Background
Acute appendicitis is one of the commonly encountered acute surgical conditions. Worldwide incidences range from 7.5 to 22.71 per 10,000 and the lifetime risk is around 16.3% [
1,
2]. Untreated appendicitis can progress into gangrene or perforation with resultant peritonitis or abscess formation. Since the very first successful appendectomy performed by Claudius Amyand in 1735 [
3], it has long been the gold standard of treatment for acute appendicitis. This surgical dogma was first challenged by Fitz in 1886, who suggested that patients with appendicitis may resolve without surgical intervention as evidence of previous appendicitis were found in many autopsy specimens [
4]. Coldrey first reported successful treatment of 471 patients with acute appendicitis using antibiotics alone in 1956 [
5]. Since then, a number of studies investigated the role of using antibiotics alone, non-operative management (NOM), in the management of acute uncomplicated appendicitis with promising results [
6‐
8]. Appendectomy, albeit a routine surgical procedure with low mortality [
9], has a complication rate of 5 to 28% [
10]. Given the evidence that supports NOM, should the paradigm of treatment for uncomplicated appendicitis changed from operative to non-operative? This review focused on the current available evidence in the literature comparing NOM and appendectomy for the treatment of acute uncomplicated appendicitis in adults in order to answer this question.
Methodology
All studies that evaluated the effectiveness of NOM over appendectomy in managing uncomplicated acute appendicitis were retrieved from Medline (PubMed), Embase (1980-) and Cochrane Library electronic databases. The search was carried out on 15th June, 2017. The MeSH term “acute appendicitis” & “antibiotic therapy” were used as search terms. Only two terms were used with the intention to include more literatures for preliminary screening. “antibiotic therapy” was chosen since operative management had been considered as the gold standard for treating appendicitis and trials working on performance of NOM should have compared NOM with the gold standard. It is reasonable to assume using “antibiotic therapy” as search term can identify all trials that compared NOM with appendectomy.
Search mode was set as best matched and “full text” for Pubmed searching. The search terms were used as subject heading for searching in Cochrane and Embase (1980-). Editorials, case reports, expert opinions, letters to the editor, reviews without original data, conference abstract and studies solely on pediatric population were excluded. The screening and selection criteria of studies were summarized in Table
1.
Table 1
A summary of the screening and selection criteria of studies
Inclusion Criteria | 1. Uncomplicated Acute Appendicitis - Excluded perforation - Excluded intra-abdominal abscess 2. Mainly focus on adult population 3. Full article published in English 4. Randomized control trials & prospective comparative studies |
Exclusion | 1. Studies that solely involved the pediatric population (Subjects’ age < 18) 2. Studies that only compared elective surgery and conservative management |
Search engine | 1. PubMed 2. Embase (1980-) 3. Cochrane Library |
Keywords | 1. Acute appendicitis 2. Antibiotic therapy |
Inclusion criteria
Studies that meet the following criteria were included: 1) Uncomplicated acute appendicitis (Excluding perforation & intra-abdominal abscess); 2) Mainly focused on the adult population; 3) Full article published in English; 4) Randomized control trials (RCT) & observational comparative studies.
Exclusion criteria
Studies were excluded if they have the following: 1) Studies that solely involved the pediatric population (Subjects’ age < 18); 2) Studies that only compared elective surgery with conservative management.
Data searches and quality assessments
Embase (1980-), Cochrane Library and Pubmed database were searched by Poon & Wong. The search process was conducted independently and the findings were filled in a preset Excel document. Authors subsequently combined the search result and duplications were removed. Literatures were independently assessed by the authors and then subsequently reviewed together. Consensus was achieved on the inclusion of articles. Quality assessments was performed by Poon and reviewed by Wong.
The primary outcomes that were measured included the success rate, morbidities rate, length of hospital stay and loss of work associated with the two treatment modalities.
Statistical analysis
Cochrane Review Manager (RevMan) Version 5.3.5 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for evaluating the studies’ results and constructing the forest plots & funnel plots. Odds ratio (OR) of successfully treated cases in patients with NOM when compared to the appendectomy group had been employed to evaluate the outcomes of the two interventions. 95% confidence intervals (95% CI) were decided to evaluate the statistical significance of the OR. An OR of greater than one dictates a superior outcome for the NOM group, and the value of OR was considered statistically significant at the p = 0.05 level. Heterogeneity was accounted by the I-square test. Fixed effect model of Mantel Haenzel method was used for analyzing dichotomous data. The analysis of continuous data employed random effect model of inverse variance with regard to the great heterogeneity.
Discussion
This review demonstrated a higher efficacy for appendectomy and was consistent with earlier meta-analysis [
21,
22]. In the meta-analysis by Sallinen et al., including five RCTs, one on pediatric patients, 8.5% of the patients treated with NOM required appendectomy within the first month [
23]. Wilms et al. published a meta-analysis involving five RCTs and 901 patients [
24]. Although 73.4% of the patients treated with NOM had resolution of acute appendicitis without major complications and recurrence in the following year, as compared to 97.4% in the appendectomy group, the author could not demonstrate non-inferiority of NOM and concluded that more than one out of five patients treated with NOM would develop either complications or recurrence requiring surgery in the following year. A consensus statement was issued by the expert panel at the 3rd World Congress of the World Society of Emergency Surgery held in Jerusalem, Israel in 2015, which stated that NOM could be successful in selected patients with uncomplicated appendicitis who wish to avoid surgery and accept a higher risk, up to 38%, of recurrence [
25].
The complications rate of appendectomy was generally higher than NOM in the literature. In Mason’s meta-analysis [
26], NOM was shown to be protective for major and minor complications with an odds ratio of 0.54 (95% CI 0.37 to 0.78). This is contrary to results from some non-randomized studies. Data from a national database involving the treatment of 436,400 cases of acute appendicitis over a 8-year period showed a significantly higher rate of in-hospital complications (27.8% vs. 7%,
p < 0.001) and longer hospital stay (3 vs. 2 days, p < 0.001) in the NOM group [
27]. It is unfortunate that all RCTs comparing NOM and surgery, except one [
15], had a high rate of open appendectomy, ranging from 82 to 100% [
6,
12,
14,
19]. Further, the choice of operative approach was not standardized and was often up to surgeons’ discretion. It is difficult to generalize these results in terms of morbidities from the available RCTs as the majority of patients, up to over 90%, with acute appendicitis were operated with the laparoscopic approach nowadays [
28]. Previous RCTs and systematic reviews have shown that laparoscopic approach was associated with fewer wound complications, less postoperative pain and shorter hospital stay [
29] but with a higher incidence of intra-abdominal collection [
30].
The results of the earlier RCTs did not show a difference between NOM and surgery in terms of hospital stay [
6,
12,
13]. The two latest RCTs published in 2011 and 2015 showed shorter hospital stay in the appendectomy group [
15,
19]. A meta-analysis showed shorter hospital stay in the appendectomy group, with a mean difference of 0.41 days (95% CI 0.26 to 0.57) [
23]. This is in line with the result of this review, which the surgically treated patients had a shorter hospital stay than those with NOM. Nevertheless, two other meta-analysis failed to demonstrate a significant difference in hospital stay when only adult RCTs were included [
21,
22]. As mentioned above, the percentage of patients operated with the laparoscopic approach in the RCTs was far less than expected. Shorted hospital stay and faster return to work would be expected in laparoscopic appendectomy. On the other hand, the use of oral antibiotics in NOM, as demonstrated in the Non Operative Treatment for Acute Appendicitis (NOTA) study conducted in Italy, would largely reduce the length of hospital stay [
31]. It is difficult to draw a conclusion whether NOM has an advantage over appendectomy based on the current evidence.
In terms of long term efficacy, results beyond one year from the published RCTs were not available in the literature. A retrospective study on 3236 patients treated with NOM revealed a long-term recurrence rate of 4.4% at a mean follow up of 7 ± 3.9 years [
32]. Another study on 118 patients treated with NOM showed a 10.2% recurrence at a median follow-up of 23 months [
33]. The NOTA study suggested a long term efficacy of 83% up to two years with NOM [
34].
Given the aforementioned one-year recurrence rate of 13.9 to 35%, the majority of the patients primarily treated with NOM would remain symptoms-free. Routine interval appendectomy after resolution of symptoms was therefore not necessary. On the other hand, the morbidities rate of interval appendectomy was low. In the study by Salminen, none of the patients suffered from intra-abdominal abscess after interval appendectomy [
19]. The surgical complication rate of elective interval appendectomy was lower than primary appendectomy by 13.4%.
Apart from a higher treatment efficacy rate, appendectomy offers definitive histology and provides a chance to diagnose rare appendiceal and extra-appendiceal pathologies. Connor reported the presence of appendiceal tumors in 0.9% of 7970 appendectomy specimens [
35]. Another study reported a 2.7% and 1.1% incidence of appendiceal diverticulitis and appendiceal tumors, which included carcinoid tumors, adenocarcinoma, mucinous cystadenoma etc. [
36].
Conclusion
NOM is definitely a feasible and effective alternative for uncomplicated appendicitis. The majority of patients primarily treated with NOM would be spared from post-operative pain, surgical risks and wound complications. The paradigm remains unchanged, however, that appendectomy should be the gold standard of treatment given its higher treatment success rate and shorter hospital stay. Current evidence in the literature mainly focused on comparing NOM with open appendectomy. With widespread adoption of the laparoscopic approach, high quality evidence is still needed in the comparison of primary laparoscopic appendectomy and NOM. Studies evaluating factors that could affect the rate of success in NOM is needed for clinical reference and to tailor treatment on an individual basis. Until then, patients should be well informed of the available treatment options, their pros and cons, so as to make informed decision and benefit from the optimal treatment.