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CME Review Article

Appendectomy or Not? An Update on the Evidence for Antibiotics Only Versus Surgery for the Treatment of Acute Appendicitis in Children

Hartford, Emily Altick MD, MPH; Woodward, George A. MD, MBA

Author Information
doi: 10.1097/PEC.0000000000002157

Abstract

TARGET AUDIENCE

This CME article is intended for medical personnel who care for children with appendicitis, including practitioners in primary care, urgent care, surgery and the emergency department. This may include pediatricians, surgeons, pediatric emergency physicians, emergency, urgent care and family practice physicians, advanced practice providers, nurses, and trainees.

LEARNING OBJECTIVES

After participating in this activity, the reader will be better able to:

  1. assess the current literature for nonoperative management of pediatric acute uncomplicated appendicitis
  2. describe factors associated with a higher risk of failure of nonoperative management
  3. explain the role of nonoperative management for complicated (perforated) appendicitis

CASE EXAMPLE

A 9 year-old boy presents with 2 days of abdominal pain and 3 episodes of nonbloody and nonbilious emesis, anorexia, and recent onset of a low-grade fever. On examination, he is generally well appearing, though appears uncomfortable. His vital signs show a heart rate of 96 beats per minute, blood pressure of 108/60 mm Hg, pulse oximeter reading of 98% in room air, respiratory rate of 22 breaths per minute and a temperature of 38.3°C. He has a soft abdomen with voluntary guarding and focal tenderness in the right lower quadrant. Acute appendicitis is suspected, and an ultrasound notes an enlarged appendix, with loss of normal architecture, presence of mural hyperemia and surrounding echogenic fat. There is no evidence of appendicolith or perforation on imaging. General pediatric surgery is consulted. The family has a history of anesthesia complications and wishes to discuss the risks and benefits of possible nonoperative management. After discussion, the family prefers not consent to surgery. Are they making the right decision?

Acute appendicitis is a frequent diagnosis in a pediatric emergency department, and the most common reason resulting in urgent abdominal surgery in children. In our regional tertiary care pediatric emergency department, with over 50,000 visits, we diagnose approximately 400 cases of appendicitis per year. An individual's lifetime risk of appendicitis is 7% to 9%, and although it can occur at any age, the incidence is highest in the second decade of life and it is slightly more common in male individuals.1

Despite its frequency, it can still present a diagnostic challenge. Clinicians must assess the factors associated with acute appendicitis from the history, examination, and diagnostic testing as well as consider the many other possible causes of abdominal pain. Clinical scoring tools such as the “pediatric appendicitis score” can help to risk-stratify patients at low, equivocal, or high likelihood of appendicitis based on a set of clinical factors.2 A recommended and cost-effective approach is to identify patients at risk of appendicitis based on clinical factors, calculate a risk score, then use ultrasound imaging by experienced operators as a first-line diagnostic advanced imaging modality for those at equivocal or high risk, followed by computerized tomography scan if clinical suspicion remains high and the ultrasound is nondiagnostic.3–5 Even with a staged and thoughtful approach by experienced clinicians, some patients will have false positive findings in their evaluation that lead to surgical intervention and ultimately pathology that is not consistent with appendicitis. The overall prevalence of negative appendectomy is approximately 2% to 5%, and there is an association with a higher rate of negative appendectomy in groups where the diagnosis is even more difficult, such as younger children and female adolescents.6

Appendicitis is considered complicated once there is evidence of perforation; which can occur early in the disease process, but is more often associated with longer duration of symptoms greater than 48 hours. Perforated appendicitis at time of presentation is more common with younger children as their symptoms are more likely to be nonspecific, atypical, and/or difficult to elucidate.7 The diagnosis of perforated appendicitis can not only be suspected based on clinical factors, imaging, or laboratory tests but can also be discovered at the time of surgery.

Surgical appendectomy has been the standard of care once acute appendicitis is suspected. Nonoperative management of appendicitis (ie, antibiotics only) has existed as another treatment modality primarily for those without access to surgical care.8 In the past 20 years, however, there has been an increasing amount of literature comparing nonoperative antibiotics-only management to the traditional surgical management. There is a growing body of literature assessing the 2 treatment paths for pediatric patients and comparing outcomes, costs, complications, and patient perspectives. The current status of the literature regarding surgical versus nonoperative management for the treatment of acute appendicitis in children is still evolving and will be reviewed here.

REVIEW OF THE CURRENT LITERATURE FOR NONOPERATIVE (ANTIBIOTICS ONLY) MANAGEMENT OF UNCOMPLICATED ACUTE APPENDICITIS

Initial Treatment Success for Nonoperative Management

Early prospective trials including pediatric patients with appendicitis undergoing treatment with nonoperative management were initially observational, frequently offering the choice of management to the family based on success in adult patients. These reports resulted in early treatment success (0–30 days) defined by resolution of symptoms and laboratory and imaging abnormalities in 87.5% to 98.7% of patients.9–13 More recent observational studies have demonstrated similar findings after offering the treatment choice to families, with treatment success at 30 days of 89.2%.14 A 2018 prospective trial involving 166 children with uncomplicated appendicitis was completed where all underwent nonoperative management; early treatment success was seen in all but 4 (97.6%) using 48 hours of intravenous (IV) antibiotics and an additional 5 days of oral doses for a total of 7 days.15 Of note, the more recent prospective studies included more stringent criteria to selection of patients eligible for nonoperative management. Abbo et al excluded patients under 5 years, those with evidence of appendicolith, peritonitis or highly elevated CRP; Minneci et al only considered for nonoperative management those with appendiceal diameter less than 1.1 cm, symptom duration of less than 48 hours, and lower CRP and WBC parameters. It has been shown that for children who undergo successful nonoperative management, pain and laboratory abnormalities typically resolve within 24 hours.16

Together these studies to date demonstrate the safety of an antibiotic only treatment option, and more importantly raise the question of the nonsuperiority of traditional surgical management, which has opened the door for randomized trials still ongoing.17,18

Recurrence of Symptoms and Risk for Perforation

The main disadvantage of nonoperative management is the risk of recurrent appendicitis. In these observational studies, some patients returned for appendectomy due to recurrence of abdominal pain with or without evidence of appendicitis, and others for elective surgery even if symptom free. Thus, treatment success for nonoperative management at 6 and 14 months ranged between 71% and 88.9%.10,12 Studies that have followed patients longer over time have shown differing proportions of recurrence: 24.3% at 1 year,14 13.3% at 18 months,15 24% after 3 years,19 and 28.6% after 4.3 years.19

In 1 trial of patients randomized to routine interval appendectomy or active observation after successful initial nonoperative management of acute appendicitis, 12% in the observation group developed recurrent appendicitis after 1 year.20

In nonoperative management, concerns have been raised about the risk of perforation in patients with recurrence, but a higher proportion of perforated appendicitis has not been demonstrated in patients who recur after an initially successful nonoperative management.15,21 Although the vast majority of patients who have recurrent appendicitis after nonoperative management undergo appendectomy, some data suggest that an additional course of antibiotics after recurrence might also be successful a second time instead of surgery.22

Complications for Surgical and Nonoperative Management

Surgical appendectomy is likely to be a definitive treatment for appendicitis, but there is also a risk of complications with surgical intervention. Complications from appendectomy occur for an estimated 1–5% of children undergoing appendectomy and include wound infection, intra-abdominal abscess formation, or bowel obstruction from paralytic ileus or mechanical obstruction.23 There is also the risk for negative appendectomy which may be considered a surgical complication. Rarely, a portion of the appendix may remain after appendectomy and become inflamed later, resulting in a recurrent stump appendicitis.24

Two meta-analyses including both adult and pediatric literature specifically compare complications of therapy for nonoperative management (including treatment failure) and surgery. They were similar at 9.6% and 12% for nonoperative and 11 and 12.5% for surgery.19,21

In the trial, where patients were randomized to routine interval appendectomy or active observation, after successful initial nonoperative management of acute appendicitis, 12% in the observation group developed recurrent appendicitis and 6% in the surgical group had complications (1 bowel obstruction, 2 wound infections) after 1 year.20

To more effectively compare the treatment options, more recent literature has shifted to comparing complication-free treatment success, both early and over time, for either appendectomy or nonoperative management with antibiotics.

Treatment Success According to Pooled Meta-Analyses

In a pooled meta-analysis published in 2017, nonoperative management showed early success (resolution of symptoms without surgical intervention within 48 hours) in 90.5% of patients, at 1 year, the average treatment success (no appendectomy) was at 73.2%.25 However, only 16.1% of patients operated on within that year had pathologically confirmed appendicitis.

Two systematic reviews of the pediatric data were published with results from early nonrandomized trials and retrospective cohort studies showing treatment success (resolution of symptoms) at 1 year to be 62% to 81% without appendectomy19 and another reporting early success of nonoperative management between 58% and 100% with 0.1% to 31.8% incidence of recurrence at 1 year.26 Of note, the latter review included a study that applied its own treatment protocol to decision making around proceeding to surgery or not27; authors included lack of improvement in inflammatory markers or imaging as reason to consider the patient having failed nonoperative management and proceed with surgery whereas most others considered resolution of pain, fever, or leukocytosis only. Therefore, inclusion of the results from this study explains the lower proportion of early successful nonoperative management in this review compared with other reports.

A meta-analysis and review from 2018 included 9 total and 2 pediatric trials. The overall recurrence at 1 year was 18.2%. The authors concluded that nonoperative management had lower treatment success with recurrence or treatment failure 12% to 32% of the time, but resulted in 23% to 86% fewer complications.28

The largest meta-analysis of uncomplicated appendicitis including both adults and children was published in 2019 including 10 studies with pediatric data and 9 more with adult data. They compared overall complication-free treatment success for initial treatment and found it to be 67.2% versus 82.3% (P < 0.01) for nonoperative and surgical management, respectively; this includes data from adult studies, but there was no significant difference in a pediatric subgroup analysis. At 1 year, treatment efficacy was 72.6% for nonoperative and 93.1% for surgery (P < 0.01).21 These numbers are lower than previously seen because this analysis included older retrospective pediatric studies as well as one that had a higher proportion of initial treatment failure after attempting nonoperative management for younger patients (ages, 3–17 years) and also those with appendicolith29 who are known to have a higher risk of failure without surgery.

In pediatric appendicitis, it has still been uncommon for patients to undergo nonoperative management. In a retrospective database analysis using the PHIS database published in 2017, nonoperative management was utilized only 6% of the time for children with appendicitis, although it was increasing over time from 2010 to 2016. In this analysis, 46% of patients with initial nonoperative management had an appendectomy within 1 year, but the authors were not able to differentiate between treatment failure for nonoperative management or planned interval appendectomy. The report also noted more ED visits and hospitalizations for the group who did not undergo an operation raising concerns regarding overall costs and complications after taking into account recurrent abdominal symptoms).30

Cost Comparison

A dedicated cost-effectiveness analysis study comparing nonoperative management with surgery in children has not yet been published, but costs have been included in several studies and meta-analyses already reviewed here. Minneci et al found costs related to appendicitis care to be significantly lower for nonoperative management at 1 year (US $4219 [US $2514–US $7795] vs US $5029 [US $4596–US $5482]) for surgery (P < 0.01, data from 2012 to 2013). In a retrospective cost analysis, the initial cost of nonoperative management was lower, but equalized when considering subsequent hospitalizations and including the treatment failures.31 In their review, Podda et al21 found that costs were lower for those with nonoperative management even though there was no difference in hospital stay. In an economic subanalysis of a randomized trial of adults undergoing surgery or antibiotic therapy in Finland, they also found overall costs (including disability days and direct costs) to be 1.6 times higher for the patients undergoing surgery.32

Disability Days and Quality of Life Assessment

There is 1 study with an adequate response rate to compare quality of life by the health-related quality of life questionnaire, and the scores were similar at 1 year after surgical or nonoperative management.14 In this same study, nonoperative management was associated with fewer disability days at 1 year (median [IQR], 8 days [5–18 days] vs 21 days [15–25 days], respectively; P < 0.001). In another study, there were also fewer overall disability days despite a longer hospital length of stay for patients who underwent nonoperative management.25 Consideration of this information may further help families and providers discussing risks and benefits.

Family and Patient Perspectives on Nonoperative Management

Given the evidence showing relatively high initial success with nonoperative management, many authors have concluded that shared informed decision making with patients/families might be a useful approach when deciding between about surgery in children. There have been multiple surveys of families asking their perspective on management of appendicitis. The majority of respondents choose surgery over nonoperative management for themselves (91%), only 9% choose antibiotics alone. When asked to choose for their children, 85% preferred surgery and 15% antibiotics.33 When asked more about their reasons behind the decision, parents of children with appendicitis overestimated the mortality and the risk for perforation. In a separate survey, most parents still preferred urgent surgery, but a larger proportion felt that antibiotics would be a good option.34 In another study on family preferences, education was provided about the diagnosis and treatment options; afterwards families actually changed their mind to prefer nonoperative management).35 In a more recent survey, a smaller majority (57–61%) still preferred surgery stating a fear of the appendix “bursting” as the main reason.36

REVIEW OF THE CURRENT LITERATURE ON RISK FACTORS FOR PATIENTS WHO FAIL NONOPERATIVE MANAGEMENT

The presence of an appendicolith and longer duration of symptoms have been associated with failure of nonoperative management in pediatric appendicitis. In 2016, a trial of children with appendicitis and appendicolith was terminated early due to safety concerns after they observed a failure rate of 60% after 4 months of follow up, noting presence of appendicolith as an important risk factor for failure of nonoperative management.37

In 2017, a prospective trial with children who had evidence of uncomplicated appendicitis included younger children than previous trials (ages 3–17 years) and reported 61.4% families choosing nonoperative management rather than surgery. Initial failure was higher in this trial at 31% of patients; associated characteristics included presence of appendicolith and longer duration of symptoms before presentation. Half of the patients with early failure of nonoperative management (8/16) had complicated appendicitis at time of surgery. Recurrence was similar to previous reports at 23% with a mean duration of follow up of 13 months.29

In the adult literature, additional risk factors for failure of nonoperative management include fever at presentation, greater appendiceal diameter greater than 13 mm, a higher Alvarado score38 (a clinical scoring system for symptoms of appendicitis in adults), and duration of symptoms less than 25 hours.39

Patient Selection for Consideration of Nonoperative Management

There have been some attempts to explore separating patients with uncomplicated appendicitis to early or late surgery based on clinical, laboratory and ultrasound data. In 1 trial, this resulted in 42% of patients undergoing surgery within the initial hospitalization. Those with uncomplicated appendicitis diagnosed clinically and by ultrasound received antibiotics only for 24 hours and then were reassessed clinically and with repeat laboratories and imaging. Treatment failure included abdominal pain, fevers, and/or any worsening of laboratory and ultrasound parameters between 24 and 48 hours.27 Unfortunately, this study did not include long term follow-up to determine if operating on a higher proportion of patients at initial presentation using laboratory and imaging data might result in a lower risk of recurrence for those who had nonoperative management.

Recent prospective trials have excluded patients from nonoperative management who are younger (<5 years or <7 years), have an appendicolith, or who have evidence of perforation on imaging. Because no imaging modality is 100% sensitive for the latter, some also exclude patients with a longer duration of symptoms or particularly large appendiceal diameter.14,15 One of the randomized trials currently ongoing to compare nonoperative management with surgery is using less strict inclusion criteria (age, 4–17 years, no evidence of appendix mass, no previous antibiotics, without mention of duration of symptoms or appendix measurement) according to their published protocol.17 Another is using similar criteria: ages 5 to 16 years, no evidence of perforation in clinical data, no previous appendicitis, or significant comorbidity.18

REVIEW OF THE ROLE FOR NONOPERATIVE MANAGEMENT IN COMPLICATED APPENDICITIS

Complicated appendicitis is a term used when there is evidence of perforation of the appendix with or without abscess formation, as is noted in approximately 30% in pediatric appendicitis at the time of diagnosis.40 The management of complicated appendicitis is more complex and there is a less data on outcomes for patients undergoing nonoperative management. There is agreement that these patients require admission, IV antibiotics, and close observation. Beyond this, options for treatment of complicated appendicitis include antibiotics only, early appendectomy, percutaneous drainage if there is abscess formation, and interval appendectomy versus continued observation. There are some early studies suggesting that complicated appendicitis can be treated successfully with nonoperative management including close inpatient follow up in as many as 80% of patients.41–43 More recently, in 2009, 40 patients with complicated appendicitis were randomized to early appendectomy or admission with antibiotics and percutaneous drainage with appendectomy approximately 10 weeks later and there were no differences seen in patient outcomes, including hospital length of stay, recurrence of abscess, or costs.44 However, a 2011 randomized control study did show significant differences between these treatment options favoring early appendectomy, including fewer disability days and complications when compared with initial nonoperative management and delayed appendectomy.45 In another trial, 81% of patients with complicated appendicitis were managed successfully initially with nonoperative management with or without abscess drainage; they reported factors associated with the initial failure in 19% to be presence of bandemia or bowel obstruction on imaging.46 More recently, even the need for interval appendectomy has been questioned in a trial published by Tanaka et al.47 In patients with complicated appendicitis, a choice between early appendectomy and initial nonoperative management with or without interval appendectomy was offered. Initial success of nonoperative management was very high at 98.2%, and in the group that chose not to undergo surgery; the recurrence rate was 34.2%. There may also be a role for repeating the antibiotic course after failure of nonoperative management in complicated appendicitis. In 1 prospective nonrandomized trial, initial success with nonoperative management was seen in 72% of patients, and 78% of those with recurrence were successfully managed with a second course of antibiotics and no surgical intervention.22

ANTIBIOTIC SELECTION AND COURSE FOR NONOPERATIVE MANAGEMENT

There is a lack of data comparing specific antibiotic courses in nonoperative management. Each trial uses different variations on type of antibiotic, route of administration, and duration of therapy. Common bacteria present in the pathogenesis of AA include fecal flora containing aerobic and anaerobic gram negative rods, commonly Escherichia coli, Peptostreptococcus species, Bacteriodes fragilis, and Pseudamonas species.48 Therefore, appropriate antibiotics need to be broad in spectrum. Most trials begin with IV antibiotic therapy for 48 to 72 hours and then convert to oral therapy for a total course of at least 7 days. Some continue the IV course until inflammatory markers show improvement; one of the highest initial treatment success rates reported (98.7%) was in a trial where IV antibiotics were continued until the C-reactive protein level had normalized.47 One meta-analysis compared treatment efficacy between surgery and nonoperative management with different antibiotic regimens across 9 adult and pediatric studies and found that a beta-lactamase with or without penicillin was associated with higher treatment success and lower complications compared with other options (penicillin alone, third-generation cephalosporin + metronidazole/tinidazole). However, the latter combination was associated with lower recurrence rates.28

There is an ongoing randomized trial in adult patients with appendicitis comparing oral antibiotics versus the more typical method of 24 to 48 hours of initial IV antibiotics followed by an oral course.49 Interestingly, there is 1 report of adult patients with appendicitis confirmed by computerized tomography scan who were randomized to receive antibiotics or no antibiotics with supportive care and there was no difference in treatment failure or recurrence; costs were lower in the group who did not receive antibiotics.50

SUMMARY

In the majority of the recent prospective trials, the early success of nonoperative management for children with uncomplicated appendicitis without presence of appendicolith is approximately 90%. Within 1 year, approximately 20% of those patients will experience a recurrence of appendicitis and may go on to have surgical treatment. Nonoperative management is associated with lower costs initially, though studies differ on the overall costs when recurrence and subsequent ED visits and hospitalizations are included. Longer duration of symptoms, younger patient age, and presence of appendicolith are associated with failure of nonoperative management in children.

There is less data available and more treatment options used for the management of complicated appendicitis. Initial nonoperative management with percutaneous abscess drainage for these cases can be successful in approximately 80% of cases, where most then undergo interval appendectomy 8 to 10 weeks later. At least 1 study raises a question about the need for surgery at all, and some have also reported success with additional antibiotic courses should appendicitis recur.

Most trials on nonoperative management of appendicitis are completed with a 24–48 hour initial course of broad spectrum IV antibiotics followed by oral antibiotics for total of at least 7 days. However, there is a lack of data comparing differing antibiotic regimens. One meta-analysis of adults and children suggested a higher initial treatment success rate with a beta-lactamase with or without penicillin, but the lowest rate of recurrence with a third-generation cephalosporin and metronidazole.

When asked, the majority of patients report a preference for surgical treatment of appendicitis although that preference changed in 1 study after education was provided on the 2 options. Patients do overestimate the severity of the diagnosis of appendicitis and the risk for perforation or mortality which may be influencing their preferences.

Given the available evidence, it appears that nonoperative management of appendicitis is an emerging and viable treatment option for appropriate low risk pediatric patients with uncomplicated appendicitis without evidence of an appendicolith. The data are less clear on management for complicated appendicitis. More evidence is needed on optimal selection, duration, and route of delivery for antibiotic therapy. Ongoing randomized trials may soon yield additional informative data. Medical providers should work with local pediatric surgical experts on an approach for patients who present with appendicitis in their setting.

ACKNOWLEDGMENTS

The authors wish to acknowledge Dr. Adam Goldin for his input and review of this manuscript.

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Keywords:

nonoperative appendicitis; appendicitis; complications of appendicitis

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