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Publicado el 11 de julio de 2018 | http://doi.org/10.5867/medwave.2018.04.7229

¿Es seguro y efectivo tratar la apendicitis aguda no complicada con antibióticos?- Primera actualización

Are antibiotics a safe and effective treatment for acute uncomplicated appendicitis?- First update

Rubén Allende, Rodrigo Muñoz

Abstract

UPDATE This Living FRISBEE (Living FRIendly Summary of the Body of Evidence using Epistemonikos) is an update of the summary published in January 2016.

INTRODUCTION Appendicitis is a typical cause of acute abdominal pain and the most frequent cause of emergency abdominal surgery. In the last two decades, increasing evidence has been published about the use of antibiotics as an exclusive treatment for acute appendicitis.

METHODS To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained through searches from multiple sources of information, including MEDLINE, EMBASE, Cochrane, among others. We extracted the data from the identified reviews, reanalyzed the data from the primary studies, performed a meta-analysis and prepared a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS We identified 23 systematic reviews including 28 primary studies, of which eight were randomized trials. We concluded the exclusive use of antibiotics for the treatment of uncomplicated acute appendicitis could be less effective than appendectomy, but it might be associated with a lower rate of complications.

About this update

This Living FRISBEE (Living Friendly Summary of the Body of Evidence using Epistemonikos) is an update of the summary published in January 2016 (doi: 10.5867/medwave.2016.6375), based on 14 new systematic reviews including two new randomized trials not included in previous reviews. In addition, we added a trial that had not been previously incorporated into the analysis, and a trial previously incorporated was removed because it was retracted due to plagiarism. Finally, the outcome ‘major complications’ was replaced by ‘complications’, since most identified systematic reviews analyzed this variable as the outcome of choice. The incorporation of this new evidence leads to a change in the direction of the effect on complications, and therefore to changes in the key messages and considerations for decision-making.

Problem

Acute appendicitis is a common cause of acute abdominal pain and the most frequent cause of emergency abdominal surgery, with an estimated life incidence between 7 and 14% [1],[2]. Since the 1890s, when McBurney described early appendectomy as the therapy of choice for acute appendicitis [3],[4], surgery has become the mainstay for the treatment of this condition, drastically decreasing its mortality rate [5].
The treatment of acute appendicitis with antibiotics as an initial strategy was historically reserved for patients with several days of evolution of the inflammatory process, who presented a plastron or appendicular abscess, to avoid major surgery [2]. In 1953, Harrison reported 42 out of 47 cases of acute appendicitis successfully treated with antibiotics only. Coldrey published in 1959 an article with 471 cases of acute appendicitis treated conservatively, with only one death, nine patients requiring abscess drainage and only 48 patients requiring appendectomy [6]. In the last two decades, the production of research on the use of antibiotics as an exclusive treatment for acute appendicitis has steadily increased, so it is important to synthesize the existing evidence.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • The use of antibiotics for the treatment of uncomplicated acute appendicitis may be less effective than appendectomy and it might be associated with a longer hospital stay.
  • The use of antibiotics for the treatment of uncomplicated acute appendicitis might be associated with fewer complications. 

About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found 23 systematic reviews [5],[6],[7],[8],[9],[10],[11],[12],
[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],
[26],[27] including 28 primary studies [28],[29],[30],[31],[32],[33],
[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],
[48],[49],[50],[51],[52],[53],[54],[55], of which eight are randomized trials [28],[29],[30],[31],[32],[33],[38],[47]. We decided to exclude a trial [47] from the analysis as it was retracted from the journal that published it for plagiarism. 

This table and the summary in general are based on seven randomized trials [28],[29],[30],[31],[32],[33],[38], since the observational studies did not increase the certainty of the existing evidence, nor did they provide relevant additional information.

What types of patients were included*

All trials included patients with suspected acute appendicitis. 

Six trials [28],[29],[30],[31],[32],[33] excluded children and one trial also excluded women [32]. One trial only included pediatric patients between 5 and 15 years old [38]. 
All trials based the suspicion of acute uncomplicated appendicitis on clinical criteria. Five trials ruled out complications by imaging, of which two [30],[33] used computed tomography, two ultrasound [28],[38] and one both ultrasound and computed tomography [31]. One trial resorted to ultrasound or computed tomography in some cases [29], and one trial did not use diagnostic imaging [32].

What types of interventions were included*

Six trials used intravenous antibiotics as the initial treatment, of which one did so for 24 hours [29], three for 48 hours [28],[32],[38] and two for 72 hours [31],[33]. Of these, two trials used cefotaxime associated with tinidazole [28,32], one used cefotaxime associated with metronidazole [29], one used ampicillin associated with gentamicin and metronidazole [31], one used meropenem associated with metronidazole [38] and one used ertapenem [33].

The remaining trial [30] used intravenous amoxicillin with clavulanic acid only if the patient presented nausea or vomiting and for a time that was not specified. 

All trials continued the treatment using oral antibiotics. One trial completed eight days [30] and six completed ten days [28],[29],[31],[32],[33],[38]. During the oral phase, two trials used the combination of ofloxacin with tinidazole [28],[32], two used ciprofloxacin with metronidazole [29],[38], one used levofloxacin with metronidazole [33], one used amoxicillin with clavulanic acid [30] and one trial did not specify the antibiotic used orally [31]. 

All trials compared antibiotic treatment against surgery. Two trials performed open appendectomy [28],[33], one performed only laparoscopic appendectomy [38] and the remaining four trials performed the procedure open or laparoscopic according to surgeon's preference [29],[30],[31],[32].

What types of outcomes
were measured

The trials measured multiple outcomes, which were pooled by the systematic reviews as follows:

  • Effects of the treatment, defined as absence of symptoms within two weeks, without major complications or recurrences within a year.
  • Complications, such as perforations, superficial and deep surgical wound infections, incisional hernias, intestinal obstruction, diarrhea, abdominal discomfort or death.
  • Recurrences.
  • Duration of hospital stay.Time needed to return to work. 

All trials followed their patients up to 12 months.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of findings 

The information on the effects of antibiotics or surgical treatment for uncomplicated acute appendicitis is based on seven randomized trials [28],[29],[30],[31],[32],[33],[38] that included 1770 participants, of whom 858 were initially treated with antibiotics and 912 with appendectomy. All trials reported treatment efficacy, complications and hospital stay. 

The summary of findings is the following: 

  • The use of antibiotics for the treatment of uncomplicated acute appendicitis might be less effective than appendectomy, but the certainty of the evidence is low. 
  • The use of antibiotics for the treatment of uncomplicated acute appendicitis might be associated with fewer complications than appendectomy, but the certainty of the evidence is low. 
  • The use of antibiotics for the treatment of uncomplicated acute appendicitis might be associated with a longer hospital stay than appendectomy, but the certainty of the evidence is low.

Following the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply
  • The conclusions of this summary are applicable to adult patients with uncomplicated acute appendicitis. 
  • These conclusions do not apply to patients presenting complicated acute appendicitis (perforation, appendiceal abscess, peritonitis, gangrene or others), since these have a different clinical course and treatment indications compared to acute uncomplicated appendicitis.
  • The conclusions of this summary are not applicable to children since they were poorly represented in the trials.
About the outcomes included in this summary
  • The selected outcomes were those considered critical for decision-making according to the authors of this summary, which agrees with those selected by most systematic reviews identified.
Balance between benefits and risks, and certainty of the evidence
  • Antibiotic treatment in uncomplicated acute appendicitis is a plausible and safe option as an initial intervention, considering that it could be associated with a lower risk of complications and avoid a surgical intervention on the patient. On the other hand, this therapy could be less effective and be associated with a longer initial hospital stay. Considering there is still uncertainty regarding the advantages of antibiotic therapy, the risk/benefit balance continues to lean towards appendectomy as the standard treatment.
  • In well-selected patients, with absence of complications confirmed by computed tomography and with high surgical risk, the risk/benefit balance could be tilted in favor of antibiotic treatment [2],[56].
Resource considerations
  • The use of antibiotics is less expensive than surgery and does not require trained personnel. 
  • Most systematic reviews and published trials have not evaluated resource considerations. 
  • There is at least one study that directly evaluated costeffectiveness of antibiotics versus appendectomy [57]. It took effects data from a meta-analysis [17], trials [29],[30],[31],[32] and observational studies [35],[37],[42],[44], and it correlated them to costs obtained from a US database [58]. They concluded that in patients effectively treated with antibiotics (so, did not present recurrent appendicitis requiring appendectomy), the costs were reduced by more than 10,000 US dollars. On the contrary, when the initial antibiotic treatment required a subsequent surgical intervention, the cost per patient increased by more than 4,000 USD. Based on these data, the authors suggested antibiotics would be the most costeffective intervention when the recurrence rate is below than 40%. 
  • Since there is uncertainty about the effectiveness of antibiotics compared with appendectomy for uncomplicated acute appendicitis, it is not possible to make an adequate costeffectiveness balance.
What would patients and their doctors think about this intervention
  • Faced with the evidence presented in this summary, some patients and health providers may prefer antibiotic treatment over appendectomy. However, this approach still has not permeated routine clinical practice [59] for various reasons, including the preference for definitive therapy, the infeasibility of obtaining computed tomography scans in all patients and the fear of health providers of eventual litigations in case of complications when using antibiotic therapy. Appendectomy is still considered the therapy of choice for this condition, and antibiotic therapy is reserved for selected cases.
  • Some clinical centers are opting for a pragmatic management in which patients are treated with antibiotherapy for 24 to 48 hours, after which it is continued if the patient is improving or appendectomy is performed if the patient is deteriorating [14].

Differences between this summary and other sources
  • The conclusions of this summary in terms of effectiveness and hospital stay are concordant with the systematic reviews identified and with a recent overview of reviews [56].
  • Regarding complications, most reviews [10],[14],[16],[17],[18] agree that antibiotic therapy could be associated with a lower rate of complications.
  • On the other hand, a systematic review [23] that only included three trials found the number of peritonitis and abscesses were greater in those treated with antibiotics. Another [26] considered that the evidence was of very low certainty, and there were no differences when conducting a sensitivity analysis. In addition, a Cochrane review [5] used the composite outcome ‘major complications’ and found they were higher in the antibiotic group. This outcome included, in addition to the complications reported by the trials, recurrences and the increase in hospital stay. At least one additional review [16] has analyzed the outcome ‘major complications’, and included perforation, deep infection, incisional hernia, intestinal obstruction and death and found no significant differences between the groups.
  • The reviews that evaluated this question in pediatric population also considered antibiotic therapy as an optional treatment according to patient’s particular circumstances, but more trials are necessary before conclusions of greater weight are given.
  • The main clinical guideline on this topic [60] states appendectomy continues to be the treatment of choice for acute appendicitis, agreeing with the results presented in this summary. It states that the use of antibiotic therapy can be safe as an initial intervention in patients with uncomplicated acute appendicitis, as long as absence of complications are certified through computed tomography, but that it is less effective in the long term due to significant recurrence rates.
Could this evidence change in the future?
  • Due to the existing uncertainty, the probability that future trials change the conclusions of this summary is high.
  • There are at least two published randomized trials not included in any systematic review identified [61],[62].
  • At least nine randomized trials are ongoing, of which six evaluate this question in adults [63],[64],[65],[66],[67],[68], two in children [69],[70] and one in children and adults [71]. In addition, there is a registered trial whose status and results are unknown [72]. Finally, at least three systematic reviews are in progress [73],[74],[75].

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Antibiotics versus appendectomy for uncomplicated acute appendicitis.

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

Autores

Rubén Allende

Rodrigo Muñoz

rmunozc@med.puc.cl.

Centro Evidencia UC, Pontificia Universidad Católica de Chile, Diagonal Paraguay 476, Santiago, Chile

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Historial

Citación Allende R, Muñoz R. Are antibiotics a safe and effective treatment for acute uncomplicated appendicitis?- First update. Medwave 2018;18(04):e7229 doi: 10.5867/medwave.2018.04.7229

Envío 27/12/2017

Aceptación 24/04/2018

Publicación 11/07/2018

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Provenance and peer review

Con revisión por pares sin ciego por parte del equipo metodológico del Epistemonikos Evidence Synthesis Project.

Referencias

  1. D’Souza N, Nugent K. Appendicitis. BMJ Clin Evid. 2014 Dec;2014.
  2. Flum DR. Clinical practice. Acute appendicitis--appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015 May;372(20:1937–43.
  3. McBurney C. II. The Indications for Early Laparotomy in Appendicitis. Ann Surg. 1891 Apr;13(4):233–54.
  4. McBurney C. IV. The Incision Made in the Abdominal Wall in Cases of Appendicitis, with a Description of a New Method of Operating. Ann Surg. 1894 Jul;20(1):38–43.
  5. Wilms IMHA, de Hoog DENM, de Visser DC, Janzing HMJ. Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane database Syst Rev. 2011 Nov;(11):CD008359.
  6. Ansaloni L, Catena F, Coccolini F, Ercolani G, Gazzotti F, Pasqualini E, et al. Surgery versus conservative antibiotic treatment in acute appendicitis: a systematic review and meta-analysis of randomized controlled trials. Dig Surg. 2011;28(3):210–21.
  7. Fitzmaurice GJ, McWilliams B, Hurreiz H, Epanomeritakis E. Antibiotics versus appendectomy in the management of acute appendicitis: a review of the current evidence. Can J Surg. 2011 Oct;54(5):307–14.
  8. Harnoss JC, Zelienka I, Probst P, Grummich K, Muller-Lantzsch C, Harnoss JM, et al. Antibiotics Versus Surgical Therapy for Uncomplicated Appendicitis: Systematic Review and Meta-analysis of Controlled Trials (PROSPERO 2015: CRD42015016882). Ann Surg. 2017 May;265(5):889–900.
  9. Liu K, Fogg L. Use of antibiotics alone for treatment of uncomplicated acute appendicitis: a systematic review and meta-analysis. Surgery. 2011 Oct;150(4):673–83.
  10. Liu Z-H, Li C, Zhang X-W, Kang L, Wang J-P. Meta-analysis of the therapeutic effects of antibiotic versus appendicectomy for the treatment of acute appendicitis. Exp Ther Med. 2014 May;7(5):1181–6.
  11. Mason RJ, Moazzez A, Sohn H, Katkhouda N. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt). 2012 Apr;13(2):74–84.
  12. Podda M, Cillara N, Di Saverio S, Lai A, Feroci F, Luridiana G, et al. Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing appendectomy and non-operative managem. Surgeon. 2017 Oct;15(5):303–14.
  13. Poon SHT, Lee JWY, Ng KM, Chiu GWY, Wong BYK, Foo CC, et al. The current management of acute uncomplicated appendicitis: should there be a change in paradigm? A systematic review of the literatures and analysis of treatment performance. World J Emerg Surg. 2017;12:46.
  14. Rollins KE, Varadhan KK, Neal KR, Lobo DN. Antibiotics Versus Appendicectomy for the Treatment of Uncomplicated Acute Appendicitis: An Updated Meta-Analysis of Randomised Controlled Trials. World J Surg. 2016 Oct;40(10):2305–18.
  15. Sakran J V, Mylonas KS, Gryparis A, Stawicki SP, Burns CJ, Matar MM, et al. Operation versus antibiotics--The “appendicitis conundrum” continues: A meta-analysis. J Trauma Acute Care Surg. 2017 Jun;82(6):1129–37.
  16. Sallinen V, Akl EA, You JJ, Agarwal A, Shoucair S, Vandvik PO, et al. Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis. Br J Surg. 2016 May;103(6):656–67.
  17. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ. 2012 Apr;344:e2156.
  18. Varadhan KK, Humes DJ, Neal KR, Lobo DN. Antibiotic therapy versus appendectomy for acute appendicitis: a meta-analysis. World J Surg. 2010 Feb;34(2):199–209.
  19. Huang L, Yin Y, Yang L, Wang C, Li Y, Zhou Z. Comparison of Antibiotic Therapy and Appendectomy for Acute Uncomplicated Appendicitis in Children: A Meta-analysis. JAMA Pediatr. 2017 May;171(5):426–34.
  20. Talutis SD, Drake FT. Comparative effectiveness of surgery versus antibiotics in acute appendicitis: a systematic review. J Comp Eff Res. 2017 Jul;6(5):471–82.
  21. Kessler U, Mosbahi S, Walker B, Hau EM, Cotton M, Peiry B, et al. Conservative treatment versus surgery for uncomplicated appendicitis in children: a systematic review and meta-analysis. Arch Dis Child. 2017 Dec;102(12):1118–24.
  22. Ehlers AP, Talan DA, Moran GJ, Flum DR, Davidson GH. Evidence for an Antibiotics-First Strategy for Uncomplicated Appendicitis in Adults: A Systematic Review and Gap Analysis. J Am Coll Surg. 2016 Mar;222(3):309–14.
  23. Kirby A, Hobson RP, Burke D, Cleveland V, Ford G, West RM. Appendicectomy for suspected uncomplicated appendicitis is associated with fewer complications than conservative antibiotic management: a meta-analysis of post-intervention complications. J Infect. 2015 Feb;70(2):105–10.
  24. Horst JA, Trehan I, Warner BW, Cohn BG. Can Children With Uncomplicated Acute Appendicitis Be Treated With Antibiotics Instead of an Appendectomy? Ann Emerg Med. 2015 Aug;66(2):119–22.
  25. Xu J, Adams S, Liu YC, Karpelowsky J. Nonoperative management in children with early acute appendicitis: A systematic review. J Pediatr Surg. 2017 Sep;52(9):1409–15.
  26. Findlay JM, Kafsi J El, Hammer C, Gilmour J, Gillies RS, Maynard ND. Nonoperative Management of Appendicitis in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Coll Surg. 2016 Dec;223(6):814–824.e2.
  27. Georgiou R, Eaton S, Stanton MP, Pierro A, Hall NJ. Efficacy and Safety of Nonoperative Treatment for Acute Appendicitis: A Meta-analysis. Pediatrics. 2017 Mar;139(3).
  28. Eriksson S, Granstrom L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg. 1995 Feb;82(2):166–9.
  29. Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg. 2009 May;96(5):473–81.
  30. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet (London, England). 2011 May;377(9777):1573–9.
  31. Turhan AN, Kapan S, Kutukcu E, Yigitbas H, Hatipoglu S, Aygun E. Comparison of operative and non operative management of acute appendicitis. Ulus Travma Acil Cerrahi Derg. 2009 Sep;15(5):459–62.
  32. Styrud J, Eriksson S, Nilsson I, Ahlberg G, Haapaniemi S, Neovius G, et al. Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial. World J Surg. 2006 Jun;30(6):1033–7.
  33. Salminen P, Paajanen H, Rautio T, Nordstrom P, Aarnio M, Rantanen T, et al. Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. JAMA. 2015 Jun;313(23):2340–8.
  34. Liu K, Ahanchi S, Pisaneschi M, Lin I, Walter R. Can acute appendicitis be treated by antibiotics alone? Am Surg. 2007 Nov;73(11):1161–5.
  35. Abes M, Petik B, Kazil S. Nonoperative treatment of acute appendicitis in children. J Pediatr Surg. 2007 Aug;42(8):1439–42.
  36. Park HC, Kim MJ, Lee BH. The outcome of antibiotic therapy for uncomplicated appendicitis with diameters ≤ 10 mm. Int J Surg. 2014;12(9):897–900.
  37. Hansson J, Korner U, Ludwigs K, Johnsson E, Jonsson C, Lundholm K. Antibiotics as first-line therapy for acute appendicitis: evidence for a change in clinical practice. World J Surg. 2012 Sep;36(9):2028–36.
  38. Svensson JF, Patkova B, Almstrom M, Naji H, Hall NJ, Eaton S, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015 Jan;261(1):67–71.
  39. Mudri M, Coriolano K, Butter A. Cost analysis of nonoperative management of acute appendicitis in children. J Pediatr Surg. 2017 May;52(5):791–4.
  40. Hartwich J, Luks FI, Watson-Smith D, Kurkchubasche AG, Muratore CS, Wills HE, et al. Nonoperative treatment of acute appendicitis in children: A feasibility study. J Pediatr Surg. 2016 Jan;51(1):111–6.
  41. Minneci PC, Mahida JB, Lodwick DL, Sulkowski JP, Nacion KM, Cooper JN, et al. Effectiveness of Patient Choice in Nonoperative vs Surgical Management of Pediatric Uncomplicated Acute Appendicitis. JAMA Surg. 2016 May;151(5):408–15.
  42. Minneci PC, Sulkowski JP, Nacion KM, Mahida JB, Cooper JN, Moss RL, et al. Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children. J Am Coll Surg. 2014 Aug;219(2):272–9.
  43. Tanaka Y, Uchida H, Kawashima H, Fujiogi M, Takazawa S, Deie K, et al. Long-term outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr Surg. 2015 Nov;50(11):1893–7.
  44. Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani S, Coccolini F, et al. The NOTA Study (Non Operative Treatment for Acute Appendicitis): prospective study on the efficacy and safety of antibiotics (amoxicillin and clavulanic acid) for treating patients with right lower quadrant abdominal pain and long-term follow-up of conser. Ann Surg. 2014 Jul;260(1):109–17.
  45. Armstrong J, Merritt N, Jones S, Scott L, Butter A. Non-operative management of early, acute appendicitis in children: is it safe and effective? J Pediatr Surg. 2014 May;49(5):782–5.
  46. Mahida JB, Lodwick DL, Nacion KM, Sulkowski JP, Leonhart KL, Cooper JN, et al. High failure rate of nonoperative management of acute appendicitis with an appendicolith in children. J Pediatr Surg. 2016 Jun;51(6):908–11.
  47. Malik AA, Bari S. Conservative management of acute appendicitis. J Gastrointest Surg. 2009 May;13(5):966–70.
  48. Gorter RR, van der Lee JH, Cense HA, Kneepkens CMF, Wijnen MHWA, In ’t Hof KH, et al. Initial antibiotic treatment for acute simple appendicitis in children is safe: Short-term results from a multicenter, prospective cohort study. Surgery. 2015 May;157(5):916–23.
  49. Kaneko K, Tsuda M. Ultrasound-based decision making in the treatment of acute appendicitis in children. J Pediatr Surg. 2004 Sep;39(9):1316–20.
  50. Steiner Z, Buklan G, Stackievicz R, Gutermacher M, Erez I. A role for conservative antibiotic treatment in early appendicitis in children. J Pediatr Surg. 2015 Sep;50(9):1566–8.
  51. Caruso AM, Pane A, Garau R, Atzori P, Podda M, Casuccio A, et al. Acute appendicitis in children: not only surgical treatment. J Pediatr Surg. 2017 Mar;52(3):444–8.
  52. Park H-C, Kim B-S, Lee BH. Efficacy of short-term antibiotic therapy for consecutive patients with mild appendicitis. Am Surg. 2011 Jun;77(6):752–5.
  53. Koike Y, Uchida K, Matsushita K, Otake K, Nakazawa M, Inoue M, et al. Intraluminal appendiceal fluid is a predictive factor for recurrent appendicitis after initial successful non-operative management of uncomplicated appendicitis in pediatric patients. J Pediatr Surg. 2014 Jul;49(7):1116–21.
  54. Paudel GR, Agrawal CS, Regmi R, Agrawal S. Conservative treatment in acute appendicitis. JNMA J Nepal Med Assoc. 2010;50(180):295–9.
  55. Minneci PC, Sulkowski JP, Nacion KM, Mahida JB, Cooper JN, Moss RL, et al. Antibiotics alone as an alternative therapy for uncomplicated pediatric appendicitis. J Am Coll Surg [Internet]. 2014;219(4):Supplement, Page e27. | Link
  56. Rocha LL, Rossi FMB, Pessoa CMS, Campos FND, Pires CEF, Steinman M. Antibiotics alone versus appendectomy to treat uncomplicated acute appendicitis in adults: what do meta-analyses say? World J Emerg Surg. 2015;10:51.
  57. Wu JX, Dawes AJ, Sacks GD, Brunicardi FC, Keeler EB. Cost effectiveness of nonoperative management versus laparoscopic appendectomy for acute uncomplicated appendicitis. Surgery. 2015 Sep;158(3):712–21.
  58. Agency for Healthcare Research and Quality. HCUP Databases. Healthcare Cost and Utilization Project (HCUP) [Internet]. 2012. | Link
  59. Kelly ME, Khan A, Ur Rehman J, Waldron RM, Khan W, Barry K, et al. A National Evaluation of the Conservative Management of Uncomplicated Acute Appendicitis: How Common Is This and What Are the Issues. Dig Surg. 2015;32(5):325–30.
  60. Sartelli M, Chichom-Mefire A, Labricciosa FM, Hardcastle T, Abu-Zidan FM, Adesunkanmi AK, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2017;12:29.
  61. Talan DA, Saltzman DJ, Mower WR, Krishnadasan A, Jude CM, Amii R, et al. Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management. Ann Emerg Med. 2017 Jul;70(1):1–11.e9.
  62. Park HC, Kim MJ, Lee BH. Randomized clinical trial of antibiotic therapy for uncomplicated appendicitis. Br J Surg. 2017 Dec;104(13):1785–90.
  63. Olive View-UCLA Education & Research Institute. Pilot Trial of Antibiotics Versus Surgery for Treating Acute Appendicitis [Internet]. Report No.: NCT02447224. | Link
  64. Raja Isteri Pengiran Anak Saleha Hospital. Raja Isteri Pengiran Anak Saleha Appendicitis Treatment Without Operation [Internet]. Report No.: NCT03169114. | Link
  65. Turku University Hospital. Antibiotics vs. Placebo in Acute Uncomplicated Appendicitis (APPACIII) [Internet]. Report No.: NCT03234296. | Link
  66. Turku University Hospital. Appendicectomy Versus Antibiotics in the Treatment of Acute Uncomplicated Appendicitis (APPAC) [Internet]. Report No.: NCT01022567. | Link
  67. Turku University Hospital. Optimizing the Antibiotic Treatment of Uncomplicated Acute Appendicitis (APPACII) [Internet]. Report No.: NCT03236961. | Link
  68. University of Washington. The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial (CODA) [Internet]. Report No.: NCT02800785. | Link
  69. Knaapen M, van der Lee JH, Bakx R, The S-ML, van Heurn EWE, Heij HA, et al. Initial non-operative management of uncomplicated appendicitis in children: a protocol for a multicentre randomised controlled trial (APAC trial). BMJ Open. 2017 Nov;7(11):e018145.
  70. Minneci PC. Randomized Controlled Trial of a Patient Activation Tool in Pediatric Appendicitis (Antibiotics Alone vs. Appendectomy) (Appy-PAT) [Internet]. Report No.: NCT02110485. | Link
  71. First Affiliated Hospital Xi’an Jiaotong University. Clinical Trial Comparing ERAT vs Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis [Internet]. Report No.: NCT02789865. | Link
  72. A.O. Ospedale Papa Giovanni XXIII. Antibiotics Versus Surgery in Acute Appendicitis (ASAA) [Internet]. Report No.: NCT01421901. | Link
  73. Porporm N, Wilasrusmee C, Rattanasiri S, Thakkinstian A. The efficacy of antibiotic treatment versus surgical treatment of uncomplicated acute appendicitis: systematic review and network meta-analysis of randomized controlled trial.
  74. Chong M, Krishnan R, Martin J, Cheng D. Antibiotics vs. appendectomy for uncomplicated appendicitis: a meta-analysis of randomized controlled trials [Internet]. Report No.: CRD42017078467. | Link
  75. Gorter RR, Gorter-Stam M, Eker H, Bakx R, van der lee H, Heij HA, et al. Systematic review of non-operative versus operative management of acute uncomplicated (simple) appendicitis in children [Internet]. Report No.: CRD42015022061. | Link