- Email: [email protected]
Are Antibiotics a Feasible Therapeutic Option for Appendicitis?
GENERAL MEDICINE/EDITORIAL
Are Antibiotics a Feasible Therapeutic Option for Appendicitis? Anupam B. Kharbanda, MD, MSc*; David J. Schmeling, MD *Corresponding Author. E-mail: [email protected], Twitter: @A_Kharbanda. 0196-0644/$-see front matter Copyright © 2016 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2016.12.001
SEE RELATED ARTICLE, P.
.
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[Ann Emerg Med. 2016;-:1-3.] Appendicitis is one of the most common abdominal surgeries performed in the United States. For more than 100 years, the standard of care for uncomplicated appendicitis has been to remove the inflamed organ by appendectomy.1 However, multiple case reports have described successful patient outcomes after nonoperative management of appendicitis with antibiotics when surgery was not possible.2 These insights, along with the clinical experience that antibiotics are effective as first-line management for conditions once considered surgical (eg, diverticulitis), have encouraged surgeons to reconsider the role of antibiotics for appendicitis. During the past decade, multiple studies have evaluated this approach both in children and adults, primarily in European patient populations.3-8 In this issue of Annals, Talan et al9 present results of a pilot study assessing the safety and feasibility of nonoperative management with antibiotics first versus standard appendectomy for pediatric and adult patients with nonperforated appendicitis at a single medical center in the United States. The authors report that their pilot data support the safety of this therapeutic option and stress the importance of further studies of nonoperative management for appendicitis through a large-scale randomized trial. The primary outcome in this study was the 30-day major complication rate, based on the American College of Surgery Quality Improvement Program definitions. Several secondary outcomes were considered in both study arms, including quality of life and hospital length of stay, as well as appendectomy rates (failure and recurrence rates) in the nonoperative group. Of 120 patients who presented to the emergency department (ED) with a presumptive diagnosis of appendicitis, 48 (40%) were eligible according to rigorous inclusion and exclusion criteria, and 30 consented to be enrolled. Sixteen patients were randomized to antibiotics Volume
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no.
-
:
-
2016
first, whereas 14 were assigned to immediate appendectomy. In an interesting methodological approach, and as opposed to those in previous studies, patients randomized to the nonoperative group were eligible for management in the ED setting. These patients received an intravenous dose of ertapenem in the ED and were then observed for a minimum of 6 hours. Patients were discharged home if they met several stringent discharge criteria (eg, stable vital signs, pain controlled, tolerating taking liquids by mouth, reliable follow-up). All patients were required to follow up the next day in the ED for reevaluation and a second dose of ertapenem. If patients remained stable, they were then discharged home with an 8day supply of antibiotics. Patients randomized to immediate appendectomy underwent either a laparoscopic or an open procedure at the discretion of the treating surgeon. Baseline characteristics of the 2 groups were similar. Of the 16 patients in the nonoperative group, one (6.3%; 95% confidence interval 0.2% to 42.5%) patient had recurrence of symptoms at day 18. None of the remaining 15 patients had a major complication, but 1 additional patient developed recurrent appendicitis within the follow-up period (13.3%; 95% confidence interval 3.7% to 37.8%). In comparison, of the 14 patients who underwent an immediate appendectomy, 2 (14.3%; 95% confidence interval 1.8% to 42.5%) had a complication. The nonoperative group had more days pain free, quicker return to normal activities, and fewer days of missed work. In contrast, these patients experienced an increased number of mild adverse events such as diarrhea and nausea. Talan et al are to be congratulated on conducting a rigorous, randomized trial assessing the safety and efficacy of nonoperative management with antibiotics. Given the small number of enrolled patients, especially children, limited generalizations should be made to current clinical practice. However, there are several informative aspects in this study that merit further comment as they relate to measurement of outcomes, study design, and potential effect on use of diagnostic imaging. Annals of Emergency Medicine 1
Antibiotics for Appendicitis
The investigators of the current study selected the 30day American College of Surgery Quality Improvement Program criteria as their primary outcome. This is in contrast to previous studies that have measured success of nonoperative management as the proportion of patients who undergo an appendectomy over time. The most recent and perhaps best designed of these studies, by Salminen et al,5 was conducted in Finland. In this study, adult patients in 6 hospitals were randomized and 12-month follow-up was used to define the success of the nonoperative approach. In total, 273 patients underwent an appendectomy, whereas 257 had nonoperative management. The success rate of appendectomy was 99.6%, whereas there was a 27.3% recurrence rate during the follow-up period within the nonoperative group. The authors concluded that they were unable to demonstrate noninferiority of nonoperative management. These data have been further bolstered by 3 recent meta-analyses10-12 aggregating data from several of the European trials. In the analyses by Mason et al,11 which included 5 adult trials and a total of 980 patients, nonoperative management was associated with an overall treatment failure rate of 40.2% versus 8.5% with appendectomy. It is our opinion that the most important endpoint to consider in the management of appendicitis is treatment efficacy; the percentage of patients who can avoid surgery with nonoperative management. This number would be composed of the immediate failure rate associated with nonoperative management as well as the recurrence rate of appendicitis over time. When outcomes were evaluated during the follow-up period, ultimately a total of 2 patients (13%) failed the nonoperative approach in the study by Talan et al. In this regard, we argue that using the 30-day complication rate provides an incomplete and potentially incorrect assessment of treatment efficacy. As the trial by Talan et al was a pilot study to determine parameters to consider for a larger trial, short-term safety was an appropriate primary measure. Yet even from this measure, the 30-day complication rate associated with nonoperative management (6.3%) was higher than the complication rate associated with appendectomy in previous studies (3.8%),13 and a recent meta-analysis revealed no significant improvement in the complication rate associated with nonoperative management.12 The above argument should not be taken as reason to dismiss nonoperative management as a feasible treatment option; rather it is our firm belief that certain subpopulations of patients may be better suited for surgery, whereas for others a nonoperative approach would be preferred. Given that approximately 65% to 75% of patients may benefit from antibiotics alone, the key 2 Annals of Emergency Medicine
Kharbanda & Schmeling
metrics for acceptance of nonoperative management is to identify which segment of patients will have improved quality of life, satisfaction, and cost metrics over appendectomy. With respect to patient satisfaction, Talan et al noted that those randomized to nonoperative management had higher quality-of-life measures. This result is in keeping with the findings of Minneci et al,14 who conducted a patient-choice trial of children aged 7 to 17 years, comparing antibiotics versus surgical management. The 1-year success rate for the nonoperative approach was 75.7%. Among the nonoperative group, the authors further noted that patients had fewer disability days and lower health care expenditures. The authors postulate that by allowing patients and families to participate in the decisionmaking process, a higher proportion of patients agreed to participate and had better acceptance of the risks associated with recurrent appendicitis. The fear of choosing the wrong course of management, especially among parents of children with appendicitis, was also recently reported by Tanaka et al.15 The authors noted that families of children enrolled in their study worried about the long-term effect on their children if they did not undergo an appendectomy. A robust assessment of quality-of-life measures, as well as allowing patients to participate in the decisionmaking process, will likely be critical elements to consider in future studies. As nonoperative management gains traction in the surgical community, a key issue that must be considered is the utilization of diagnostic imaging. In essentially all of the previous studies describing the experience of nonoperative management, confirmation of uncomplicated appendicitis has been based on diagnostic imaging. In European studies, ultrasonography was often the test of choice. However, in the US experience, including in the study by Talan et al, the diagnosis was confirmed by computed tomography (CT) for adult patients. This approach may be problematic among pediatric patients, given the risks associated with ionizing radiation, and would be counter to the efforts of the Image Gently Initiative.16 Although the study by Talan et al did allow ultrasonography among pediatric patients, given the differential availability and performance of ultrasonography nationwide, CT use would likely increase if nonoperative management were to become more common.17 Finally, several other issues with nonoperative management should be considered. First, the impact on bacterial resistance and adverse effects associated with broad-spectrum antibiotics cannot be minimized; these metrics will need to be included in future trials. Second, a small percentage of appendectomy specimens harbor a Volume
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no.
-
:
-
2016
Kharbanda & Schmeling
neoplasm, and thus longer-term follow-up of patients managed nonoperatively is important.18 Finally, there is an increasing body of literature countering the belief that the appendix is a vestigial organ without benefit.1,19
Antibiotics for Appendicitis
4.
5.
CONCLUSIONS In aggregate, the available literature supports that the nonoperative approach, in which antibiotics are offered first, is safe and effective for selected patients with uncomplicated appendicitis. These benefits need to be balanced with the high lifelong recurrence rate, potential adverse effects associated with antibiotic delivery, and the quality-of-life effect associated with not undergoing an appendectomy. Future efforts should aim to identify which subgroups of patients with appendicitis are most likely to benefit from a nonoperative approach.
6.
7.
8.
9.
Supervising editor: Steven M. Green, MD Author affiliations: From the Department of Emergency Medicine (Kharbanda), and the Department of Surgery (Schmeling), Children’s Minnesota, Minneapolis, MN.
10.
11.
Authorship: All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. Dr. Kharbanda reports receiving salary support from R01 HD079463-01A1 from the National Institutes of Health to implement clinical decision support for pediatric appendicitis.
12.
13.
14.
15.
16.
17.
REFERENCES 1. Flum DR. Clinical practice. Acute appendicitis—appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372:1937-1943. 2. Campbell MR, Johnston SL 3rd, Marshburn T, et al. Nonoperative treatment of suspected appendicitis in remote medical care environments: implications for future spaceflight medical care. J Am Coll Surg. 2004;198:822-830. 3. Svensson JF, Patkova B, Almstrom M, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in
Volume
-,
no.
-
:
-
2016
18.
19.
children: a pilot randomized controlled trial. Ann Surg. 2015;261:67-71. Steiner Z, Buklan G, Stackievicz R, et al. A role for conservative antibiotic treatment in early appendicitis in children. J Pediatr Surg. 2015;50:1566-1568. Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA. 2015;313:2340-2348. Hartwich J, Luks FI, Watson-Smith D, et al. Nonoperative treatment of acute appendicitis in children: a feasibility study. J Pediatr Surg. 2016;51:111-116. Armstrong J, Merritt N, Jones S, et al. Non-operative management of early, acute appendicitis in children: is it safe and effective? J Pediatr Surg. 2014;49:782-785. Di Saverio S, Sibilio A, Giorgini E, 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 conservatively treated suspected appendicitis. Ann Surg. 2014;260:109-117. Talan DA, Saltzman DJ, Mower WR, et al. Antibiotics-first versus surgery for appendicitis: a US pilot randomized controlled trial allowing outpatient antibiotic management. Ann Emerg Med. 2016; http://dx.doi.org/ 10.1016/j.annemergmed.2016.08.446. Ehlers AP, Talan DA, Moran GJ, et al. Evidence for an antibiotics-first strategy for uncomplicated appendicitis in adults: a systematic review and gap analysis. J Am Coll Surg. 2016;222:309-314. Mason RJ, Moazzez A, Sohn H, et al. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt). 2012;13:74-84. Findlay JM, Kafsi JE, Hammer C, et al. Nonoperative management of appendicitis in adults: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Surg. 2016;223:814-824.e2. Bliss LA, Yang CJ, Kent TS, et al. Appendicitis in the modern era: universal problem and variable treatment. Surg Endosc. 2015;29:1897-1902. Minneci PC, Mahida JB, Lodwick DL, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis. JAMA Surg. 2016;151:408-415. Tanaka Y, Uchida H, Kawashima H, et al. Long-term outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr Surg. 2015;50:1893-1897. Miglioretti DL, Johnson E, Williams A, et al. The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr. 2013;167:700-707. Richards MK, Kotagal M, Goldin AB. Campaigns against ionizing radiation and changed practice patterns for imaging use in pediatric appendicitis. JAMA Pediatr. 2015;169:720-721. Furman MJ, Cahan M, Cohen P, et al. Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy. JAMA Surg. 2013;148:703-706. Sanders NL, Bollinger RR, Lee R, et al. Appendectomy and Clostridium difficile colitis: relationships revealed by clinical observations and immunology. World J Gastroenterol. 2013;19:5607-5614.
Annals of Emergency Medicine 3
Are Antibiotics a Feasible Therapeutic Option for Appendicitis? Anupam B. Kharbanda, MD, MSc*; David J. Schmeling, MD *Corresponding Author. E-mail: [email protected], Twitter: @A_Kharbanda. 0196-0644/$-see front matter Copyright © 2016 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2016.12.001
SEE RELATED ARTICLE, P.
.
---
[Ann Emerg Med. 2016;-:1-3.] Appendicitis is one of the most common abdominal surgeries performed in the United States. For more than 100 years, the standard of care for uncomplicated appendicitis has been to remove the inflamed organ by appendectomy.1 However, multiple case reports have described successful patient outcomes after nonoperative management of appendicitis with antibiotics when surgery was not possible.2 These insights, along with the clinical experience that antibiotics are effective as first-line management for conditions once considered surgical (eg, diverticulitis), have encouraged surgeons to reconsider the role of antibiotics for appendicitis. During the past decade, multiple studies have evaluated this approach both in children and adults, primarily in European patient populations.3-8 In this issue of Annals, Talan et al9 present results of a pilot study assessing the safety and feasibility of nonoperative management with antibiotics first versus standard appendectomy for pediatric and adult patients with nonperforated appendicitis at a single medical center in the United States. The authors report that their pilot data support the safety of this therapeutic option and stress the importance of further studies of nonoperative management for appendicitis through a large-scale randomized trial. The primary outcome in this study was the 30-day major complication rate, based on the American College of Surgery Quality Improvement Program definitions. Several secondary outcomes were considered in both study arms, including quality of life and hospital length of stay, as well as appendectomy rates (failure and recurrence rates) in the nonoperative group. Of 120 patients who presented to the emergency department (ED) with a presumptive diagnosis of appendicitis, 48 (40%) were eligible according to rigorous inclusion and exclusion criteria, and 30 consented to be enrolled. Sixteen patients were randomized to antibiotics Volume
-,
no.
-
:
-
2016
first, whereas 14 were assigned to immediate appendectomy. In an interesting methodological approach, and as opposed to those in previous studies, patients randomized to the nonoperative group were eligible for management in the ED setting. These patients received an intravenous dose of ertapenem in the ED and were then observed for a minimum of 6 hours. Patients were discharged home if they met several stringent discharge criteria (eg, stable vital signs, pain controlled, tolerating taking liquids by mouth, reliable follow-up). All patients were required to follow up the next day in the ED for reevaluation and a second dose of ertapenem. If patients remained stable, they were then discharged home with an 8day supply of antibiotics. Patients randomized to immediate appendectomy underwent either a laparoscopic or an open procedure at the discretion of the treating surgeon. Baseline characteristics of the 2 groups were similar. Of the 16 patients in the nonoperative group, one (6.3%; 95% confidence interval 0.2% to 42.5%) patient had recurrence of symptoms at day 18. None of the remaining 15 patients had a major complication, but 1 additional patient developed recurrent appendicitis within the follow-up period (13.3%; 95% confidence interval 3.7% to 37.8%). In comparison, of the 14 patients who underwent an immediate appendectomy, 2 (14.3%; 95% confidence interval 1.8% to 42.5%) had a complication. The nonoperative group had more days pain free, quicker return to normal activities, and fewer days of missed work. In contrast, these patients experienced an increased number of mild adverse events such as diarrhea and nausea. Talan et al are to be congratulated on conducting a rigorous, randomized trial assessing the safety and efficacy of nonoperative management with antibiotics. Given the small number of enrolled patients, especially children, limited generalizations should be made to current clinical practice. However, there are several informative aspects in this study that merit further comment as they relate to measurement of outcomes, study design, and potential effect on use of diagnostic imaging. Annals of Emergency Medicine 1
Antibiotics for Appendicitis
The investigators of the current study selected the 30day American College of Surgery Quality Improvement Program criteria as their primary outcome. This is in contrast to previous studies that have measured success of nonoperative management as the proportion of patients who undergo an appendectomy over time. The most recent and perhaps best designed of these studies, by Salminen et al,5 was conducted in Finland. In this study, adult patients in 6 hospitals were randomized and 12-month follow-up was used to define the success of the nonoperative approach. In total, 273 patients underwent an appendectomy, whereas 257 had nonoperative management. The success rate of appendectomy was 99.6%, whereas there was a 27.3% recurrence rate during the follow-up period within the nonoperative group. The authors concluded that they were unable to demonstrate noninferiority of nonoperative management. These data have been further bolstered by 3 recent meta-analyses10-12 aggregating data from several of the European trials. In the analyses by Mason et al,11 which included 5 adult trials and a total of 980 patients, nonoperative management was associated with an overall treatment failure rate of 40.2% versus 8.5% with appendectomy. It is our opinion that the most important endpoint to consider in the management of appendicitis is treatment efficacy; the percentage of patients who can avoid surgery with nonoperative management. This number would be composed of the immediate failure rate associated with nonoperative management as well as the recurrence rate of appendicitis over time. When outcomes were evaluated during the follow-up period, ultimately a total of 2 patients (13%) failed the nonoperative approach in the study by Talan et al. In this regard, we argue that using the 30-day complication rate provides an incomplete and potentially incorrect assessment of treatment efficacy. As the trial by Talan et al was a pilot study to determine parameters to consider for a larger trial, short-term safety was an appropriate primary measure. Yet even from this measure, the 30-day complication rate associated with nonoperative management (6.3%) was higher than the complication rate associated with appendectomy in previous studies (3.8%),13 and a recent meta-analysis revealed no significant improvement in the complication rate associated with nonoperative management.12 The above argument should not be taken as reason to dismiss nonoperative management as a feasible treatment option; rather it is our firm belief that certain subpopulations of patients may be better suited for surgery, whereas for others a nonoperative approach would be preferred. Given that approximately 65% to 75% of patients may benefit from antibiotics alone, the key 2 Annals of Emergency Medicine
Kharbanda & Schmeling
metrics for acceptance of nonoperative management is to identify which segment of patients will have improved quality of life, satisfaction, and cost metrics over appendectomy. With respect to patient satisfaction, Talan et al noted that those randomized to nonoperative management had higher quality-of-life measures. This result is in keeping with the findings of Minneci et al,14 who conducted a patient-choice trial of children aged 7 to 17 years, comparing antibiotics versus surgical management. The 1-year success rate for the nonoperative approach was 75.7%. Among the nonoperative group, the authors further noted that patients had fewer disability days and lower health care expenditures. The authors postulate that by allowing patients and families to participate in the decisionmaking process, a higher proportion of patients agreed to participate and had better acceptance of the risks associated with recurrent appendicitis. The fear of choosing the wrong course of management, especially among parents of children with appendicitis, was also recently reported by Tanaka et al.15 The authors noted that families of children enrolled in their study worried about the long-term effect on their children if they did not undergo an appendectomy. A robust assessment of quality-of-life measures, as well as allowing patients to participate in the decisionmaking process, will likely be critical elements to consider in future studies. As nonoperative management gains traction in the surgical community, a key issue that must be considered is the utilization of diagnostic imaging. In essentially all of the previous studies describing the experience of nonoperative management, confirmation of uncomplicated appendicitis has been based on diagnostic imaging. In European studies, ultrasonography was often the test of choice. However, in the US experience, including in the study by Talan et al, the diagnosis was confirmed by computed tomography (CT) for adult patients. This approach may be problematic among pediatric patients, given the risks associated with ionizing radiation, and would be counter to the efforts of the Image Gently Initiative.16 Although the study by Talan et al did allow ultrasonography among pediatric patients, given the differential availability and performance of ultrasonography nationwide, CT use would likely increase if nonoperative management were to become more common.17 Finally, several other issues with nonoperative management should be considered. First, the impact on bacterial resistance and adverse effects associated with broad-spectrum antibiotics cannot be minimized; these metrics will need to be included in future trials. Second, a small percentage of appendectomy specimens harbor a Volume
-,
no.
-
:
-
2016
Kharbanda & Schmeling
neoplasm, and thus longer-term follow-up of patients managed nonoperatively is important.18 Finally, there is an increasing body of literature countering the belief that the appendix is a vestigial organ without benefit.1,19
Antibiotics for Appendicitis
4.
5.
CONCLUSIONS In aggregate, the available literature supports that the nonoperative approach, in which antibiotics are offered first, is safe and effective for selected patients with uncomplicated appendicitis. These benefits need to be balanced with the high lifelong recurrence rate, potential adverse effects associated with antibiotic delivery, and the quality-of-life effect associated with not undergoing an appendectomy. Future efforts should aim to identify which subgroups of patients with appendicitis are most likely to benefit from a nonoperative approach.
6.
7.
8.
9.
Supervising editor: Steven M. Green, MD Author affiliations: From the Department of Emergency Medicine (Kharbanda), and the Department of Surgery (Schmeling), Children’s Minnesota, Minneapolis, MN.
10.
11.
Authorship: All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. Dr. Kharbanda reports receiving salary support from R01 HD079463-01A1 from the National Institutes of Health to implement clinical decision support for pediatric appendicitis.
12.
13.
14.
15.
16.
17.
REFERENCES 1. Flum DR. Clinical practice. Acute appendicitis—appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372:1937-1943. 2. Campbell MR, Johnston SL 3rd, Marshburn T, et al. Nonoperative treatment of suspected appendicitis in remote medical care environments: implications for future spaceflight medical care. J Am Coll Surg. 2004;198:822-830. 3. Svensson JF, Patkova B, Almstrom M, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in
Volume
-,
no.
-
:
-
2016
18.
19.
children: a pilot randomized controlled trial. Ann Surg. 2015;261:67-71. Steiner Z, Buklan G, Stackievicz R, et al. A role for conservative antibiotic treatment in early appendicitis in children. J Pediatr Surg. 2015;50:1566-1568. Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA. 2015;313:2340-2348. Hartwich J, Luks FI, Watson-Smith D, et al. Nonoperative treatment of acute appendicitis in children: a feasibility study. J Pediatr Surg. 2016;51:111-116. Armstrong J, Merritt N, Jones S, et al. Non-operative management of early, acute appendicitis in children: is it safe and effective? J Pediatr Surg. 2014;49:782-785. Di Saverio S, Sibilio A, Giorgini E, 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 conservatively treated suspected appendicitis. Ann Surg. 2014;260:109-117. Talan DA, Saltzman DJ, Mower WR, et al. Antibiotics-first versus surgery for appendicitis: a US pilot randomized controlled trial allowing outpatient antibiotic management. Ann Emerg Med. 2016; http://dx.doi.org/ 10.1016/j.annemergmed.2016.08.446. Ehlers AP, Talan DA, Moran GJ, et al. Evidence for an antibiotics-first strategy for uncomplicated appendicitis in adults: a systematic review and gap analysis. J Am Coll Surg. 2016;222:309-314. Mason RJ, Moazzez A, Sohn H, et al. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt). 2012;13:74-84. Findlay JM, Kafsi JE, Hammer C, et al. Nonoperative management of appendicitis in adults: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Surg. 2016;223:814-824.e2. Bliss LA, Yang CJ, Kent TS, et al. Appendicitis in the modern era: universal problem and variable treatment. Surg Endosc. 2015;29:1897-1902. Minneci PC, Mahida JB, Lodwick DL, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis. JAMA Surg. 2016;151:408-415. Tanaka Y, Uchida H, Kawashima H, et al. Long-term outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr Surg. 2015;50:1893-1897. Miglioretti DL, Johnson E, Williams A, et al. The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr. 2013;167:700-707. Richards MK, Kotagal M, Goldin AB. Campaigns against ionizing radiation and changed practice patterns for imaging use in pediatric appendicitis. JAMA Pediatr. 2015;169:720-721. Furman MJ, Cahan M, Cohen P, et al. Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy. JAMA Surg. 2013;148:703-706. Sanders NL, Bollinger RR, Lee R, et al. Appendectomy and Clostridium difficile colitis: relationships revealed by clinical observations and immunology. World J Gastroenterol. 2013;19:5607-5614.
Annals of Emergency Medicine 3