Nonoperative treatment (NOT) with antibiotics alone of acute uncomplicated appendicitis (AUA) in children has been proposed as an alternative to appendectomy.
To determine safety and efficacy of NOT based on current literature.
Three electronic databases.
All articles reporting NOT for AUA in children.
Two reviewers independently verified study inclusion and extracted data.
Ten articles reporting 413 children receiving NOT were included. Six, including 1 randomized controlled trial, compared NOT with appendectomy. The remaining 4 reported outcomes of children receiving NOT without a comparison group. NOT was effective as the initial treatment in 97% of children (95% confidence interval [CI] 96% to 99%). Initial length of hospital stay was shorter in children treated with appendectomy compared with NOT (mean difference 0.5 days [95% CI 0.2 to 0.8]; P = .002). At final reported follow-up (range 8 weeks to 4 years), NOT remained effective (no appendectomy performed) in 82% of children (95% CI 77% to 87%). Recurrent appendicitis occurred in 14% (95% CI 7% to 21%). Complications and total length of hospital stay during follow-up were similar for NOT and appendectomy. No serious adverse events related to NOT were reported.
The lack of prospective randomized studies limits definitive conclusions to influence clinical practice.
Current data suggest that NOT is safe. It appears effective as initial treatment in 97% of children with AUA, and the rate of recurrent appendicitis is 14%. Longer-term clinical outcomes and cost-effectiveness of NOT compared with appendicectomy require further evaluation, preferably in large randomized trials, to reliably inform decision-making.
Comments
RE: Future studies on non-operative management of appendicitis
We commend Georgiou and colleagues for their well performed meta-analysis investigating the efficacy and safety of non-operative management of acute appendicitis (NOT). While we agree with the authors’ conclusion that “longer-term clinical outcomes and cost-effectiveness of NOT compared with appendectomy require further evaluation”, we disagree that it should be in the form of large randomized trials (RCTs).
We advocate that the current evidence base is sufficient to offer non-operative management of appendicitis in current practice. In this meta-analysis, the authors demonstrated consistent results across 10 pediatric studies with overall success rates of NOT of 97% during the initial admission (I2=0%) and 82% at the last reported follow-up (I2=34%) with a similar risk of complications between surgery and NOT (risk difference=2%, I2=0%). In addition to the consistency of the efficacy and safety of NOT across the 10 pediatric studies included in this meta-analysis, there have been 6 RCTs, 8 observational studies, and at least 6 systematic reviews to date in adults that demonstrate similar efficacy and safety of NOT for acute appendicitis. Additional prospective studies comparing the effectiveness of NOT with appendectomy for acute appendicitis are needed but not to establish the efficacy of NOT. The goal of future studies should be to determine the comparative effectiveness of these two treatments in clinical practice.
The authors have proposed that future studies should be large RCTs; however, these RCTs will not likely be reflective of the effectiveness of NOT in clinical practice. Even in the best RCTs, only 30-40% of eligible patients will enroll. In addition, it is known that there are differences between patients that will and will not participate in a RCT. Therefore, the question becomes how representative and informative will the results of a RCT be if less than 1 out 3 patients enroll? We advocate that future trials should (1) generate additional information that can further inform patients and families about the different risks and benefits of these two treatments including long term rates of treatment success and treatment-related complications, disability, costs, and quality of life, and (2) utilize a patient choice design. As compared to a RCT, potential benefits of a patient choice design include allowing for broad enrollment with greater representation of minority groups, minimizing the effects of patient/parent preferences on outcomes by aligning their preferences with the treatment, and allowing for rapid adoption of the results. In a previous study comparing NOT with appendectomy using a patient choice design, 83% of approached eligible patients enrolled.1 Future studies should be reflective of clinical practice in which patients and families choose their treatment based on their values and preferences as part of a shared decision making process. 2-5
References:
1. Minneci PC, Mahida JB, Lodwick DL, Sulkowski JP, Nacion KM, Cooper JN, Ambeba EJ, Moss RL, Deans KJ. Effectiveness of Patient Choice in Nonoperative vs Surgical Management of Pediatric Uncomplicated Acute Appendicitis. JAMA Surg. 2016 May 1;151(5):408-15. PubMed PMID: 26676711.
2: Harnoss JC, Zelienka I, Probst P, Grummich K, Müller-Lantzsch C, Harnoss JM, Ulrich A, Büchler MW, Diener MK. Antibiotics Versus Surgical Therapy forUncomplicated Appendicitis: Systematic Review and Meta-analysis of Controlled Trials (PROSPERO 2015: CRD42015016882). Ann Surg. 2016 Oct 17. [Epub ahead of print] PubMed PMID: 27759621.
3: Sallinen V, Akl EA, You JJ, Agarwal A, Shoucair S, Vandvik PO, Agoritsas T, Heels-Ansdell D, Guyatt GH, Tikkinen KA. Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis. Br J Surg. 2016 Mar 17. [Epub ahead of print] Review. PubMed PMID: 26990957.
4: Hasday SJ, Chhabra KR, Dimick JB. Antibiotics vs Surgery for Acute Appendicitis: Toward a Patient-Centered Treatment Approach. JAMA Surg. 2016 Feb;151(2):107-8. PubMed PMID: 26579853.
5: Telem DA. Shared Decision Making in Uncomplicated Appendicitis: It Is Time to Include Nonoperative Management. JAMA. 2016 Feb 23;315(8):811-2. PubMed PMID: 26903339.
RE: Meta-analysis to determine efficacy of non-operative treatment of appendicitis.
Dear Editor:
I read with interest the recently published meta-analysis1 combining results of 10 studies evaluating efficacy of non-operative treatment [NOT] in managing acute uncomplicated appendicitis [AUA]. Aside from a significantly shorter duration of hospitalization in those receiving appendectomy, NOT was found to be a safe treatment option for AUA.
I believe there are quality issues characterizing the studies used for the meta-analysis which preclude making an accurate assertion regarding NOT safety:
1. Presumably, patients eligible for NOT have “milder” degrees of AUA. In one study2, inclusion criteria defining NOT eligibility was abdominal imaging showing lesser degrees of appendiceal dilation [0.6 - 1.1 cm]. Yet in prior reports3-5 nearly half of patients imaged to evaluate for a non-appendicitis condition had a “normal” measured appendiceal diameter of >0.6 cm; raising the possibility that a number of study cases categorized as “milder appendicitis” which “resolved” using NOT may have not actually had appendicitis.
2. An important outcome measure, in-hospital length of stay, was significantly longer in those receiving medical vs surgical management. Longer hospital stay impacts health care utilization/cost, inconvenience to families, and potential for iatrogenic complications. An additional important outcome measure not assessed is the need for repeat medical evaluation for possible recurrent appendicitis each time the patient who received NOT experiences abdominal pain; including ED visits, performance of laboratory testing and advanced imaging, surgical consultation, and possible hospitalization. Consistent with this, 68 of 396 children in the meta-analysis cohort who had NOT management subsequently experienced recurrent appendicitis.
3. An essential prerequisite to defining AUA in prior studies comparing NOT vs appendectomy is accurate distinction of non-perforated vs perforated appendicitis. Some studies included in the meta-analysis exclusively utilized pathologist histologic examination to determine this; which has been shown to be highly inaccurate for distinguishing perforation status6-8 and may have resulted in misclassification of a substantial proportion of AUA cases as being “without perforation”.
References
1. Georgiou R, Eaton S, Stanton M, et al: Efficacy and Safety of Nonoperative Treatment for Acute Appendicitis: A Meta-analysis. Pediatrics Mar 2017, 139 (3) e20163003; DOI: 10.1542/peds.2016-3003
2. Minneci PC, Sulkowski JP, Nacion KM, et al. Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children. J Am Coll Surg. 2014;219(2):272–27919.
3. Webb E, Zhen W, Fergus V, et al: The equivocal appendix at CT: prevalence in a control population. Emerg Radiol 2010;17:57-61
4. Tamburrini S, Brunetti A, Brown M, et al: CT appearance of the normal appendix in adults. Eur J Radiol 2005;15:2096–2103
5. Benjam O, Atri M, Hamilton P, et al: Frequency of visualization and thickness of normal appendix at non-enhanced helical CT. Radiology 2002;225:400-6
6. Bonadio WA: Accurate classification of perforation outcome with pediatric appendicitis. Letter to the Editor. Pediatr Emerg Care 2017;33:March p e3
7. Fallon S, Kim M, Hallmark C, et al: Correlating surgical and pathological diagnoses in pediatric appendicitis. J Pediatr Surg 2015;50:638-41
8. Bliss D, McKee J, Cho D, et al: Discordance of the pediatric surgeon’s intraoperative assessment of pediatric appendicitis with the pathologist’s report. J Pediatr Surg 2010;45:1398-1403
RE: Perforation after Nonoperative Treatment (NOT) of appendicitis has been reported
I appreciate the authors work on this metaanalysis and agree that it serves as an excellent summary of the reported outcomes for nonoperative treatment of appendicitis (NOT). However, I do want to point out one minor discrepancy: the authors state that NOT has not been associated with perforation. However, the article by Tanaka et al (J Pediatr Surg 2015; 50:1893 did report one case of perforation after an attempt at nonoperative treatment (NOT) during the initial hospital stay as follows: "Nonoperative treatment failed in one patient, leading to perforation of the appendix."
This study differed from some of the other studies because they proceeded with NOT in patient with appendicoliths (which this patient had) and performed NOT in patients with elevated CRPs. It is true that no perforation has been reported in pediatric patients undergoing NOT who did not have an appendicolity.