local factors, including antimicrobial
      stewardship and drug cost (26) and (ii) a lack of evidence to support a specific antibiotic
      regimen for childhood appendicitis. Allowing each center to maintain current antibiotic
      protocols will improve study feasibility and increase generalizability of the results.
      However, the duration of combined intravenous and oral therapy will be standardized to 10
      days.

      Following discharge, children who receive non-operative treatment will not be offered
      elective appendectomy. They will be counselled about the risk of recurrence as part of the
      permission process for the trial using best available current data. Recurrence of
      appendicitis within the 1 year follow-up period will be treated with appendectomy; these
      children will not be eligible for re-enrollment.

      Appendectomy group: Children allocated to appendectomy will undergo laparoscopic appendectomy
      within approximately 18 hours of randomization which is the current standard of care in all
      centers participating in this study. Participants will receive intravenous antibiotics from
      the time of randomization and be treated post-operatively with intravenous antibiotics
      according to a defined and standardized treatment regime based on consensus for this trial.
      Specifically, children with a macroscopically normal appendix or non-perforated acute
      appendicitis will receive no further antibiotics. Children with perforated appendicitis will
      continue to receive intravenous antibiotics for a minimum of 3 days, and may receive
      additional antibiotics per local practice. The type of antibiotics used in each center will
      be identical to those used in the non-operative treatment group. Following cessation of
      intravenous antibiotics, criteria for discharge home will be identical to those in the
      non-operative treatment group.
    

Intervention name(s): Non-operative treatment; Appendectomy
Intervention type(s): Other; Procedure
Intervention description(s): will receive a minimum of 12 hours intravenous antibiotics and then receive oral antibiotics once they have shown clinical improvement (a total course of 10 days of antibiotics (intravenous and oral). They will be discharged home once they meet a standardized set of criteria to be used in all centers.
The choice of antibiotics will vary between centers and will be the antibiotic regimen that is current standard of care in that center allowing each center to maintain current protocols will improve study feasibility and increase generalization of the results.; will undergo laparoscopic appendectomy within 18 hours of randomization and will receive intravenous antibiotics per each site's standard care, from the time of randomization and post-operatively according to a defined and standardized treatment regimen based on consensus for this trial.
Children with a visibly normal appendix or non-perforated acute appendicitis will receive no further antibiotics; children with perforated appendicitis will continue to receive intravenous antibiotics for a minimum of 3 days, and then per local practice. The type of antibiotics used in each center will be identical to those used in the non-operative treatment group and are not specified by the study.
Other intervention name(s): Laparoscopic appendectomy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pediatric Surgery; Pediatrics; Randomized controlled trial,; Antibiotics; Cost effectiveness