AUTHORS
Ryan Lamm MD1, Sunjay S. Kumar MD1*, Amelia T. Collings MD2,Ivy N. Haskins MD DABOM3, Ahmed Abou-Setta MD PhD4, Nisha Narula MD5, Pramod Nepal MD PhD6, Nader M. Hanna MBBS MSc7, Dimitrios I. Athanasiadis MD8, Stefan Scholz MD9, Joel F. Bradley 3rd MD10, Arianne T. Train DO MPH11, Philip H Pucher MD PhD12, Francisco Quinteros MD13, Bethany Slater MD14
*Corresponding author
ABSTRACT
Background: The optimal diagnosis and treatment in cases of appendicitis remains controversial. This systematic review details the evidence and current best clinical practices for the evaluation and management of uncomplicated and complicated appendicitis in both adults and children.
Methods: Eight key questions regarding the diagnosis and management of appendicitis were formulated. PubMed, Embase, CINAHL, Cochrane and clinicaltrials.gov were queried for articles published from 2010-2022 that had key words related to at least one key question. Randomized and non-randomized studies were included. Two reviewers screened each publication for study eligibility and then extracted data from eligible studies. Random effects meta-analyses were performed on all quantitative data. The quality of randomized and non-randomized studies was assessed using the Cochrane Risk of Bias 2.0 or Newcastle Ottawa Scale, respectively.
Results: 2,792 studies were screened and 261 were included. Most had a high risk of bias. Computerized tomography scan yielded the highest sensitivity (>80%) and specificity (>93%) in the adult population, although high variability existed. In adults with uncomplicated appendicitis, non-operative management with antibiotics alone resulted in higher odds of readmission (OR 6.10) and need for operation (OR 20.09), but less time to return to work/school (SMD -1.78). In pediatric patients with uncomplicated appendicitis, non-operative management also resulted in higher odds of need for operation (OR 38.31). In adult patients with complicated appendicitis, there were higher odds of need for operation following antibiotic treatment only (OR 29.00), while pediatric patients had higher odds of abscess formation (OR 2.23). In pediatric patients undergoing appendectomy for complicated appendicitis, higher risk of reoperation at any time point was observed in patients who had drains placed at the time of operation (RR 2.04).
Conclusions: This review demonstrates the diagnosis and treatment of appendicitis remains nuanced. A personalized approach and appropriate patient selection for the available treatment modalities remains key to treatment success. Further research focused on specific continued controversies in treatment would be useful for optimal management.
Key Words: Appendicitis; Appendectomy; Meta-analysis; Systematic review; Antibiotic treatment
INTRODUCTION
Acute appendicitis remains one of the most common pathologies resulting in hospital admission. Lifetime risk of appendicitis in the United States (US) is estimated to be around 9% [1]. This rate is similar in Europe (8%), but lower in Africa (2%) with peak presentation occurring between the ages of 10 and 30 years old [2]. Complicated appendicitis upon presentation has a rate of 16-40% with higher rates being reported in both younger age groups and patients older than 50 years [3]. While the mortality rate for uncomplicated appendicitis is around 0.1%, complicated appendicitis carries a far higher mortality risk at 5%, emphasizing the importance of timely diagnosis and treatment [4].
From a resource utilization standpoint, managing appendicitis is burdensome. One study estimates hospitalization cost in the US alone at $3 billion annually [5]. High variability regarding the diagnosis and treatment of acute appendicitis has contributed to high resource utilization within the US and globally [6]. This variability contributes to high cost, poorer outcomes which have been linked to country income and reveals the need for data to streamline practices and reduce costs [6].
Due to the high variability and controversies surrounding ‘best practices’ concerning the diagnosis and treatment of acute appendicitis, key questions were identified by this research group and data were explored.
Clinical diagnosis of appendicitis remains challenging due to the fact that many of its signs and symptoms mimic other abdominal pathologies [7, 8]. While imaging studies undoubtedly increase the sensitivity and specificity of diagnosis, debate still exists on which modality to use when considering resources required to perform the exams, timeliness of the exams, and the amount of radiation exposure, especially in the pediatric population [9]. Nevertheless, as the treatment for uncomplicated and complicated appendicitis can be drastically different, selecting the optimal imaging modality to differentiate between them is critical.
Once the diagnosis is made, controversy persists regarding the best treatment strategy. Specifically, multicenter, non-inferiority trials such as the Appendicitis acuta (APPAC) trial reported antibiotic only treatment to be safe and effective in adults with first episode uncomplicated appendicitis, which has been corroborated in additional systematic reviews and meta-analyses [10-12]. Similar data, albeit more limited, has also been demonstrated in children [13, 14]. While approximately 90% of patients in these studies were able to avoid initial surgery for uncomplicated appendicitis, recurrence was estimated to be roughly 20-30% at 5-year follow-up [15-17]. Because the long-term nonoperative management of uncomplicated appendicitis may not be successful in all patients, it is commonly suggested that treatment options should be presented to the patient, allowing for shared decision-making.
Patients with complicated appendicitis are often treated based on clinical presentation with some being trialed on antibiotic treatment while others undergo immediate surgical intervention [18]. If treated nonoperatively, many surgeons recommend interval appendectomy, but approaches vary and are not universally agreed upon [19, 20].
Operative approach and post-operative management also vary. Questions persist regarding timing of operation following diagnosis [21], drain placement during surgery for complicated appendicitis [22], suction versus suction and lavage for perforated appendicitis [23], as well as duration of postoperative antibiotics in cases of complicated appendicitis [24].
In an attempt to better characterize and consolidate the current data detailing the diagnosis and treatment of appendicitis, to clarify some of the controversies surrounding the management of appendicitis, and to inform a Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guideline with evidence-based recommendations, a systematic review and meta-analysis were conducted.
METHODS AND MATERIALS
A systematic review and meta-analysis comparing diagnostic and treatment options for appendicitis was performed by members of the SAGES guidelines committee according to the Preferred Reporting Items for Systematic Revies and Meta-Analyses (PRISMA) guidelines [25]. Eight key questions (KQs) were created by the guidelines committee according to the PICO (Population, Intervention, Comparator, and Outcomes) format. The KQs were as follows:
Key Question 1 (KQ 1): Should alternative imaging versus abdominal CT be used for managing acute appendicitis?
Outcomes: true positive, false positive, false negative, and true negative values, sensitivity, specificity, rate of needing additional imaging following initial imaging, rate of negative appendectomy following false positive initial imaging, rate of nondiagnostic finding following initial imaging
Key Question 2 (KQ 2): Should adult and pediatric patients with acute, uncomplicated appendicitis be managed nonoperatively with antibiotics versus appendectomy?
Outcomes: abscess formation, cost, need for percutaneous drain placement, intensive care unit (ICU) admission, length of hospital stay, mortality, need for new course of antibiotics, quality of life, readmission, reoperation/need for operation within 30 days, reoperation/need for operation between 30 days and 1 year, reoperation (at any time point), time to return to work/school
Key Question 3 (KQ 3): In adult and pediatric patients with complicated appendicitis, should operative management versus nonoperative management be used?
Outcomes: abscess formation, cost, drain placement, ICU admission, length of hospital stay, mortality, need for new course of antibiotics, quality of life, readmission, reoperation/need for operation (at any time point), time to return to work/school
Key Question 4 (KQ 4): In adult and pediatric patients with uncomplicated appendicitis undergoing appendectomy, do outcomes differ based on early (< 12 hours from diagnosis) versus late (>12 hours from diagnosis) surgical intervention?
Outcomes: abscess formation, drain placement, length of hospital stay, readmission, reoperation/need for operation (at any time point)
Key Question 5 (KQ 5): In adult and pediatric patients undergoing appendectomy for perforated appendicitis, should suction and lavage versus suction alone be used?
Outcomes: abscess formation, drain placement, length of hospital stay, mortality, readmission, reoperation/need for operation (at any time point)
Key Question 6 (KQ 6): In adult and pediatric patients undergoing appendectomy for complicated appendicitis, should routine drain placement versus no routine drain placement be used?
Outcomes: abscess formation, drain placement, need for new course of antibiotics, readmission, reoperation/need for operation (at any time point)
Key Question 7 (KQ 7): Should adult and pediatric patients who undergo appendectomy for complicated appendicitis be given postoperative antibiotics for short term vs. long term (based on study authors’ criteria)?
Outcomes: abscess formation, contraction of Clostridium difficile, drain placement, length of hospital stay, need for new course of antibiotics, readmission, reoperation/need for operation (at any time point), total complications
Key Question 8 (KQ 8): In asymptomatic adult and pediatric patients with previous complicated appendicitis treated nonoperatively, should an interval appendectomy be performed versus observation?
Outcomes: abscess formation, drain placement, length of hospital stay, mortality, readmission, rate of neoplasm/missed neoplasm, reoperation/need for operation within 30 days, reoperation/need for operation between 30 days and 1 year
Subgroup Analysis
For each of the KQs a subgroup analysis was performed for the adult and pediatric population when data was available.
Literature Search and Eligibility Criteria
Assisted by a professional librarian, an extensive search of PubMed, Embase, CINAHL, and Cochrane Library as well as Clinicaltrials.gov was performed for each KQ. Eligible studies included those published in English between the years of 2010 and 2021. Studies included in the analysis consisted of randomized control trials (RCTs), as well as non-randomized comparative studies. All identified studies were combined and uploaded using Covidence for screening and data extraction purposes [26]. An updated search was performed in 2022 to capture published studies since our initial search. Full search strategies can be found in the Supplementary material, Appendix B.
Study Selection
To calibrate guideline committee member responses, reviewers were asked to rate 50 abstracts on Abstrackr (Brown University, Providence, Rhode Island) and discuss any discrepancies in scoring during a scheduled conference call. After calibration, all identified titles and abstracts in the screening process were reviewed by a minimum of two committee members for relevance and eligibility using Covidence. Any discrepancies were addressed by a third reviewer/consensus discussion. Publications deemed irrelevant to the key questions, duplicate studies, and/or had only a non-English language version available were excluded. Additional exclusion criteria included: case reports, single-arm studies with less than 50 patients, articles with patients who were pregnant, and studies where greater than 50% of the operations were performed open. Next, full text review was conducted on all eligible and available published manuscripts. Previously published systematic reviews’ reference lists were hand checked to identify additional relevant articles.
Risk of Bias
The Cochrane Risk of Bias 2.0 tool was used for quality assessment of included RCTs [27]. Criteria included sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete data, non-comparable groups, performance bias, and detection bias. Non-randomized studies were evaluated using the Newcastle-Ottawa Scale [28]. Criteria included selection bias, comparability of groups, and outcome reporting. Two independent investigators scored each study for all appropriate criteria. For each study a final risk of bias assessment was determined, with any discrepancies resolved by a discussion between the two reviewers or a third part tie-breaker where necessary.
Data Extraction
Covidence was again used to complete data extraction forms for included studies. These forms included data points for study characteristics, methods, population, interventions, and outcomes. These forms were completed by two independent reviewers. Outcomes of interest included time to return to work/school, readmission, mortality, intensive care unit (ICU) admission, organ space infection (defined as abscess found on imaging), hospital length of stay (LOS), requirement of new course of antibiotics, drain placement, reoperation ( defined as reoperation or conversion of nonoperative management to surgical management), cost-effectiveness, and quality of life. Outcomes for diagnostic imaging comparison included sensitivity, specificity, and negative appendectomy rate, true positive, false positive, false negative, and true negative values, sensitivity, specificity, rate of needing additional imaging following initial imaging, rate of negative appendectomy following false positive initial imaging, and rate of nondiagnostic finding following initial imaging.
Data Synthesis and Analysis
RevMan (Version 5.3.5) [29] was used to perform meta-analysis using a random-effects model. Risk ratios (RR) and odds ratios (OR) were calculated for dichotomous outcomes from randomized and non-randomized studies, respectively, using a Mantel-Haenszel random effects model. Inverse variance weighted mean difference for continuous outcomes was utilized. For continuous outcomes using multiple scales, a standardized mean difference (SMD) was used. Heterogeneity between studies was assessed using measures of I2 and χ2. All comparative studies, including observational and high risk of bias, are presented, but results and conclusions focus on randomized controlled trials and low risk of bias studies when available.
RESULTS
2,792 studies were identified following database and handsearching queries. 261 studies met inclusion criteria and were included to answer KQ1-8. 155 of the studies involved adult patient populations and 106 studies involved pediatric patients. 26 studies included were randomized control trials (RCTs), while the remaining 235 were observational studies. A PRISMA flow diagram showing screening results and exclusion rationale can be found in Appendix A.
Key Question 1 (KQ 1):
Should abdominal CT versus alternative imaging be used for diagnosing acute appendicitis?
Adults
A total of 94 studies met inclusion criteria for KQ1 in the adult subpopulation composed of all observational studies.
Of the studies included 26 (28%) were determined to have low risk of bias, 47 had high (50%) and the remaining 21 (22%) had an unclear risk of bias (Table 1).
Table 1. Risk of bias for the observational studies included under KQ1 as assessed by a modified Newcastle Ottawa Scale.
Twenty-seven studies reported sensitivity and specificity for computed tomography (CT) scan with all reporting a sensitivity higher than 80% and specificity varying from 35-100% (Figure 1a, 1b) [30-56].
Figure 1a. Forrest plot for CT scan sensitivity and specificity
Figure 1b. Punnett square for CT scan sensitivity and specificity (based on prevalence of 70%)
Three studies reported sensitivity and specificity for low dose computed tomography (CT) scan with all reporting a sensitivity higher than 95% and specificity varying from 93-100% (Figure 1c, 1d) [38, 39, 57].
Figure 1c. Forrest plot for low dose CT scan sensitivity and specificity
Figure 1d. Punnett square for low dose CT scan sensitivity and specificity (based on prevalence of 70%)
Five studies reported sensitivity and specificity for non-contrast computed tomography (CT) scan with sensitivity ranging from 59 to 92% and specificity varying from 83 to 100% (Figure 1e, 1f) [34, 37, 58-60].
Figure 1e. Forrest plot for non-contrast CT scan sensitivity and specificity
Figure 1f. Punnett square for non-contrast CT scan sensitivity and specificity (based on prevalence of 70%)
Eighteen studies reported sensitivity and specificity for magnetic resonance imaging (MRI) with all reporting a sensitivity higher than 80% and specificity varying from 0 to 100% (Figure 1g, 1h) [31, 36, 40, 50, 59-72].
Figure 1g. Forrest plot for MRI sensitivity and specificity
Figure 1h. Punnett square for MRI sensitivity and specificity (based on prevalence of 70%)
Sixty-two studies reported sensitivity and specificity for ultrasound (US) studies with sensitivity ranging from 37 to – 100% and specificity varying from 0 to 100% (Figure 1i, 1j) [30, 31, 35, 40, 43-45, 47-49, 51-53, 55, 58, 60, 68, 69, 73-116].
Figure 1i. Forrest plot for ultrasound sensitivity and specificity
Figure 1j. Punnett square for ultrasound sensitivity and specificity (based on prevalence of 70%)
Twelve studies reported sensitivity and specificity for point of care ultrasound (POCUS) studies with sensitivity ranging from 43 – 100% and specificity varying from 32-98% (Figure 1k/l) [42, 63, 87, 93, 113, 117-123].
Figure 1k. Forrest plot for point of care ultrasound sensitivity and specificity
Figure 1l. Punnett square for point of care ultrasound sensitivity and specificity (based on prevalence of 70%)
Pediatric
A total of 57 studies met inclusion criteria for KQ1 in the pediatric subpopulation composed of 1 RCTs and 56 observational studies. Of the studies included, the one RCT was determined to be low risk of bias (100%) (Table 2a). Of the observational studies, 12 (21%) were determined to have low risk of bias, 37 had high (66%) and the remaining 7 (13%) had an unclear risk of bias (Table 2b).
Table 2a. Risk of bias for the RCTs included under KQ1 as assessed by a Cochrane Risk of Bias tool.
Table 2b. Risk of bias for the observational studies included under KQ1 as assessed by a modified Newcastle Ottawa Scale.
For pediatric patients, rate of needing additional imaging was 0.3% (Range 0-1.6%) for CT scan, 3.6% (No range 1 study) for low dose CT scan, 17.3% (Range 0 – 49.4%) for ultrasound, 64.2% (Range 45 – 83.3%) for POCUS, and 0.7% (Range 0 – 3.4%) for MRI (Table 3a). Rate of negative diagnostic laparoscopy following imaging was 6.7% (Range 1.2-15%) for CT scan, 0% (No range 1 study) for low dose CT scan, 9.6% (Range 0 – 35.5%) for ultrasound, 3.2% (Range 0 – 12.9%) for POCUS, and 8.4% (Range 0 – 23.3%) for MRI (Table 3b). Rate of nondiagnostic finding on imaging was 5.5% (Range 0-13.3%) for CT scan, not available for low dose CT scan, 35.7% (Range 0 – 80.8%) for ultrasound, 43.6% (Range 17.5 – 69.3%) for POCUS, and 13.9% (Range 0 – 62.5%) for MRI (Table 3c) [116, 124-177].
Table 3a. Rate of needing for additional imaging following initial imaging
Table 3b. Rate of negative diagnostic laparoscopy following false positive initial imaging
Table 3c. Rate of nondiagnostic finding following initial imaging
Key Question 2 (KQ 2)
Should adult and pediatric patients with acute, uncomplicated appendicitis be managed nonoperatively with antibiotics versus appendectomy?
Adults
A total of 18 studies met inclusion criteria for KQ2 in the adult subpopulation composed of 6 RCTs and 12 observational studies. Of the six RCTs, three (50%) were determined to have a low risk of bias, one was determined to have a high risk of bias (17%), and the remaining two (33%) had an unclear risk of bias (Table 4a). Of the observational studies, 2 (17%) were determined to have low risk of bias, 8 had high (67%) and the remaining 2 (17%) had an unclear risk of bias (Table 4b).
Table 4a. Risk of bias for the RCTs included under KQ2 as assessed by a Cochrane Risk of Bias tool.
Table 4b. Risk of bias for the observational studies included under KQ2 as assessed by a modified Newcastle Ottawa Scale.
Three RCTs reported on abscess formation comparing antibiotics (201 patients) versus appendectomy (198 patients). These studies demonstrated no statistical difference in abscess formation. Five cohort studies reported on abscess formation which also showed no statistical difference (Figure 2a) [124, 178-185].
Figure 2a. Forrest plot for abscess formation
One RCT reported on cost comparing antibiotics (91 patients) versus appendectomy (89 patients) which demonstrated lower cost with antibiotics (SMD -1.01, 95% CI = -1.32, -0.70). Six cohort studies reported on cost which also showed lower cost with antibiotics (SMD -0.41, 95% CI = -0.68, -0.14) with high heterogeneity (I2 = 100) (Figure 2b) [44, 179, 181, 186-189].
Figure 2b. Forrest plot for cost
One RCT reported on drain placement comparing antibiotics (676 patients) versus appendectomy (656 patients) which demonstrated higher rates of drain placement in antibiotics (SMD 4.02, 95% CI = 1.66, 9.71) . Two cohort studies reported on drain placement which showed no statistical difference (Figure 2c) [179, 182, 190].
Figure 2c. Forrest plot for drain placement
Five RCTs reported on length of hospital stay comparing antibiotics (852 patients) versus appendectomy (839 patients). These studies demonstrated no statistical difference in length of hospital stay. Eight cohort studies reported on length of hospital stay which also showed no statistical difference (Figure 2d) [179, 180, 182, 184, 187-194].
Figure 2d. Forrest plot for length of hospital stay
One RCTs reported on mortality comparing antibiotics (676 patients) versus appendectomy (676 patients). This study demonstrated zero mortality for either. Six cohort studies reported on mortality which demonstrated higher mortality in antibiotics (OR 37.19, 95% CI = 19.37, 71.38) with high heterogeneity (I2 = 97) (Figure 2e) [178, 179, 182, 185, 188, 190, 191].
Figure 2e. Forrest plot for mortality
One RCT reported on need for new course of antibiotics comparing antibiotics (16 patients) versus appendectomy (14 patients). This study demonstrated no statistical difference in need for new course of antibiotics. One cohort study reported on need for new course of antibiotics which showed lower odds of needing a new course of antibiotics following antibiotics (OR 0.30, 95% CI = 0.21, 0.42) (Figure 2f) [179, 183].
Figure 2f. Forrest plot for new course of antibiotics
One RCT reported on quality of life comparing antibiotics (683 patients) versus appendectomy (664 patients). This study demonstrated no statistical difference in quality of life. No cohort studies reported on quality of life (Figure 2g) [190].
Figure 2g. Forrest plot for quality of life
Two RCTs reported on readmission comparing antibiotics (726 patients) versus appendectomy (702 patients). This study demonstrated higher odds of readmission following antibiotics (OR 6.10, 95% CI = 4.21, 8.84) with low heterogeneity (I2 = 0). Six cohort studies reported on readmission which showed no statistical difference in readmission (Figure 2h) [179, 181, 182, 185, 188-190, 195].
Figure 2h. Forrest plot for readmission
Four RCTs reported on reoperation at any time point comparing antibiotics (191 patients) versus appendectomy (190 patients). This study demonstrated higher odds of reoperation at any time point following antibiotics (OR 20.09, 95% CI = 5.39, 74.90) with low heterogeneity (I2 = 0). Four cohort studies reported on reoperation at any time point which showed higher odds of reoperation following antibiotics (OR 26.91, 95% CI = 4.33, 167.37) with high heterogeneity (I2 = 57) (Figure 2i) [180, 182, 183, 189, 191-193, 195].
Figure 2i. Forrest plot for reoperation (any time point)
One RCT reported on reoperation within 30 days comparing antibiotics (19 patients) versus appendectomy (22 patients). This study no statistical difference in reoperation within 30 days. Three cohort studies reported on reoperation within 30 days which showed higher odds of reoperation following antibiotics (OR 11.37, 95% CI = 1.66, 77.74) with high heterogeneity (I2 = 52) (Figure 2j) [182, 191-193].
Figure 2j. Forrest plot for reoperation (<30 d)
Two RCTs reported on reoperation between 30 days and 1 year comparing antibiotics (156 patients) versus appendectomy (154 patients). This study demonstrated higher odds of reoperation between 30 days and 1 year following antibiotics (OR 30.37, 95% CI = 5.77, 159.77) with low heterogeneity (I2 = 0). Two cohort studies reported on reoperation between 30 days and 1 year which showed higher odds of reoperation following antibiotics (OR 74.69, 95% CI = 10.18, 548.13) with low heterogeneity (I2 = 0) (Figure 2k) [180, 182, 189, 193].
Figure 2k. Forrest plot for reoperation (30 d-1y)
Four RCTs reported on return to work/school comparing antibiotics (708 patients) versus appendectomy (703 patients). This study demonstrated less time to return to work/school following antibiotics (SMD -1.78, 95% CI = -3.48, -0.08) with low heterogeneity (I2= 0). One cohort study reported on return to work/school which also showed less time to return to work/school following antibiotics (SMD -8.64, 95% CI = -10.65, -6.63) (Figure 2l) [184, 189-192].
Figure 2l. Forrest plot for return to work/school
Pediatric
A total of 17 studies met inclusion criteria for KQ2 in the pediatric subpopulation composed of 4 RCTs and 13 observational studies. Of the four RCTs, two (50%) were determined to have a low risk of bias, one was determined to have a high risk of bias (25%), and the remaining one (25%) had an unclear risk of bias (Table 5a). Of the observational studies, 2 (15%) were determined to have low risk of bias, 8 had high (62%) and the remaining 3 (23%) had an unclear risk of bias (Table 5b).
Table 5a. Risk of bias for the RCTs included under KQ2 as assessed by a Cochrane Risk of Bias tool.
Table 5b. Risk of bias for the observational studies included under KQ2 as assessed by a modified Newcastle Ottawa Scale.
No RCTs reported on abscess formation comparing antibiotics versus appendectomy. Four cohort studies reported on abscess formation which showed no statistically significant difference (Figure 3a) [196-199].
Figure 3a. Forrest plot for abscess formation
One RCT reported on cost comparing antibiotics (24 patients) versus appendectomy (26 patients). This study demonstrated no statistically significant difference in cost. Three cohort studies reported on cost also which showed no statistically significant difference in cost (Figure 3b) [187, 200-202].
Figure 3b. Forrest plot for cost
No RCTs reported on need for drain placement comparing antibiotics versus appendectomy. Two cohort studies reported on need for drain placement which showed no statistically significant difference (Figure 3c) [198, 199].
Figure 3c. Forrest plot for drain placement
No RCTs reported on ICU admission comparing antibiotics versus appendectomy. One cohort study reported on ICU admission which showed no statistically significant difference (Figure 3d) [197].
Figure 3d. Forrest plot for ICU admission
No RCTs reported on length of hospital stay comparing antibiotics versus appendectomy. Six cohort study reported on length of hospital stay which showed no statistically significant difference (Figure 3e) [187, 196, 200, 201, 203, 204].
Figure 3e. Forrest plot for length of hospital stay
One RCT reported on mortality comparing antibiotics versus appendectomy. This study had no mortality in either treatment arm. No cohort studies reported on mortality (Figure 3f) [205].
Figure 3f. Forrest plot for mortality
One RCT reported on need for new course of antibiotics comparing antibiotics (27 patients) versus appendectomy (27 patients). This study demonstrated no statistically significant difference in need for new course of antibiotics. Two cohort studies reported on need for new course of antibiotics which showed no statistically significant difference (Figure 3g) [196, 197, 205].
Figure 3g. Forrest plot for new course of antibiotics
No RCTs reported on quality of life comparing antibiotics versus appendectomy. Two cohort studies reported on quality of life which showed no statistically significant difference (Figure 3h) [199, 201].
Figure 3h. Forrest plot for quality of life
Four RCTs reported on readmission comparing antibiotics (95 patients) versus appendectomy (98 patients). This study demonstrated higher odds of readmission following antibiotics (OR 10.57, 95% CI = 2.30, 48.69) with high heterogeneity (I2 = 36). Nine cohort studies reported on readmission which also showed higher odds of readmission following antibiotics (OR 5.49, 95% CI = 2.60, 11.56) with high heterogeneity (I2 = 79) (Figure 3i) [14, 197-199, 201-203, 205-209].
Figure 3i. Forrest plot for readmission
Two RCTs reported on need for reoperation at any time point comparing antibiotics (48 patients) versus appendectomy (52 patients). This study demonstrated higher odds of reoperation at any time point following antibiotics (OR 38.31, 95% CI = 4.90, 299.69) with low heterogeneity (I2 = 0). Six cohort studies reported on need for reoperation at any time point which also showed higher odds of reoperation at any time point following antibiotics (OR 54.37, 95% CI = 25.13, 117.66) with low heterogeneity (I2 = 0) (Figure 3j) [196-199, 201, 202, 209, 210].
Figure 3j. Forrest plot for reoperation (any time point)
Two RCTs reported on reoperation within 30 days comparing antibiotics (48 patients) versus appendectomy (52 patients). These studies demonstrated no statistically significant difference. Seven cohort studies reported on reoperation within 30 days which showed higher odds of reoperation within 30 days following antibiotics (OR 11.15, 95% CI = 2.81, 44.25) with high heterogeneity (I2 = 36) (Figure 3k) [196-199, 201, 202, 204, 209, 210].
Figure 3k. Forrest plot for reoperation (<30d)
Two RCTs reported on reoperation between 30 days and 1 year comparing antibiotics (48 patients) versus appendectomy (52 patients). This study demonstrated higher odds of reoperation between 30 days and 1 year following antibiotics (OR 22.71, 95% CI = 2.87, 179.78) with low heterogeneity (I2 = 0). Six cohort studies reported on reoperation between 30 days and 1 year which also showed higher odds of reoperation following antibiotics (OR 31.67, 95% CI = 14.17, 70.82) with low heterogeneity (I2 = 0) (Figure 3l) [196-199, 201, 202, 209, 210].
Figure 3l. Forrest plot for reoperation (30d-1y)
One RCT reported on time to return to work/school comparing antibiotics (20 patients) versus appendectomy (19 patients). This study demonstrated no statistically significant difference. Four cohort studies reported on time to return to work/school which showed less time to return to work/school following antibiotics (SMD -1.98, 95% CI = -3.15, -0.81) with high heterogeneity (I2 =65) (Figure 3m) [14, 203, 207, 208, 210].
Figure 3m. Forrest plot for return to work/school
Key Question 3 (KQ 3)
In adult and pediatric patients with complicated appendicitis, should operative management versus nonoperative management be used?
Adults
A total of 11 studies met inclusion criteria for KQ3 in the adult subpopulation composed of 1 RCTs and 10 observational studies. The one RCT was determined to have a low risk of bias (Table 6a). Of the observational studies, 1 (10%) were determined to have low risk of bias, 6 had high (60%) and the remaining 3 (30%) had an unclear risk of bias (Table 6b).
Table 6a. Risk of bias for the RCTs included under KQ3 as assessed by a Cochrane Risk of Bias Tool.
Table 6b. Risk of bias for the observational studies included under KQ3 as assessed by a modified Newcastle Ottawa Scale.
One RCT reported on abscess formation comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated no statistically significant difference. Eight cohort studies reported on abscess formation which also showed no statistically significant difference (Figure 4a) [211-219].
Figure 4a. Forrest plot for abscess formation
One cohort study reported on cost comparing antibiotics and appendectomy which showed no statistically significant difference (Figure 4b) [214].
Figure 4b. Forrest plot for cost
One RCT reported on need for drain placement comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated no statistically significant difference. Four cohort studies reported on need for drain placement which showed higher odds of drain placement following antibiotics (OR 16.28, 95% CI = 4.21, 62.98) with high heterogeneity (I2= 75) (Figure 4c) [213, 215, 216, 219, 220].
Figure 4c. Forrest plot for drain placement
One cohort study reported on ICU admission comparing antibiotics versus appendectomy which showed lower odds of ICU admission following antibiotics (OR 0.16, 95% CI = 0.03, 0.80) (Figure 4d) [220].
Figure 4d. Forrest plot for ICU admission
One RCT reported on hospital length of stay (LOS) comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated longer hospital lengths of stay following antibiotics (SMD 1.12, 95% CI = 0.65, 1.59). Five cohort studies reported on hospital length of stay which showed no statistically significant difference (Figure 4e) [213-215, 217, 218, 220].
Figure 4e. Forrest plot for length of hospital stay
One RCT reported on mortality comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated no statistically significant difference. Three cohort studies reported on mortality which also showed no statistically significant difference (Figure 4f) [214, 215, 217, 221].
Figure 4f. Forrest plot for mortality
One RCT reported on readmission comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated higher odds of readmission following antibiotics (OR 10.55, 95% CI = 1.23, 90.66). Eight cohort studies reported on readmission which also showed higher odds of readmission following antibiotics (OR 3.22, 95% CI 1.30, 8.02) with high heterogeneity (I2=80) (Figure 4g) [211, 213-217, 219, 220, 222].
Figure 4g. Forrest plot for readmission
One RCT reported on reoperation at any time point comparing antibiotics (30 patients) versus appendectomy (30 patients). This study demonstrated higher odds of reoperation at any time point following antibiotics (OR 29.00, 95% CI = 3.49, 241.13). Four cohort studies reported on reoperation at any time point comparing antibiotics and appendectomy which also showed higher odds of reoperation at any time point following antibiotics (OR 47.46, 95% CI 12.94, 174.11) with low heterogeneity (I2=0) (Figure 4h) [212, 214-216, 219].
Figure 4h. Forrest plot for reoperation (any time point)
Pediatric
A total of 12 studies met inclusion criteria for KQ3 in the pediatric subpopulation composed of 3 RCTs and 9 observational studies. Of the three RCTs, one (33%) was determined to have a low risk of bias, none were determined to have a high risk of bias (0%), and the remaining two (67%) had an unclear risk of bias (Table 7a). Of the observational studies, 3 (33%) were determined to have low risk of bias, 4 had high (44%) and the remaining 2 (22%) had an unclear risk of bias (Table 7b).
Table 7a. Risk of bias for the RCTs included under KQ3 as assessed by a Cochrane Risk of Bias tool.
Table 7b. Risk of bias for the observational studies included under KQ3 as assessed by a modified Newcastle Ottawa Scale.
Two RCTs reported on abscess formation comparing antibiotics (87 patients) versus appendectomy (84 patients). This study demonstrated higher odds of abscess formation following antibiotics (OR 2.23, 95% CI = 1.10, 4.50) with low heterogeneity (I2=0). Four cohort studies reported on abscess formation comparing antibiotics and appendectomy which showed no statistically significant difference (Figure 5a) [129, 223-227].
Figure 5a. Forrest plot for abscess formation
One RCT reported on cost comparing antibiotics (67 patients) versus appendectomy (64 patients). This study demonstrated no statistically significant differences. One cohort study reported on cost comparing antibiotics and appendectomy which showed higher cost following antibiotics (SMD 6,700.00, 95% CI = 255.47, 13,144.53) (Figure 5b) [129, 224].
Figure 5b. Forrest plot for cost
Two cohort studies reported on need for drain placement comparing antibiotics (196 patients) versus appendectomy (215 patients). This study demonstrated higher odds of drain placement following antibiotics (OR 5.94, 95% CI = 1.50, 23.54) with high heterogeneity (I2=87) (Figure 5c) [225, 228].
Figure 5c. Forrest plot for drain placement
Two RCTs reported on length of hospital stay comparing antibiotics (87 patients) versus appendectomy (84 patients). This study demonstrated no statistically significant difference. Six cohort studies reported on abscess formation comparing antibiotics and appendectomy which showed longer length of hospital stay following antibiotics (OR 2.94, 95% CI = 1.71, 4.18) with high heterogeneity (I2=96) (Figure 5d) [129, 224, 225, 227-231].
Figure 5d. Forrest plot for length of hospital stay
One cohort study reported on need for new course of antibiotics comparing antibiotics (148 patients) versus appendectomy (168 patients). This study demonstrated higher odds for needing a new course of antibiotics following antibiotics (OR 2.42, 95% CI = 1.01, 5.84) (Figure 5e) [223].
Figure 5e. Forrest plot for new course of antibiotics
One RCT reported on quality of life comparing antibiotics (20 patients) versus appendectomy (20 patients). This study demonstrated higher quality of life following antibiotics (SMD -2.88, 95% CI = -3.79, -1.97). One cohort study reported on quality of life which showed no statistically significant difference (Figure 5f) [226, 232].
Figure 5f. Forrest plot for quality of life
One RCT reported on readmission comparing antibiotics (67 patients) versus appendectomy (64 patients). This study demonstrated higher odds of readmission following antibiotics (OR 5.39, 95% CI = 1.89, 15.37). Six cohort studies reported on readmission which also showed higher odds of readmission following antibiotics (OR 6.90 95% CI 1.27, 37.67) with high heterogeneity (I2=93) (Figure 5g) [199, 224, 225, 228, 230, 233, 234].
Figure 5g. Forrest plot for readmission
One RCT reported on reoperation at any time point comparing antibiotics (20 patients) versus appendectomy (20 patients). This study demonstrated no statistically significant difference. Three cohort studies reported on reoperation at any time point which also showed no statistically significant difference (Figure 5h) [199, 223, 227, 234].
Figure 5h. Forrest plot for reoperation (any time point)
One RCT reported on time to return to work/school comparing antibiotics (67 patients) versus appendectomy (64 patients). This study demonstrated longer times to return to work/school following antibiotics (SMD 5.60, 95% CI = 2.82, 8.38) (Figure 5i) [224].
Figure 5i. Forrest plot for return to work/school
Key Question 4 (KQ 4)
In adult and pediatric patients with uncomplicated appendicitis undergoing appendectomy, do outcomes differ based on early (< 12 hours from diagnosis) versus late (>12 hours from diagnosis) surgical intervention?
Adults
A total of 9 studies met inclusion criteria for KQ4 in the adult subpopulation composed of all observational studies. Of the observational studies, 3 (33%) were determined to have low risk of bias, 5 had high (55%) and the remaining 1 (11%) had an unclear risk of bias (Table 8).
Table 8. Risk of bias for the observational studies included under KQ4 as assessed by a modified Newcastle Ottawa Scale.
Eight cohort studies reported on abscess formation which showed no statistically significant difference between surgery within 12 hours or after 12 hours of diagnosis (Figure 6a) [235-242].
Figure 6a. Forrest plot for abscess formation
One cohort study reported on need for drain placement which showed no statistically significant difference between surgery within 12 hours or after 12 hours of diagnosis (Figure 6b) [235].
Figure 6b. Forrest plot for drain placement
One cohort study reported on length of hospital stay which showed no statistically significant difference between surgery within 12 hours or after 12 hours of diagnosis (Figure 6c) [241].
Figure 6c. Forrest plot for length of hospital stay
Four cohort studies reported on need for readmission which showed no statistically significant difference between surgery within 12 hours or after 12 hours of diagnosis (Figure 6d) [235, 236, 239, 242].
Figure 6d. Forrest plot for readmission
One cohort study reported on reoperation at any time point which showed no statistically significant difference between surgery within 12 hours or after 12 hours of diagnosis (Figure 6e) [241].
Figure 6e. Forrest plot for reoperation (any time point)
Pediatric
A total of 3 studies met inclusion criteria for KQ4 in the pediatric subpopulation composed of all observational studies. Of the observational studies, 1 (33%) were determined to have low risk of bias, none had high (0%) and the remaining 2 (67%) had an unclear risk of bias (Table 9).
Table 9. Risk of bias for the observational studies included under KQ4 as assessed by a modified Newcastle Ottawa Scale.
Two cohort studies reported on abscess formation comparing surgery within 12 hours (1,871 patients) or after 12 hours (1,133 patients) of diagnosis which no statistical difference if surgery was performed before or after 12 hours of diagnosis (Figure 7a) [243, 244].
Figure 7a. Forrest plot for abscess formation
One cohort study reported on readmission comparing surgery within 12 hours (1,653 patients) or after 12 hours (1,103 patients) of diagnosis which showed lower odds of abscess formation if surgery was performed after 12 hours of diagnosis (OR 0.66, 95% CI 0.45, 0.96) (Figure 7b) [243].
Figure 7b. Forrest plot for readmission
One cohort study reported on reoperation at any time point comparing surgery within 12 hours (1,653 patients) or after 12 hours (1,103 patients) of diagnosis which showed no statistically significant difference (Figure 7c) [243].
Figure 7c. Forrest plot for reoperation (any time point)
Key Question 5 (KQ 5):
In adult and pediatric patients undergoing appendectomy for perforated appendicitis, should suction and lavage versus suction alone be used?
Adults
A total of 6 studies met inclusion criteria for KQ5 in the adult subpopulation composed of 4 RCTs and 2 observational studies. Of the four RCTs, three (75%) was determined to have a low risk of bias, one was determined to have a high risk of bias (25%), and none (0%) had an unclear risk of bias (Table 10a). Of the observational studies, 1 (50%) was determined to have low risk of bias and one had high (50%) risk of bias (Table 10b).
Table 10a. Risk of bias for the RCTs included under KQ5 as assessed by a Cochrane Risk of Bias tool.
Table 10b. Risk of bias for the observational studies included under KQ5 as assessed by a modified Newcastle Ottawa Scale.
Four RCTs reported on abscess formation comparing suction and lavage (324 patients) versus suction alone (389 patients). This study demonstrated no statistically significant difference in abscess formation. Two cohort studies reported on abscess formation which again showed no statistically significant difference (Figure 8a) [245-250].
Figure 8a. Forrest plot for abscess formation
Three RCTs reported on need for drain placement comparing suction and lavage (194 patients) versus suction alone (259 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 8b) [246, 248, 249].
Figure 8b. Forrest plot for drain placement
Two RCTs reported on length of hospital stay comparing suction and lavage (242 patients) versus suction alone (304 patients). These studies demonstrated shorter length of hospital stays following suction and lavage (SMD -1.56, 95% CI -2.07, -1.04) with high heterogeneity (I2=93) (Figure 8c) [246, 250].
Figure 8c. Forrest plot for length of hospital stay
One RCT reported on mortality comparing suction and lavage (112 patients) versus suction alone (174 patients). This study demonstrated no statistically significant difference in mortality (Figure 8d) [246].
Figure 8d. Forrest plot for mortality
Two RCTs reported on readmission comparing suction and lavage (152 patients) versus suction alone (215 patients). This study demonstrated no statistically significant difference in readmission (Figure 8e) [246, 249].
Figure 8e. Forrest plot for readmission
Three RCTs reported on reoperation at any time point comparing suction and lavage (194 patients) versus suction alone (259 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 8f) [246, 248, 249].
Figure 8f. Forrest plot for reoperation (any time point)
Pediatric
A total of 5 studies met inclusion criteria for KQ5 in the pediatric subpopulation composed of 3 RCTs and 2 observational studies.
Of the three RCTs, all three (100%) was determined to have a low risk of bias (Table 11a) [23, 251, 254]. Of the observational studies both (100%) had an unclear risk of bias (Table 11b) [252, 253].
Table 11a. Risk of bias for the RCTs included under KQ5 as assessed by a Cochrane Risk of Bias tool.
Table 11b. Risk of bias for the observational studies included under KQ5 as assessed by a modified Newcastle Ottawa Scale.
Three RCTs reported on abscess formation comparing suction and lavage (204 patients) versus suction alone (202 patients). This study demonstrated no statistically significant difference in abscess formation. Two cohort studies reported on abscess formation which showed lower risk of abscess formation suction and lavage (RR 0.69 95% CI 0.49, 0.98) with high heterogeneity (I2=95) (Figure 9a) [23, 251-254].
Figure 9a. Forrest plot for abscess formation
Two RCTs reported on need for drain placement comparing suction and lavage (160 patients) versus suction alone (160 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 9b) [23, 251].
Figure 9b. Forrest plot for drain placement
Two RCTs reported on length of hospital stay comparing suction and lavage (160 patients) versus suction alone (160 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 9c) [23, 251].
Figure 9c. Forrest plot for length of hospital stay
Three RCTs reported on mortality comparing suction and lavage (642 patients) versus suction alone (363 patients), both of which had no mortalities (Figure 9d) [23, 252, 254].
Figure 9d. Forrest plot for mortality
Two RCTs reported on readmission comparing suction and lavage (160 patients) versus suction alone (160 patients). These studies demonstrated no statistically significant difference in readmission (Figure 9e) [23, 251].
Figure 9e. Forrest plot for readmission
Four RCTs reported on reoperation at any time point comparing suction and lavage (692 patients) versus suction alone (413 patients). This study demonstrated no statistically significant difference in reoperation at any time point (Figure 9f) [23, 251, 252, 254].
Figure 9f. Forrest plot for reoperation (any time point)
Key Question 6 (KQ 6)
In adult and pediatric patients undergoing appendectomy for complicated appendicitis, should routine drain placement versus no routine drain placement be used?
Adults
A total of 6 studies met inclusion criteria for KQ6 in the adult subpopulation composed of all observational studies. Of the observational studies, 1 (17%) was determined to have low risk of bias, 4 had high (67%) and the remaining 1 (17%) had an unclear risk of bias (Table 12).
Table 12. Risk of bias for the observational studies included under KQ6 as assessed by a modified Newcastle Ottawa Scale.
Six cohort studies reported on abscess formation comparing drain placement (583 patients) and no drain placement (1,144 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 10a) [255-260].
Figure 10a. Forrest plot for abscess formation
Three cohort studies reported on drain placement comparing drain placement in initial operation (116 patients) and no drain placement in initial operation (360 patients). This study demonstrated no statistically significant difference in subsequent drain placement (Figure 10b) [257, 259, 260].
Figure 10b. Forrest plot for drain placement
Two cohort studies reported on need for new course of antibiotics comparing drain placement (72 patients) and no drain placement (255 patients). This study demonstrated no statistically significant difference in need for new course of antibiotics (Figure 10c) [257, 260].
Figure 10c. Forrest plot for new course of antibiotics
Two cohort studies reported on readmission comparing drain placement (337 patients) and no drain placement (654 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 10d) [256, 258].
Figure 10d. Forrest plot for readmission
One cohort study reported on reoperation at any time point comparing drain placement (56 patients) and no drain placement (169 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 10e) [259].
Figure 10e. Forrest plot for reoperation (any time point)
Two cohort studies reported on length of stay comparing drain placement (59 patients) and no drain placement (191 patients). These studies did not demonstrate a statistically significant difference in length of stay (Figure 10f) [257, 260].
Figure 10f. Forrest plot for length of stay
Pediatric
A total of 3 studies met inclusion criteria for KQ6 in the pediatric subpopulation composed of all observational studies. Of the observational studies, two (67%) were determined to have a low risk of bias and one was determined to have a high risk of bias (Table 13) [261-263].
Table 13. Risk of bias for the observational studies included under KQ6 as assessed by a modified Newcastle Ottawa Scale.
Three cohort studies reported on abscess formation comparing drain placement (803 patients) and no drain placement (1,530 patients). These studies demonstrated higher risk of abscess formation in patients who had drains placed (RR 1.68, 95% CI 1.32, 2.13) with high heterogeneity (I2= 87) (Figure 11a) [261-263].
Figure 11a. Forrest plot for abscess formation
One cohort study reported on subsequent drain placement comparing initial drain placement (24 patients) and no initial drain placement (109 patients). This study demonstrated no statistically significant difference in need for subsequent drain placement (Figure 11b) [261].
Figure 11b. Forrest plot for drain placement
Two cohort studies reported on readmission comparing drain placement (728 patients) and no drain placement (1,413 patients). This study demonstrated no statistically significant difference in readmission (Figure 11c) [261, 263].
Figure 11c. Forrest plot for readmission
Two cohort studies reported on reoperation at any time point comparing drain placement (728 patients) and no drain placement (1,413 patients). These studies demonstrated higher risk of reoperation at any time point in patients who had drains placed (RR 2.04, 95% CI 1.20, 3.46) with low heterogeneity (I2= 15) (Figure 11d) [261, 263].
Figure 11d. Forrest plot for reoperation (any time point)
Key Question 7 (KQ 7)
Should adult and pediatric patients who undergo appendectomy for complicated appendicitis be given postoperative antibiotics for short term vs. long term?
Adults
A total of 8 studies met inclusion criteria for KQ7 in the adult subpopulation composed of 1 RCTs and 7 observational studies. The one RCTs (100%) had an unclear risk of bias (Table 14a). Of the observational studies, 3 (43%) were determined to have low risk of bias and 4 had high (57%) risk of bias (Table 14b) [96, 264-269].
Table 14a. Risk of bias for the RCTs included under KQ7 as assessed by a Cochrane Risk of Bias tool.
Table 14b. Risk of bias for the observational studies included under KQ7 as assessed by a modified Newcastle Ottawa Scale.
One RCT reported on abscess formation comparing short-term postoperative antibiotics (39 patients) versus long-term postoperative antibiotics (41 patients). This study demonstrated no statistically significant difference in abscess formation. Six cohort studies reported on abscess formation which also showed no statistically significant difference in abscess formation (Figure 12a) [96, 264-269].
Figure 12a. Forrest plot for abscess formation
Two cohort studies reported on risk of contracting Clostridium difficile comparing short-term postoperative antibiotics (235 patients) versus long-term postoperative antibiotics (401 patients). This study demonstrated no statistically significant difference in contracting Clostridium difficile (Figure 12b) [266, 270].
Figure 12b. Forrest plot for contracting Clostridium difficile
One RCT reported on drain placement comparing short-term postoperative antibiotics (39 patients) versus long-term postoperative antibiotics (41 patients). This study demonstrated no statistically significant difference in drain placement (Figure 12c) [268].
Figure 12c. Forrest plot for drain placement
One RCT reported on length of hospital stay comparing short-term postoperative antibiotics (39 patients) versus long-term postoperative antibiotics (41 patients). This study demonstrated shorter length of hospital stays in patients receiving short term hospital stays (SMD -0.90, 95% CI -1.65, -0.15). One cohort study reported on length of hospital stay which showed no statistically significant difference (Figure 12d) [265, 268].
Figure 12d. Forrest plot for length of hospital stay
One RCT reported on need for new course of antibiotics comparing short-term postoperative antibiotics (39 patients) versus long-term postoperative antibiotics (41 patients). This study demonstrated no statistically significant difference in need for new course of antibiotics (Figure 12e) [268].
Figure 12e. Forrest plot for new course of antibiotics
One RCT reported on readmission comparing short-term postoperative antibiotics (39 patients) versus long-term postoperative antibiotics (41 patients). This study demonstrated no statistically significant difference in readmission. Six cohort studies reported on readmission which showed no statistically significant difference (Figure 12f) [96, 264-269].
Figure 12f. Forrest plot for readmission
Two cohort studies reported on reoperation at any time point comparing short-term postoperative antibiotics (231 patients) versus long-term postoperative antibiotics (654 patients). This study demonstrated no statistically significant difference in reoperation at any time point (Figure 12g) [264, 269].
Figure 12g. Forrest plot for reoperation (any time point)
One RCT and one cohort study reported on total complications comparing short-term postoperative antibiotics (114 patients) versus long-term postoperative antibiotics (232 patients). These studies demonstrated no statistically significant difference in total complications (Figure 12h) [268, 269].
Figure 12h. Forrest plot for total complications
Pediatric
A total of 8 studies met inclusion criteria for KQ7 in the pediatric subpopulation composed of 2 RCTs and 6 observational studies. Of the two RCTs, one (50%) was determined to have a low risk of bias and one (50%) had an unclear risk of bias (Table 15a) [273, 276]. Of the observational studies, 2 (33%) were determined to have low risk of bias and 4 had high (67%) risk of bias (Table 15b) [271-272, 274-275, 277-278].
Table 15a. Risk of bias for the RCTs included under KQ7 as assessed by a Cochrane Risk of Bias tool.
Table 15b. Risk of bias for the observational studies included under KQ7 as assessed by a modified Newcastle Ottawa Scale.
Two RCTs reported on abscess formation comparing short-term postoperative antibiotics (82 patients) versus long-term postoperative antibiotics (386 patients). This study demonstrated no statistically significant difference in abscess formation. Six cohort studies reported on abscess formation which also showed no statistically significant difference in abscess formation (Figure 13a) [271-278].
Figure 13a. Forrest plot for abscess formation
One RCT reported on contracting Clostridium difficile comparing short-term postoperative antibiotics (350 patients) versus long-term postoperative antibiotics (336 patients). This study demonstrated no statistically significant difference in abscess formation. One cohort study reported on contracting Clostridium difficile which also showed no statistically significant difference (Figure 13b) [276, 278].
Figure 13b. Forrest plot for contracting Clostridium difficile
Three cohort studies need for drain placement comparing short-term postoperative antibiotics (477 patients) versus long-term postoperative antibiotics (533 patients). These studies demonstrated no statistically significant difference in need for drain placement (Figure 13c) [271, 274, 278].
Figure 13c. Forrest plot for drain placement
Two RCTs reported on length of hospital stay comparing short-term postoperative antibiotics (402 patients) versus long-term postoperative antibiotics (386 patients). These studies demonstrated no statistically significant difference in LOS. Three cohort studies reported on length of hospital stay which also which also did not demonstrate a statistically significant difference (Figure 13d) [271-273, 278].
Figure 13d. Forrest plot for length of hospital stay
One cohort study reported on need for new course of antibiotics comparing short-term postoperative antibiotics (97 patients) versus long-term postoperative antibiotics (82 patients). This study demonstrated no statistically significant difference in need for new course of antibiotics (Figure 13e) [271].
Figure 13e. Forrest plot for new course of antibiotics
One RCT reported on readmission comparing short-term postoperative antibiotics (350 patients) versus long-term postoperative antibiotics (336 patients). This study demonstrated lower risk of readmission with short-term postoperative antibiotics (RR 0.44, 95% CI 0.21, 0.91). Four cohort studies reported on readmission which showed no statistically significant difference (Figure 13f) [271, 274-276, 278].
Figure 13f. Forrest plot for readmission
One RCT reported on reoperation at any time point comparing short-term postoperative antibiotics (350 patients) versus long-term postoperative antibiotics (336 patients). This study demonstrated no statistically significant difference in reoperation at any time point. One cohort study reported no reoperations at any time point for both short-term and long-term postoperative antibiotic time courses (Figure 13g) [271, 276].
Figure 13g. Forrest plot for reoperation (any time point)
Key Question 8 (KQ 8)
In asymptomatic adult and pediatric patients with previous complicated appendicitis treated nonoperatively, should an interval appendectomy be performed versus observation?
Adults
A total of 3 studies met inclusion criteria for KQ8 in the adult subpopulation composed of 1 RCTs and 2 observational studies. The one RCT was determined to have a low risk of bias (100%) (Table 16a) [279]. Of the observational studies, 1 had high (50%) and one had an unclear (23%) risk of bias (Table 16b) [221, 280].
Table 16a. Risk of bias for the RCTs included under KQ8 as assessed by a Cochrane Risk of Bias tool.
Table 16b. Risk of bias for the observational studies included under KQ8 as assessed by a modified Newcastle Ottawa Scale.
One RCT reported on abscess formation comparing interval appendectomy (25 patients) versus observation (27 patients). This study demonstrated no statistically significant difference in abscess formation (Figure 14a) [279].
Figure 14a. Forrest plot for abscess formation
One RCT reported on need for drain placement comparing interval appendectomy (25 patients) versus observation (27 patients). This study demonstrated no statistically significant difference in drain placement (Figure 14b) [279].
Figure 14b. Forrest plot for drain placement
One cohort study reported on length of hospital stay comparing interval appendectomy (9 patients) versus observation (26 patients). This study demonstrated no statistically significant difference in length of hospital stay (Figure 14c) [221].
Figure 14c. Forrest plot for length of hospital stay
One cohort study reported on mortality comparing interval appendectomy (64 patients) versus observation (106 patients). This study demonstrated no statistically significant difference in mortality (Figure 14d) [280].
Figure 14d. Forrest plot for mortality
One RCT reported on neoplasm formation comparing interval appendectomy (25 patients) versus observation (27 patients). This study demonstrated no statistically significant difference in neoplasm formation (Figure 14e) [279].
Figure 14e. Forrest plot for neoplasm formation
One RCT reported on reoperation within 30 days of diagnosis comparing interval appendectomy (25 patients) versus observation (27 patients). This study demonstrated no statistically significant difference in reoperation within 30 days of diagnosis. One cohort study reported on reoperation within 30 days of diagnosis which also showed no statistically significant difference (Figure 14f) [221, 279].
Figure 14f. Forrest plot for reoperation (<30d)
One RCT reported on reoperation between 30 days and 1 year following diagnosis comparing interval appendectomy (25 patients) versus observation (27 patients). This study demonstrated lower odds of reoperation between 30 days and 1 year for patient who received interval appendectomy (OR 0.01, 95% CI 0.00, 0.16) (Figure 14g) [279].
Figure 14g. Forrest plot for reoperation (30d-1y)
Pediatric
A total of 1 study met inclusion criteria for KQ8 in the pediatric subpopulation composed of a single observational study. The one observational study had an unclear (100%) risk of bias (Table 17) [229].
Table 17. Risk of bias for the observational studies included under KQ8 as assessed by a modified Newcastle Ottawa Scale.
One observation study reported on readmission comparing interval appendectomy (16 patients) versus observation (29 patients). This study demonstrated lower odds of readmission for patients who received an interval appendectomy (OR 0.03, 95% CI 0.00, 0.48) (Figure 15) [229].
Figure 15. Forrest plot for readmission
DISCUSSION
Appendicitis is one of the most commonly treated surgical diagnoses worldwide. Despite its high incidence, controversy exists regarding optimal diagnostic and treatment pathways, as well as ideal postoperative management. Our systematic review synthesized the available literature and produced evidence for eight key questions regarding the diagnosis and management of appendicitis in adults and children.
Summary of Evidence
KQ1: CT scan yielded the highest sensitivity (>80%) and specificity (>93%) in the adult population compared to other modalities, although high variability existed within the pediatric population.
KQ2: In adults with uncomplicated appendicitis, when nonoperative management was attempted, consisting of antibiotic treatment rather than appendectomy, there was six times higher odds of readmission and 20 times higher odds of requiring an operation following initial treatment, especially within the first year. On the other hand, for patients where nonoperative treatment with antibiotics was successful, adult patients were able to return to work/school a median of 1.8 days sooner. Pediatric patients with acute uncomplicated appendicitis experienced 38 times higher odds of requiring an operation at any time point, and did not, on average, return to school faster.
KQ3: Adult patients treated nonoperatively with antibiotics for complicated appendicitis had 29 times higher odds of requiring an additional surgery following initial treatment and pediatric patients were twice as likely to form a new abscess.
KQ4: There were no significant differences in outcomes between performing an appendectomy within 12 hours or greater than 12 hours after initial diagnosis of acute uncomplicated appendicitis.
KQ5: There were no significant differences in outcomes of complicated appendicitis between suction only and suction and lavage.
KQ6: In pediatric patients undergoing appendectomy for complicated appendicitis, patients who had drains placed at the time of operation were twice as likely to require reoperation. In adults, no significant differences in outcomes were found between patients who did or did not have drains placed at the time of operation.
KQ7: There were no significant differences in outcomes of complicated appendicitis when short- versus long-term postoperative antibiotics were prescribed. Duration of antibiotics for ‘short-term’ ranged from 1 – 7 days, while ‘long-term’ ranged from 4 to 21 days postoperatively.
KQ8: There were no significant differences in outcomes in adult or pediatric patients with complicated appendicitis who did and did not undergo interval appendectomy after treatment with antibiotics. Rates of malignancy were reported between 3 and 34% across all studies included. Follow-up with patients following diagnosis ranged from 3 to 108 months.
Relationship to Literature
The findings of this systematic review are consistent with existing systematic reviews addressing some of the questions similar to KQ 1-8. Bhangu et al. evaluated the data regarding treating patients with acute appendicitis with antibiotics alone [281]. The rate of failure (25–30%) within 1 year reported by this group matches the data found in this review [281]. A systematic review by Cameron et al. found level 3–4 evidence that appendectomies performed within 24 hours of admission in pediatric patients with acute appendicitis does not appear to be associated with increased perforation rates or other adverse events which is corroborated by the data reported here (in both adult and pediatric patients) [21]. The same study found level 4 evidence that time from admission to appendectomy, as long as it is within 24 hours, does not increase hospital cost or length of stay (LOS) in pediatric patients [21]. The key question in this review compared appendectomy within the first 12 hours and greater than twelve hours and concluded similarly. Finally, this review found duration of postoperative antibiotics equivocal when comparing short-term versus long-term postoperative antibiotics, which is consistent with a previous systematic review conclusion exploring antibiotic duration and incidence of intra-abdominal abscess by van den Boom et al [282].
Limitations
There are a number of limitations with this review. Most of the included studies were found to have a moderate to high degree risk of bias. For those that had a low risk of bias, often a high level of heterogeneity existed within any given key question. The most common weakness within the RCT studies themselves was difficulty with randomization and blinding patients and providers due to the drastically different treatment algorithms. For cohort studies, selection bias was the most cited source of bias. These studies may have suffered from confounding by indication as clinicians may have favored non-operative management in patients that are elderly or comorbid.
Additionally, it is important to acknowledge the inherent limitations within a systematic review. One limitation is failure to capture all relevant studies based on selected search term criteria. This was partially combatted with the use of a librarian and hand searching relevant systematic reviews and guidelines to ensure thoroughness. Finally, many of the temporal variables/definitions (i.e., short-term versus long-term postoperative antibiotics) were created a priori; however, various studies chose different time points by which to anchor their study, which may introduce misclassification bias. This limitation, amongst the others listed, may limit generalizability of results reported in this study.
Relevance to Clinical Practice
Findings from this systematic review explored the debate regarding operative versus nonoperative appendicitis treatment; unfortunately, the answer is likely more nuanced than expected. The rate of antibiotic only treatment failure is high, with many patients progressing to operative management. However, this does not occur in the majority of patients, and for those successfully treated with nonoperative management, patients are able to return to work/school faster. This highlights the importance of informed consent, shared decision making, and both surgeon and patient risk tolerance. What is essential is continued data analysis to inform these conversations, so patients and families are provided with the most up-to-date and reliable information to make their decision. The findings of this review are likely not generalizable to all patient populations afflicted with appendicitis, including pregnant patients (high nonoperative risk rate), elderly/co-morbid patients (high operative risk rate), in cases where administration of general anesthesia alone can be higher risk, immunocompromised patients, those with limited access to care, and others.
CT scan was the imaging modality with the highest sensitivity and specificity in the adult population consistent with current practice at most institutions, while which study to choose for pediatric patients is less clear. Data revealed little difference between performing an appendectomy within or after 12 hours of the diagnosis. While it is common practice to perform an appendectomy shortly after presentation, even overnight, this may not be necessary. However, we did not have an upper limit on performing an appendectomy and cannot comment on longer delays (ie, substantially greater than 12 hours) and the safety of this. In complicated appendicitis, no significant differences were seen between suction versus suction and lavage techniques. Routine drain placement in children, but not adults, may lead to higher odds of reoperation. This requires further investigation, but if true, could challenge the practice of routinely placing drains for perforated appendicitis. Findings showed there is likely no benefit to ‘long-term’ antibiotic use (which ranged from 4 – 21 days postoperatively in the included studies) after appendectomy for complicated appendicitis, in terms of abscess formation. Finally, interval appendectomy should likely be pursued in patients treated initially with antibiotics alone for complicated appendicitis as this study found a sizeable malignancy rate discovered on final pathology with special consideration for the paucity of data concerning malignancy rates for pediatric patients who do not undergo interval appendectomy and patients with a family history of colorectal/other gastrointestinal malignancy.
Future Research Recommendations
High-quality data are essential to continue to inform this discussion. Along the same lines, there is a paucity of quality-of-life measure-based studies, as well as cost-effective analyses that could augment the clinical outcome data presented in this review. The patient perspective on both short- and long-term outcomes would be helpful in studies going forward. These data are required to fully illustrate the risk versus benefit profile in any of the decisions posed in the key questions of this study. Large database studies may provide some additional insight without the inherent challenges of randomized controlled trials [283, 284]. However, these studies have additional sets of limitations which can limit the interpretability and generalizability of conclusions drawn from them.
CONCLUSION
Comparative evidence available from this review revealed that diagnosis with CT scan is superior in adults, but is less clear in children. Antibiotic treatment of appendicitis alone is associated with high failure rates, but is a reasonable option in select patients willing to accept the risk. This study revealed timing of surgery, postoperative antibiotic duration, and suctioning/lavage techniques were equivocal in the investigated outcomes. High-quality data describing quality of life and cost-effectiveness is necessary to characterize superior diagnostic and treatment algorithms.
ACKNOWLEDGEMENTS
The authors would like to acknowledge Holly Ann Burt for her contribution in performing the literature search for all included studies. We would also like to acknowledge Sarah Colón for her help in organizing the guidelines committee meetings and communications.
Funding: No funding was used for this study.
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Appendix
Appendix A: PRISMA Flow Diagrams
Appendix B: Literature Search Strategies
Author Affiliations
Ryan Lamm MD1, Sunjay S. Kumar MD1, Amelia T. Collings MD2,Ivy N. Haskins MD DABOM3, Ahmed Abou-Setta MD PhD4, Nisha Narula MD5, Pramod Nepal MD PhD6, Nader M. Hanna MBBS MSc7, Dimitrios I. Athanasiadis MD8, Stefan Scholz MD9, Joel F. Bradley 3rd MD10, Arianne T. Train DO MPH11, Philip H Pucher MD PhD12, Francisco Quinteros MD13, Bethany Slater MD14
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
- Hiram C. Polk, Jr Department of Surgery, University of Louisville, KY, USA
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE USA
- Centre for Healthcare Innovation, University of Manitoba, Winnipeg, MB, CAN
- Department of Surgery, Rutgers, New Jersey Medical School, Newark, NJ, USA
- Division of Colon and Rectal Surgery, University of Illinois at Chicago, Chicago, IL, USA
- Department of Surgery, Queen’s University, Kingston, ON, Canada
- Department of Surgery, Section of Bariatric and Minimally Invasive Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- Division of General and Thoracic Pediatric Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- Division of General Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Surgery, Penn Medicine Lancaster General Health, Lancaster, PA, USA
- Department of Surgery, Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
- Division of Colorectal Surgery, Advocate Lutheran General Hospital, Park Ridge, IL, USA.
- Division of Pediatric Surgery, University of Chicago Medicine, Chicago, IL
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Guidelines are developed under the auspices of the Society of American Gastrointestinal and Endoscopic Surgeons and its various committees, and approved by the Board of Governors. Each clinical practice guideline has been systematically researched, reviewed and revised by the guidelines committee, and reviewed by an appropriate multidisciplinary team. The recommendations are therefore considered valid at the time of its production based on the data available. Each guideline is scheduled for periodic review to allow incorporation of pertinent new developments in medical research knowledge, and practice.