Impact of Delay in Appendectomy on the Outcome of Appendicitis: A Post Hoc Analysis of an EAST Multicenter Study

Abstract

Background:

Association between time-to-appendectomy and clinical outcomes is controversial with conflicting data regarding risk of perforation. The purpose of this study was to explore the associations between in-hospital delay in treatment of simple appendicitis with the incidence of complicated appendicitis discovered at appendectomy.

Methods:

The Eastern Association for the Surgery of Trauma (EAST) Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG) database was queried and patients with acute appendicitis diagnosed on imaging were included. Upgrade was defined as gangrenous or perforated finding at appendectomy. Time intervals from emergency department (ED) triage to appendectomy were recorded in six-hour groups. Upgrade percentage for each group was presented and rates of a composite end point (30-day incidence of surgical site infection, abscess, wound complication, Clavien-Dindo complication, secondary intervention, ED visit, hospital re-admission, and mortality) were compared with Bonferroni correction to determine statistical significance (p = 0.05/9 = 0.005).

Results:

Of 3,004 included subjects, 484 (16%) experienced upgrade at appendectomy. Upgrade rates (%, 95% confidence interval [CI]) were: group 0–6 hours, 17% (95% CI, 14–19); group 6–11 hours, 15% (95% CI, 13–17%); group 12–17 hours, 16% (95% CI, 13–19); group 18–23 hours, 17% (95% CI, 12–23); group 24–29 hours, 30% (95% CI, 20–43); and group 30+ hours, 24% (95% CI, 14–37) (p = 0.014, NS by Bonferroni). Of 484 subjects with upgrade, 200 (41%; 95% CI, 37–46) had a worse composite outcome compared with 518 (21%; CI, 19–22) of 2,520 subjects with no upgrade (p < 0.001). The upgrade group was older (49 ± 17 years vs 39 ± 16 years), had a higher Charlson comorbidity index (CCI; 1.6 ± 1.9 vs 0.7 ± 1.4) and was more likely to have positive smoking history (20% vs 14%), and prior surgery (30% vs 22%; p < 0.001).

Conclusions:

We propose that ≥24-hour delay from ED triage to appendectomy is not associated with increased rate of severity upgrade from simple to complicated appendicitis. When upgrade occurs, it is correlated with older age, higher CCI, smoking history, and prior surgery and is associated with worse clinical outcomes.

Appendectomy is the most common non-elective procedure performed by general surgeons [1] and has been the standard of care treatment for patients presenting with acute appendicitis in the United States since 1886 [2]. Because of the urgency of the diagnosis, several recommendations state that appendectomy should be performed expeditiously after a diagnosis is made, yet data on this are controversial [3 –7]. Extensive research has been conducted on this topic, but there has been no conclusive answer to the question of acceptable in-hospital delay so far.

As soon as a patient is diagnosed with appendicitis, antibiotic agents are usually initiated in the emergency department (ED) as the preparations for surgery are made. The role of antibiotic agents in minimizing the risk of progression from simple to complicated appendicitis remains unclear, but a recent systematic review of 13 studies concluded that the evidence strongly supports pre-operative, broad-spectrum antibiotic agents for patients with acute appendicitis [8].

Two theories exist on the relation between simple and complicated appendicitis. One theory is that complicated appendicitis represents the natural history of untreated simple appendicitis whereas another theory challenges this paradigm and posits that simple and complicated appendicitis are actually two different diseases. Observations supporting the latter theory include complicated appendicitis presenting after a short duration of symptoms and simple appendicitis persisting despite long durations of delay prior to hospital presentation. This alternative model was proposed by Andersson [9] and supported by data from a previous study by our group [10]. The purpose of this study was to explore the associations between in-hospital time-to-appendectomy in simple appendicitis with the incidence of complicated appendicitis discovered at appendectomy.

Methods

This is a post hoc analysis of the Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG) study that collected data prospectively from 28 centers in the United States between January 2017 and June 2018 [10]. The database was queried, and only subjects diagnosed with acute appendicitis on computed tomography (CT) were included in the study. An upgrade in appendicitis category was defined as progression from simple appendicitis to any higher grade diagnosed by the surgeon intra-operatively at appendectomy. The time intervals from ED triage to appendectomy were recorded in six-hour groups. A composite end point for complications was created to include 30-day incidence of: surgical site infection, abscess, wound complication, any Clavien-Dindo complication, any secondary intervention, ED visit, hospital re-admission, and mortality.

Demographic data of the Upgrade and No Upgrade groups were compared, including: age, sex, body mass index (BMI), tobacco use, previous abdominal operations, Charlson comorbidity index (CCI), and duration of symptoms defined as the time from onset of symptoms to presentation to the ED. The American Association for the Surgery of Trauma (AAST) severity grading scale was used to assign a grade using the clinical, imaging, operative, and pathology dimensions. Pathology data including intra-operative microbiologic specimens and the final pathologic diagnosis (normal appendix, acute appendicitis, gangrenous appendicitis, perforated appendicitis, chronic appendicitis, adenocarcinoma, neuroendocrine [carcinoid] tumor, or other) were also compared.

Continuous data are reported as mean ± standard deviation or median (interquartile range) for nonparametric distributions. Comparisons between groups were performed using analysis of the variance (ANOVA) and Pearson χ² test, and 95% confidence intervals (CI) and p values are reported. Upgrade percentage for each group was calculated and rates of the composite end point were compared among the groups using the Bonferroni correction to guard against the increased risk of type 1 statistical errors with multiple comparisons. There were nine comparison groups, so the adjusted α value was calculated to be p = 0.05/9 = 0.005 (Bonferroni correction). Thus, p < 0.005 was considered statistically significant, and all p values were compared with this threshold. Statistical analysis was performed using RStudio Version 1.1.456 and R package table1, plotrix (RStudio, Boston, MA) were used for assisting demographic tables and graphics, respectively.

Results

Among 3,004 subjects included in the study (Table 1), 484 subjects (16%) experienced an upgrade at the time of appendectomy. The upgrade rates (95% CI) were as follows: 17% (95% CI, 14–19) for group 0–6 hours, 15% (95% CI, 13–17) for group 6–11 hours, 16% (95% CI, 13–19) for group 12–17 hours, 17% (95% CI, 12–23) for group 18–23 hours, 30% (95% CI, 20–43) for group 24–29 hours, and 24% (95% CI, 14–37) for group 30+ hours (p = 0.014; Fig. 1). After Bonferroni correction, none of these comparisons were statistically significant.

FIG. 1.

Rate of evolution of appendicitis from grade 1 to any higher grade for each time group with a 95% confidence interval.

Table 1.

Clinical Characteristics

Demographics	All (n = 3,004)
Age (y)	41.6 ± 16.7
Male (%)	1836 (53.7)
BMI (missing = 103)	28.8 ± 6.68
CCI	0.98 ± 1.67
Prior abdominal operations (%)	784 (22.9)
Tobacco (%)
Never	2,267 (66.2)
Former	632 (18.5)
Current	517 (15.1)
Clinical AAST Appendicitis Severity (%)
Grade 1, 2, and 3	2696 (78.8)
Grade 4	179 (5.2)
Grade 5	161 (4.7)

Of the 484 upgrade subjects, 200 (41%; 95% CI, 37–46) had a worse composite outcome compared with 518 subjects (21%; 95% CI, 19–22) of 2,520 with no upgrade (p < 0.001; Table 2). The upgrade group had an older mean age of 49 ± 17 years compared with the mean age of the no upgrade group, which was 39 ± 16 years (p < 0.001). The upgrade group also had a higher CCI of 1.6 ± 1.9 compared with the no upgrade group with CCI of 0.7 ± 1.4 (p < 0.001), and was more likely to have a positive smoking history and positive abdominal surgical history (20% and 30%, respectively) compared with the no upgrade group (14% and 22%, respectively (p < .001; Table 3).

Table 2.

Incidence of Composite End Point and Individual Complications in No Upgrade and Upgrade Groups (%; 95% CI)

	No upgrade (n = 2,520)	Upgrade (n = 484)	Overall (n = 3,004)
Composite end point
Did not occur	2,002 (79.4%; 77.8%–81.0%)	284 (58.7%; 54.1%–63.1%)	2,286 (76.1%; 74.5%–77.6%)
Occurred	518 (20.6%; 19.0%–22.2%)	200 (41.3%; 36.9%–45.9%)	718 (23.9%; 22.4%–25.5%)
Intra-abdominal abscess
Did not occur	2,453 (97.3%; 96.6%–97.9%)	435 (89.9%; 86.8%–92.3%)	2,888 (96.1%; 95.4%–96.8%)
Occurred	67 (2.7%; 2.1%–3.4%)	49 (10.1%; 7.7%–13.2%)	116 (3.9%; 3.2%–4.6%)
Wound complication
Did not occur	2,493 (98.9%; 98.4%–99.3%)	468 (96.7%; 94.6%–98.0%)	2,961 (98.6%; 98.1%–98.9%)
Occurred	27 (1.1%; 0.7%–1.6%)	16 (3.3%; 2.0%–5.4%)	43 (1.4%; 1.1%–1.9%)
Clavien-Dindo complication
Did not occur	2,213 (87.8%; 86.5%–89.1%)	324 (66.9%; 62.5%–71.1%)	2,537 (84.5%; 83.1%–85.7%)
Occurred	307 (12.2%; 10.9%–13.5%)	160 (33.1%; 28.9%–37.5%)	467 (15.5%; 14.3%–16.9%)
Secondary intervention
Did not occur	2,457 (97.5%; 96.8%–98.1%)	435 (89.9%; 86.8%–92.3%)	2,892 (96.3%; 95.5%–96.9%)
Occurred	63 (2.5%; 1.9%–3.2%)	49 (10.1%; 7.7%–13.2%)	112 (3.7%; 3.1%–4.5%)
ED visit
Did not occur	2,212 (87.8%; 86.4%–89.0%)	407 (84.1%; 80.5%–87.2%)	2,619 (87.2%; 85.9%–88.3%)
Occurred	308 (12.2%; 11.0%–13.6%)	77 (15.9%; 12.8%–19.5%)	385 (12.8%; 11.7%–14.1%)
Hospital re-admission
Did not occur	2,412 (95.7%; 94.8%–96.5%)	439 (90.7%; 87.7%–93.1%)	2,851 (94.9%; 94.0%–95.7%)
Occurred	108 (4.3%; 3.5%–5.2%)	45 (9.3%; 6.9%–12.3%)	153 (5.1%; 4.3%–6.0%)
Mortality
Did not occur	2,510 (99.6%; 99.2%–99.8%)	478 (98.8%; 97.2%–99.5%)	2,988 (99.5%; 99.1%–99.7%)
Occurred	10 (0.4%; 0.2%–0.8%)	6 (1.2%; 0.5%–2.8%)	16 (0.5%; 0.3%–0.9%)

CI = confidence interval; ED = emergency department.

Table 3.

Demographics of the No Upgrade and Upgrade Groups with a 95% Confidence Interval

	No upgrade (n = 2,520)	Upgrade (n = 484)	Overall (n = 3,004)
Age	39.1 (38.5–39.7)	49.4 (47.9–50.9)	40.7 (40.1–41.3)
Male	1,353 (53.7%; 51.7%–55.6%)	264 (54.5%; 50.0%–59.0%)	1,617 (53.8%; 52.0%–55.6%)
BMI	28.7 (28.5–29.0)	29.6 (29.0–30.3)	28.9 (28.6–29.1)
CCI	0.75 (0.69–0.80)	1.59 (1.42–1.76)	0.88 (0.83–0.94)
Prior abdominal surgery	543 (21.4%; 20–23.2)	143 (29.5%; 25.6–33.9)	686 (22.8%; 21.4–24.4)
Tobacco use
Never	1,711 (67.9%; 66.0%–69.7%)	288 (59.5%; 55.0%–63.9%)	1,999 (66.5%; 64.8%–68.2%)
Former	458 (18.2%; 16.7%–19.7%)	98 (20.2%; 16.8%–24.2%)	556 (18.5%; 17.1%–20.0%)
Current	346 (13.7%; 12.4%–15.1%)	97 (20.0%; 16.6%–23.9%)	443 (14.7%; 13.5%–16.1%)

BMI = body mass index; CCI = Charlson comorbidity index.

Discussion

This aim of this study was to investigate the possible association between in-hospital time-to-appendectomy and the incidence of severity upgrade of appendicitis from simple to complicated and to explore possible correlations between patient demographics and clinical outcomes. Our results show that increased delay from ED triage and appendectomy is not associated with increased rates of upgrade from simple to complicated appendicitis, however, in-hospital delay of 24 hours or more displayed a non-significant trend toward a higher grade of appendicitis discovered at operation compared to imaging.

Our findings support previously published studies on the acceptable duration of delay. A single-center retrospective study of 309 patients with acute appendicitis undergoing appendectomy reported no differences in upgrade of appendicitis severity from acute to complicated among time groups 0–12 hours and 12–24 hours, however, that study did not look at rates of progression for delays >24 hours, so its findings are only partially comparable to ours [12]. One recently published meta-analysis of 11 non-randomized studies that examined 8,858 patients with acute appendicitis revealed that a delay of 12 to 24 hours after admission did not increase the risk of complicated appendicitis (odds ratio [OR] 0.97, p = 0.75) [13]. Another two meta-analyses also reported no higher risk of complicated appendicitis when appendectomy was delayed for up to 24 hours after ED presentation. However, patients with a 24- to 48-hour delay had double the risk of complicated appendicitis, and those with >48-hour delay had more than seven times the risk [14,15]. Our study is different in several ways. We enrolled a large number of subjects over a relatively short period of time in the modern era of laparoscopy using CT to confirm the initial diagnosis of simple appendicitis pre-operatively. We used a standardized, validated severity grading schema (AAST) [16,17], used standardized definitions for complications (National Cancer Institute Common Terminology Criteria for Adverse Events v.3), and created a composite end point of important patient-centered complications occurring up to 30 days after operation.

Other investigators have arrived at conflicting conclusions. A prospective multicenter study of 1,827 subjects conducted in 11 hospitals across Switzerland between 2003 and 2006 concluded that a delay of >12 hours is associated with increased rates of perforation compared to a delay of <12 hours (30% to 23%, respectively) [18]. However, unlike our patient cohort, not all enrolled subjects underwent pre-operative CT imaging to confirm the diagnosis. Therefore, it is unclear how many subjects in that Swiss study already had perforated appendicitis upon arrival to the hospital. The American College of Surgeons National Surgical Quality Improvement Project (NSQIP) dataset was used to analyze 69,926 patients undergoing appendectomy between 2007 and 2012. That study reported that in-hospital delays of <24 hours and 24–48 hours did not increase the risk of complications, whereas delay of >48 hours was associated with a two-fold increase in the risk of complications [19]. Because of the small number of subjects with >30-hour delay, we could not continue to subdivide them into six-hour intervals, so we could not test the association between delay >48 hours with increased appendicitis grade at operation.

The common thread in all these discrepant research investigations is that none can prove causality, only associations. To truly prove that a delay in appendectomy is the reason for disease progression from simple to complicated appendicitis, one would need to enroll patients presenting with unambiguously simple acute appendicitis and randomize them to appendectomy occurring at varying intervals of in-hospital delay, from <6 hours to >48 hours. Such a trial is unlikely to be performed because of ethical concerns secondary to a lack of individual and community equipoise and hospital resource considerations. Thus, the highest quality evidence at this time remains observational data collected in a prospective manner with contemporaneous controls and accounting for all known confounders.

Association between demographics and outcome of appendicitis

The rate of occurrence of the composite endpoint was twice as high in the upgrade group compared to the no upgrade group. However, it should also be noted that the upgrade group was substantially older, on average by 10 years, than the no upgrade group. Additionally, the upgrade group had an average CCI that was double that of the no upgrade group and were more likely to have a positive smoking history and prior abdominal operations. Similar findings with regards to both age and CCI were reported by Busch et al. [18] in their multicenter Swiss study: patients aged >65 years and CCI >0 had increased rates of perforation compared with patients aged <65 and CCI = 0 [18]. These confounding factors may explain the increased rate of complications in the upgrade group.

In recent years, the dominance of immediate appendectomy of acute appendicitis has been challenged and high-profile publications have been used to justify antibiotic treatment alone for simple appendicitis [20]. Although it is true that non-perforated acute appendicitis is no longer considered a surgical emergency, same admission appendectomy is still the dominant treatment offered in the United States [10]. Our study has implications for surgeons and hospital administrators alike.

In the past, rates of perforated appendicitis were considered an indicator of quality of care. It was believed that performing appendectomy earlier in the disease course would result in decreased rates of perforated appendicitis and improved patient outcomes. We did not find evidence of such an association. Similarly, previous generations of surgeons accepted (and even encouraged) high rates of negative appendectomies, thinking that aggressively operating on all patients with possible simple acute appendicitis would result in decreased rates of perforated appendicitis. We cannot comment on this, because our rate of negative appendectomy was low (2%), likely because of the high rate of pre-operative CT imaging.

Appendectomies may be performed electively by surgeons sporadically covering general surgery call or acute care surgeons specializing in emergency general surgery. To continue to treat acute appendicitis as a “surgical emergency” or even “surgical urgency” may affect the surgeon negatively as well as other providers and patients. For example, if a surgeon interrupts a busy day of elective operations to perform an “emergency” appendectomy, the other patients will be delayed or rescheduled and may not receive optimal care. A surgeon taking a call at home may feel obligated to drive to the hospital to perform an emergency appendectomy in the middle of the night, thus requiring mobilization of the anesthesiologist and operating room nursing staff. A surgeon performing an overnight appendectomy at a busy hospital may delay other patients who require emergency surgical care and also contribute to sleep deprivation of not only the surgeon, but affiliated staff. Our results suggest, but do not prove, that it may be acceptable to defer appendectomy up to 24 hours after presentation to the ED for simple acute appendicitis until it is logistically more straightforward. However, the benefit of delaying appendectomy should necessarily be weighed against the detriment of prolonging hospitalization for an operation for which most patients are discharged home within 24 hours of surgery.

Limitations

We acknowledge several limitations to this study. First, this study used data from a multicenter study that was purely observational in study design. Therefore, the clinical end points included in our composite outcome were dependent on follow-up clinical encounters and subjects were not contacted routinely by study teams for research follow-up. If patients suffering complications were more or less likely to have follow-up clinical encounters, this may have led to selection bias when assessing the 30-day outcomes included in our composite outcome. Second, as mentioned above, the observational design of the original study limits us to describing associations without drawing any conclusions about causality. The strengths of our study include the use of data from a set that included a large sample size and a diverse population. The dataset included patients from 28 different sites from all regions of the United States, urban and rural, academic and community, large and small hospitals. This broad representation improves the generalizability of our findings.

This study contributes to the existing literature by asserting the absence of an association between an in-hospital delay of ≥24 hours in performing appendectomy and the increase in AAST severity grade of appendicitis from acute (imaging diagnosis) to complicated (intra-operative diagnosis). Additionally, we provide supporting evidence of the impact of age, CCI, smoking history, and history of abdominal surgeries on the outcome of appendicitis.

Conclusions

In-hospital delay of ≥24 hours from ED triage to appendectomy in patients presenting with simple acute appendicitis is not associated with increased rates of complicated appendicitis encountered at surgery. Upgrade in appendicitis severity grade is associated with older age, higher number of medical comorbidities, smoking, and prior abdominal surgery. Patients who experience upgrade have worse clinical outcomes.

Footnotes

Acknowledgments

We are grateful to the following colleagues from the EAST Appendicitis Research Group for their contribution to data collection in the original EAST MUSTANG Database. Without their work, this article would not have been possible:

Baystate Medical Center: Reginald Alouidor and Kailyn Kwong Hing

Beaumont Hospital: Victoria Sharp and Thomas Serena

Boston Medical Center: George Kasotakis and Sean Perez

Carilion Clinic: Stacie L. Allmond and Bruce Long

Cooper University Hospital: Nadine Barth and Janika San Roman

Denver Health: Ryan A. Lawless and Alexis L. Cralley

Emory University: Rondi Gelbard and Crystal Szczepanski

Essentia Health: Steven Eyer and Kaitlyn Proulx

Geisinger Medical Center: Jeffrey Wild and Katelyn A. Young

Inova Fairfax: Erik J. Teicher and Elena Lita

Intermountain Medical Center: David Morris and Laura Juarez

Loma Linda University: Richard D. Catalano and David Turay

Marshfield Clinic: Daniel C. Cullinane and Jennifer C. Roberts

Massachusetts General Hospital: Haytham M.A. Kaafarani and Ahmed I. Eid

Mayo Clinic: Mohamed Ray-Zack and Tala Kana'an

Medical City Plano: Victor Portillo and Morgan Collom

Medical College of Wisconsin: Chris Dodgion and Savo Bou Zein Eddine

North Shore Medical Center: Maryam B. Tabrizi and Ahmed Elsayed Mohammed Elsharkawy

Ryder Trauma Center: D. Dante Yeh and Georgia Vasileiou

Ohio State University Wexner Medical Center: David C. Evans and Daniel E. Vazquez

St. Vincent Hospital Indianapolis: Jonathan Saxe and Lewis Jacobson

Oregon Health Sciences University: Brandon Behrens and Martin Schreiber

University of Arizona, Tucson: Bellal Joseph and Muhammad Zeeshan

University of California, Irvine: Jeffry Nahmias and Beatrice Sun

University of Florida, Jacksonville: Marie Crandall and Jennifer Mull

University of Maryland: Jason D. Pasley and Lindsay O'Meara

University of Southern California: Ali Fuat Kann Gok and Jocelyn To

Walter Reed National Military Medical Center: Carlos Rodriguez and Matthew Bradley

Funding Information

No external funding was received for this study.

Author Disclosure Statement

No competing financial interests exist.

References

Pittman-Waller

, Myers

, Stewart

, et al. Appendicitis: Why so complicated? Analysis of 5755 consecutive appendectomies. Am Surg, 2000; 66:548–554.

Fitz

. Perforating inflammation of the vermiform appendix: With special reference to its early diagnosis and treatment. Am J Med Sci, 1886; 92:321–346.

Fisher

. Acute appendicitis. Curr Probl Surg, 2001; 7:267–272.

Liu

, McFadden

. Acute abdomen and appendix. Surgery, 1997; 2:1246–1261.

Prystowsky

, Birkhahn

, Gaeta

, et al. Appendicitis. Curr Probl Surg, 2005; 42:688–742.

Garfield

, Fahim

, Shirjeel

, et al. Diagnostic pathways and delays on route to operative intervention in acute appendicitis. Am Surg, 2004; 70:1010–1013.

Fahim

, Broderisk-Villa

, Burchette

, et al. A comparison between presentation time and delay in surgery in simple and advanced appendicitis. J Ayub Med Coll Abbottabad, 2005; 17:37–39.

Daskalakis

, Juhlin

, and Påhlman

. The use of pre- or postoperative antibiotics in surgery for appendicitis: A systematic review. Scand J Surg, 2014; 103:4–120.

Andersson

. The natural history and traditional management of appendicitis revisited: Spontaneous resolution and predominance of prehospital perforations imply that a correct diagnosis is more important than an early diagnosis. World J Surg, 2007; 31:86–92.

10.

Yeh

, Eid

, Young

, et al. Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG), an EAST Multicenter Study. Ann Surg [Epub ahead of print; DOI: 10.1097/SLA.0000000000003661].

11.

Giraudo

, Baracchi

, Pellegrino

, et al. Prompt or delayed Appendectomy? Influence of timing of surgery for acute appendicitis. Surg Today, 2013; 43:392–396.

12.

Abou-Nukta

, Bakhos

, Arroyo

, et al. Effects of delaying appendectomy for acute appendicitis for 12 to 24 hours. Arch Surg, 2006; 141:504–507.

13.

United Kingdom National Surgical Research

Collaborative

, Bhangu

. Safety of short, in-hospital delays before surgery for acute appendicitis: Multicentre cohort study, systematic review, and meta-analysis. Ann Surg, 2014; 259:849–903.

14.

Van Dijk

, Van Dijk

, Dijkgraaf

, et al. Meta-analysis of in-hospital delay before surgery as a risk factor for complications in patients with acute appendicitis. Br J Surg, 2018; 105:933–945.

15.

, Xu

, Hu

, et al. Effect of delay to operation on outcomes in patients with acute appendicitis: A systematic review and meta-analysis. J Gastrointest Surg, 2019; 23:210–223.

16.

Tominaga

, Staudenmayer

, Shafi

, et al. The American Association for the Surgery of Trauma grading scale for 16 emergency general surgery conditions: Disease-specific criteria characterizing anatomic severity grading. J Trauma Acute Care Surg, 2016; 81:593–602.

17.

Vasileiou

, Ray-Zack

, Zielinski

, et al. Validation of the American Association for the Surgery of Trauma Emergency General Surgery Score for Acute Appendicitis—an EAST Multicenter Study. J Trauma Acute Care Surg, 2019; 87:134–139.

18.

Busch

, Gutzwiller

, Aellig

, et al. In-hospital delay increases the risk of perforation in adults with appendicitis. World J Surg, 2011; 35:1626–1633.

19.

Fair

, John

, Janssen

, et al. The impact of operative timing on outcomes of appendicitis: A National Surgical Quality Improvement Project Analysis. Am J Surg, 2015; 209:498–502.

20.

Salminen

, Paajanen

, Rautio

, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: The APPAC Randomized Clinical Trial. JAMA, 2015; 313:2340–2348.