Monitoring Complications of Medically Managed

Acute Appendicitis
ANAAR SILETZ, M.D., PH.D.,* JONATHAN GROTTS, M.A.,† CATHERINE LEWIS, M.D.,* ARETI TILLOU, M.D.,*
ALI CHEAITO, M.D.,* HENRY CRYER, M.D., PH.D.*

From the Departments of *Surgery and †Medicine Statistics Core, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, California

Nonoperative management of acute appendicitis is becoming widespread, but recurrence and the
potential for a complicated course are important concerns. An admission report-based institutional
database was created to monitor appendicitis treatment outcomes. Complications and complexity of
surgery were recorded based on manual chart review. A cohort of patients spanning one year was
analyzed. Initial management was operative in 181 (82%) and nonoperative in 39 (18%) cases. There
were no differences in demographics, BMI, or Alvarado score. One operative patient and 17 non-
operative patients required additional treatment for recurrence/nonresolution (0.6% vs 44%, P <
0.00001). Twenty-eight (15%) operative patients and 17 (44%) nonoperative patients had complica-
tions (P 5 0.0003). Thirty-six (19.9%) operations in the operative group and 8 (53.3%) in the non-
operative group were classified as complex (P 5 0.007). Hospital stay was longer in the nonoperative
group (one vs two days, P 5 0.005). Two incidental malignancies in the operative group and one in
the nonoperative group were identified. These results are consistent with prior studies showing that
recurrence/nonresolution is common after nonoperative management. For patients with recurrence/
nonresolution, surgery may be more complex.

A CUTE APPENDICITIS IS one of the most common

indications for urgent abdominal surgery, with
300,000 annual cases in the United States and a lifetime
risk of 7 to 9 per cent.1 Changes in the management
of acute appendicitis have widespread implications for
public health in addition to the impact on individual
patients. Surgical appendectomy has been the mainstay
of treatment for more than 120 years.2 Recent trials
have suggested nonoperative management with anti-
biotics only as a safe alternative in select cases. 3–10
However, a rigorous meta-analysis failed to show
noninferiority of nonoperative compared with opera-
tive management and noted limitations in generaliz-
ability of prior studies.11 Nonoperative management is
associated with a 25 per cent risk of requiring eventual
operative management,12 and there is a concern that
failed medical management delays definitive treatment
and might lead to a more complicated clinical course.13
By contrast, up to 75 per cent of patients treated non-
operatively may be able to avoid surgery altogether,
along with the accompanying incisional pain, recu-
peration time, and risk of operative complications.14
A large trial is presently underway to evaluate the
Address correspondence to Anaar Siletz, M.D., Ph.D., De-
partment of surgery, David Geffen School of Medicine, University
of California Los Angeles, 757 Westwood Plaza, Los Angeles, CA
90095. E-mail: aeastoak-siletz@mednet.ucla.edu.
balance of these factors on patient quality of life.15 At
our institution, nonoperative management is being
cautiously adopted, but concerns persist regarding
appropriate patient selection and risks outside the
structure of a clinical trial. A long-term database was
created to monitor all patients treated for acute ap-
pendicitis at two large hospitals within the University
of California Los Angeles Health medical system
allowing in-depth review of the clinical course for each
patient. The initial results from one year of accumu-
lated data were analyzed to address concerns regarding
nonoperative management, including complexity of sur-
gery after recurrence, time course of recurrence, and
patient factors associated with the success of non-
operative management.
Methods
All patients presenting to Ronald Reagan or Santa
Monica University of California Los Angeles Medical
Centers between August 2016 to August 2017, with a
diagnosis code for acute appendicitis (corresponding
to ICD10 codes K35.2, K35.3, K35.80, and K35.89)
were identified retrospectively by monthly admission
reports. Data for each patient were manually reviewed
and entered into the institutional database by a trained
research resident. Exclusion criteria include age <18
years; no admission diagnosis of appendicitis (i.e.,

1684
No. 10 MEDICALLY MANAGED ACUTE APPENDICITIS
erroneous coding or presentation not consistent with
appendicitis per the surgical team); treatment decisions
outside the scope of the study (i.e. cases inappro-
priate for a choice between operative or nonoperative
management, such as those with delayed diagnosis
with abscess or phlegmon); no treatment received;
and duplicate and incomplete records precluding
analysis.
Patients were assigned to operative or nonoperative
groups based on initial treatment for appendicitis.
Nonoperative management consisted of initial intra-
venous antibiotics and nil per os status followed in
most cases by transition to oral antibiotics after clinical
improvement. The choice and duration of antibiotics
was per the discretion of the treating surgeon and was
not protocolized. Complications and recurrence were
identified from discharge summaries for index and
subsequent related admissions and outpatient follow-
up notes. Final diagnosis was obtained from pathology
reports for patients who had surgery, and from dis-
charge diagnosis, confirmed in concordance with
imaging, for patients who did not have surgery. A
category of “any complication” was defined as ileus,
perforation, need for drain placement, recurrence/
nonresolution, or need for operation after initial man-
agement, superficial or deep wound infection, venous
thromboembolism, pneumonia, urinary tract infection,
Clostridium difficile infection, and others. Recurrence/
nonresolution was included as a single variable to
capture the spectrum of clinical courses including clear
nonresolution during a single hospital admission, symptom
improvement and discharge followed by re-presentation,
and complete resolution of symptoms followed by remote
re-presentation. Time to recurrence/nonresolution was
defined as time between initial management and de-
termination that additional or alternative treatment was
necessary. Complex operations were defined as those
requiring conversion to an open from a laparoscopic
approach, extensive lysis of adhesions, operative com-
plications, including enterotomies and anesthetic reac-
tions, extended operation such as ileocecectomy, drain
placement, and more than routine complexity noted by
the surgeon in the operative report. Operations lacking
these features were considered routine. Statistical anal-
ysis was performed in the R Statistical Computing En-
vironment (R Core Team, Vienna, Austria). Fisher’s
exact test was used to test for significance for discrete
variables and Wilcoxon rank sum test was used for
continuous data. Variables that were significant on
univariate analysis were chosen for a multivariable
logistic regression model identifying risk factors for
any complication. The logistic regression model was
summarized using odds ratios (OR) and confidence
intervals (CI) with a likelihood ratio test used to test the
significance of the predictors. A P-value below 0.05
? Siletz et al. 1685
was considered statistically significant and all hypoth-
esis tests were two-sided.
Results
Three hundred and fifty-one patients with an ad-
mission diagnosis of acute appendicitis were identified
during the study period, of which 131 were excluded
(Fig. 1). Patients initially managed with surgery (op-
erative group, n 4 181) were compared with patients
initially managed with antibiotics only (nonoperative
group, n 4 39). There were no significant differences
between groups in age, gender, race, BMI, or admis-
sion vital signs (Table 1). Patients initially managed
with surgery had a higher median admission white
blood cell count than nonoperative group patients (me-
dian 13.0, IQR 10.7–15.4 vs 12.1, IQR 9.1–13.9, P 4
0.014) and were more likely to have imaging concerning
for appendicolith (36.% vs 17.9%, P 4 0.051). There
were no significant differences between groups in find-
ings concerning for severe inflammation or perforation
(fat stranding, free or loculated fluid, and concern for
perforation).
There were no significant differences between
groups in final diagnosis (Table 2). Sixteen of 39
(41%) nonoperative patients required eventual sur-
gical management with one recurrence treated non-
operatively; and one patient in the operative group
required an additional procedure after appendec-
tomy for a periappendiceal abscess (0.6%). Non-
operative patients were more likely to experience
any complication (43.6% vs 15.0%, P 4 0.0003),
and for those patients who went on to require surgery,
to have operations classified as complex (53.3% vs
20.2%, P 4 0.007). Hospital length of stay was
longer in the nonoperative group (median two days,
IQR 1–3, vs median one day, IQR 1–2, P 4 0.005).
Two malignancies were identified in the operative
group (1.1%), and one in the nonoperative group who
failed to respond to antibiotics (2.6%), representing
an overall incidence of 1.4 per cent. A majority of
complications were recurrence and perforation, and
the resulting need for operation and drain placement,
respectively (Fig. 2). In the nonoperative group,
clinical courses eventually requiring operative man-
agement ranged from clear nonresolution of symptoms
followed by operative management during the same
admission, to symptom improvement followed by re-
presentation soon after discharge, to clear recurrence
after a long asymptomatic period (Fig. 3). Two patients
were managed operatively within one day of the de-
cision to attempt nonoperative management and 11
patients underwent operations in two days or less of
initial management decisions. The longest recorded in-
terval between episodes of appendicitis in this cohort was
1686 THE AMERICAN SURGEON
FIG. 1. Patient inclusion and exclusion.
474 days. A multivariable logistic regression model
identified longer symptom duration (OR 1.18, 95% CI
1.02–1.39, P 4 0.023) and initial nonoperative man-
agement (OR 5.30, CI 2.06–13.87, P 4 0.001) as factors
significantly associated with the development of any
complication (Table 3).
In nonoperative patients, there was a trend toward
longer duration of symptoms before presentation in
patients, who went on to require surgery compared
with those who were successfully managed (median
2.0 days, IQR 1.0–3.0 vs 1.0 days, IQR 0.6–2.0 days,
P 4 0.107) (Table 4). A nonsignificant higher pro-
portion of patients with nonresolution/recurrence had
concern for appendicolith on admission CT scan (31.2%
vs 8.7%, P 4 0.081). No significant differences were
detected in intravenous or oral antibiotics administered
to patients with nonresolution/recurrence compared with
those who were successfully managed.
October 2018 Vol. 84
Discussion
This study found that patients treated with non-
operative management have higher complication rates
and more complex surgeries than those initially man-
aged with surgery. The eventual appendectomy rate
after nonoperative management of 41 per cent is com-
parable with previous reports of 25 to 40 per cent.14, 16
By contrast, a large population-based study with seven
years of follow-up found a rate of nonoperative treat-
ment failure of 5.9 per cent and a recurrence rate of 4.4
per cent.17 The population-based study had a low rate of
nonoperative management (1.5%), which may reflect
a more conservative selection of patients for this novel
management strategy in a statewide database compared
with academic medical centers.
Synthesis of data on nonoperative management for
appendicitis has been limited by inconsistent definitions
No. 10 MEDICALLY MANAGED ACUTE APPENDICITIS ? Siletz et al. 1687

TABLE 1. Presenting Characteristics of Operative and Nonoperative Groups

Variable Operative (n 4 181) Nonoperative (n 4 39) P Value
Age, median (IQR) 33 (26–50) 33 (23.5–43) 0.327
Gender 0.774
Male 90 (49.7%) 18 (46.2%)
Female 90 (49.7%) 21 (53.8%)
Race 0.129
Asian 17 (9.4%) 8 (20.5%)
Black or African American 4 (2.2%) 3 (7.7%)
Pacific Islander 2 (1.1%) 0 (0%)
White 129 (71.3%) 22 (56.4%)
Unknown 29 (16.0%) 6 (15.4%)
BMI, median (IQR) 25 (22.2–27.9) 23.4 (21.4–25.9) 0.155
Presenting symptoms and signs, median (IQR)
Symptom duration 1 (1–2) 1 (1–3) 0.155
Systolic blood pressure 123 (113–137) 124 (111.5–130) 0.181
Diastolic blood pressure 74 (63–82) 76 (65–81) 0.997
Respiratory rate 18 (16–18) 18 (16–19) 0.1
Temperature 36.8 (36.6–37.1) 36.8 (36.6–37.2) 0.547
White blood cell count 13 (10.7–15.4) 12.1 (9.1–13.9) 0.014
Modified Alvarado Score 5 (4–6) 5 (4–6) 0.617
Imaging characteristics
Fat stranding 142 (79.3%) 28 (71.8%) 0.331
Free fluid 68 (37.8%) 12 (30.8%) 0.059
Loculated fluid/suspected abscess 1 (0.6%) 0 (0%) 1
Concern for perforation in report 16 (8.9%) 4 (10.3%) 0.871
Concern for appendicolith in report 66 (36.5%) 7 (17.9%) 0.051

TABLE 2. Outcomes for Operative and Nonoperative Groups

Variable Operative (n 4 181) Nonoperative (n 4 39) P Value
Final diagnosis, pathology 0.236
Uncomplicated acute appendicitis 144 (80.9%) 31 (79.5%)
Perforated acute appendicitis 26 (14.6%) 4 (10.3%)
Chronic appendicitis 2 (1.1%) 0 (0%)
Malignancy 3 (1.7%) 1 (2.6%)
Others 3 (1.7%) 3 (7.7%)
Any complication 28 (15.0%) 17 (43.6%) <0.001
Nonresolution/recurrence of appendicitis 1 (0.6%) 17 (43.6%) <0.001
Total operative time, median (IQR) 52 (37.8–74) 62.5 (45.8–75.5) 0.114
Complexity of surgery 0.007
Routine 142 (79.8%) 7 (46.7%)
Complex 36 (20.2%) 8 (53.3%)
Length of hospital stay, median (IQR) 1 (1–2) 2 (1–3) 0.005

of complications across studies,11, 18 with complica-
tion rates favoring nonoperative management in some
studies and operative management in others.6, 13 In
this study we defined “any complication” to cap-
ture factors substantially altering patient care, such
as drain placement, in addition to common post-
operative complications. The inclusion of nonresolution/
recurrence in the category of any complication in this
study, although clinically meaningful, predisposes to
the finding of a higher complication rate in the non-
operative group. The ongoing CODA trial of nonoperative
vs operative management of acute appendicitis avoids
assigning relative importance to different complications
by focusing on patient quality of life as the primary
outcome.15
One concern with nonoperative treatment is that
delaying definitive treatment will result in a more
complex operation should surgery ultimately be re-
quired. This study found that surgeries after failed
nonoperative treatment did tend to be more complex
than appendectomies performed as initial treatment.
These findings parallel those of a recent meta-analysis
which found that although only 4 per cent of all pa-
tients treated with antibiotics had complicated appen-
dicitis compared with 10 per cent of those treated with
surgery, in patients in whom antibiotics failed, 46 per
cent had complicated appendicitis.18 Of note, there
was no difference in operative times between groups
in our study despite the difference in complexity, likely
because of variation in anesthesia times. Another concern
1688 THE AMERICAN SURGEON October 2018 Vol. 84

FIG. 2. Complications as a percentage of total complications

for operative and nonoperative groups. There were 49 total com-
plications for operative group (28 patients) and 43 total compli-
cations for the nonoperative group (17 patients). Patients were
considered to have an instance of “any complication,” if they ex-
perienced one or more of the following: Ileus, perforation, need
for percutaneous drain, need for operation not planned as initial
management, superficial or deep wound infection, venous throm-
boembolism, pneumonia, urinary tract infection, C. difficile in-
fection, or other complications. Four other complications occurred
in the operative group: Enterotomy (1), laryngospasm after extu-
bation (1); anaphylaxis on induction (1); and urinary retention (1).
There were no instances in either group of pneumonia, urinary tract
infection, or C. difficile infection.
FIG. 3. Time to nonresolution/recurrence. The median time to
regarding nonoperative management is the potential for nonresolution/recurrence requiring additional treatment was two
missing an appendiceal malignancy. This study found days, IQR 1 to 13 days.
a rate of malignancy in final pathology comparable with
other reports.18
Elevated C-reactive protein and appendicolith have TABLE 3. Multivariable Logistic Regression Model Identifying
Risk Factors for Any Complication. Included Variables Were
been previously identified as risk factors for failure of Significant on Univariate Analysis of Patients with Any
nonoperative management.19, 20 In this study, appen- Complication vs No Complication
dicolith and duration of symptoms before presentation Variable OR (95% CI) P Value
seemed to be risk factors for failure of nonoperative
Symptom duration 1.18 (1.02–1.39) 0.023
management, but the analysis was limited by sample Female gender 0.5 (0.21–1.15) 0.104
size. Variation in antibiotic regimens prescribed in both Treatment 0.001
successful and unsuccessful cases of nonoperative man- Operative Reference
agement indicates a need for further study and guide- Nonoperative 5.3 (2.06–13.87)
lines for optimal regimens. Data on outpatient adherence
to prescribed antibiotics were generally not available.
Other study limitations include retrospective data provide granular detail over the long term without the
collection, reliance on record completeness, small risk of coding errors.
sample size, and inclusion of only one year of data.
Conclusions
Recurrences treated at outside hospitals were also not
known. The major strength of the study is the manual Initial results from a longitudinal database indicate
extraction of data, allowing detailed information to be that recurrence/nonresolution is common after non-
collected for each patient. Reliance on codes in admin- operative management. For those patients who go on to
istrative databases can introduce error through inaccurate require operation, surgery may become more complex.
coding.21 Over time, this database has the potential to Patients with a short duration of symptoms before
No. 10 MEDICALLY MANAGED ACUTE APPENDICITIS ? Siletz et al. 1689

TABLE 4. Characteristics of Nonoperative Patients Requiring Surgery vs Successfully Managed Nonoperative Patients. Two
Patients in the Successfully Managed Group Completed the Full Prescribed Course of Antibiotics Intravenously. Seven of the
Patients Who Required Surgery Were Prescribed Oral Antibiotics Before the Decision was Made to Proceed to Surgery
Variable Successfully Managed (n 4 23) Required Surgery (n 4 16) P Value
Age, median (IQR) 32 (23.5–38) 39 (23.8–48.2) 0.346
Gender 0.342
Male 9 (39.1%) 9 (56.2%)
Female 14 (60.9%) 7 (43.8%)
Race 0.492
Asian 4 (17.4%) 4 (25%)
Black or African American 3 (13%) 0 (0%)
Pacific Islander 0 (0%) 0 (0%)
White 13 (56.5%) 9 (56.2%)
Unknown 3 (13%) 3 (18.7%)
BMI, median (IQR) 21.8 (20.9–25) 23.8 (22.5–26) 0.225
Presenting symptoms/signs,
median (IQR)
Symptom duration 1 (0.6–2) 2 (1–3) 0.107
Systolic blood pressure 115 (109.5–127.5) 128 (114–132.5) 0.166
Diastolic blood pressure 74 (63–82) 76 (65–81) 0.997
Respiratory rate 18 (18–18) 18 (16–20) 0.514
Temperature 36.7 (36.6–36.9) 37 (36.6–37.4) 0.136
White blood cell count 12.6 (9.3–13.9) 10.9 (9.1–13.5) 0.511
Modified alvarado score 5 (4–5.5) 6 (4–6) 0.189
Imaging characteristics
Fat stranding 14 (60.9%) 14 (87.5%) 0.111
Free fluid 6 (26.1%) 6 (37.5%) 0.368
Loculated fluid/suspected abscess 0 (0%) 0 (0%) 1
Concern for perforation in report 1 (4.3%) 3 (18.8%) 0.286
Concern for appendicolith in report 2 (8.7%) 5 (31.2%) 0.081
IV Antibiotics 0.356
Cefoxitin 13 (57%) 5 (31%)
Cefoxitin/Metronidazole 1 (4%) 0 (0%)
Ceftriaxone, then Ciprofloxacin/ 1 (4%) 1 (6%)
Metronidazole
Ceftriaxone/Metronidazole 4 (17%) 5 (31%)
Ciprofloxacin 1 (4%) 0 (0%)
Ciprofloxacin/Metronidazole 1 (4%) 0 (0%)
Ertapenem 0 (0%) 3 (19%)
Piperacillin/Tazobactam 2 (9%) 2 (13%)
PO antibiotics 0.099
Amoxicillin/Clavulanate 14 (61%) 5 (31%)
Ampicillin/Sulbactam 0 (0%) 1 (6%)
Cephalexin/Metronidazole 1 (4%) 0 (0%)
Ciprofloxacin 2 (9%) 0 (0%)
Ciprofloxacin/Metronidazole 4 (17%) 1 (6%)
IV antibiotics only 2 (9%) 9 (56%)
PO, per os.

presentation and without appendicoliths seem more
likely to be treated successfully with nonoperative
management.
REFERENCES
1. Addiss DG, Shaffer N, Fowler BS, et al. The epidemiology
of appendicitis and appendectomy in the United States. Am J
Epidemiol 1990;132:910–25.
2. Flum DR. Clinical practice. Acute appendicitis–appendectomy
or the “antibiotics first” strategy. N Engl J Med 2015;372:1937–43.
3. Talan DA, Saltzman DJ, Mower WR, et al. Antibiotics-first
versus surgery for appendicitis: a US pilot randomized controlled
trial allowing outpatient antibiotic management. Ann Emerg Med
2017;70:1–11.e9.
4. Eriksson S, Granstrom L. Randomized controlled trial of
appendicectomy versus antibiotic therapy for acute appendicitis.
Br J Surg 1995;82:166–9.
5. Hansson J, Korner U, Khorram-Manesh A, et al. Randomized
clinical trial of antibiotic therapy versus appendicectomy as pri-
mary treatment of acute appendicitis in unselected patients. Br J
Surg 2009;96:473–81.
6. Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs
appendectomy for treatment of uncomplicated acute appendicitis:
the APPAC randomized clinical trial. JAMA 2015;313:2340–8.
7. Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus
antibiotic treatment in acute appendicitis. a prospective multicenter
randomized controlled trial. World J Surg 2006;30:1033–7.
8. Turhan AN, Kapan S, Kutukcu E, et al. Comparison of op-
erative and non operative management of acute appendicitis. Ulus
Travma Acil Cerrahi Derg 2009;15:459–62.
1690 THE AMERICAN SURGEON
9. Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic
acid versus appendicectomy for treatment of acute uncomplicated
appendicitis: an open-label, non-inferiority, randomised controlled
trial. Lancet 2011;377:1573–9.
10. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of
antibiotics compared with appendicectomy for treatment of un-
complicated acute appendicitis: meta-analysis of randomised
controlled trials. Br Med J 2012;344:e2156.
11. Wilms IM, de Hoog DE, de Visser DC, et al. Appendectomy
versus antibiotic treatment for acute appendicitis. Cochrane Da-
tabase Syst Rev 2011;CD008359.
12. Talan DA, Moran GJ, Saltzman DJ. Nonoperative man-
agement of appendicitis: avoiding hospitalization and surgery. J
Am Coll Surg 2017;224:994.
13. Khalil M, Rhee P, Jokar TO, et al. Antibiotics for appen-
dicitis! Not so fast. J Trauma Acute Care Surg 2016;80:923–32.
14. Ehlers AP, Talan DA, Moran GJ, et al. Evidence for an
antibiotics-first strategy for uncomplicated appendicitis in adults:
a systematic review and gap analysis. J Am Coll Surg 2016;222:
309–14.
15. Davidson GH, Flum DR, Talan DA, et al. Comparison of
outcomes of antibiotic drugs and appendectomy (CODA) trial:
October 2018 Vol. 84
a protocol for the pragmatic randomised study of appendicitis
treatment. BMJ Open 2017;7:e016117.
16. Mason RJ, Moazzez A, Sohn H, et al. Meta-analysis of
randomized trials comparing antibiotic therapy with appendec-
tomy for acute uncomplicated (no abscess or phlegmon) appen-
dicitis. Surg Infect 2012;13:74–84.
17. McCutcheon BA, Chang DC, Marcus LP, et al. Long-term
outcomes of patients with nonsurgically managed uncomplicated
appendicitis. J Am Coll Surg 2014;218:905–13.
18. Findlay JM, Kafsi JE, Hammer C, et al. Nonoperative man-
agement of appendicitis in adults: a systematic review and meta-analysis
of randomized controlled trials. J Am Coll Surg 2016;223:814–24.e2.
19. Shindoh J, Niwa H, Kawai K, et al. Predictive factors for
negative outcomes in initial non-operative management of sus-
pected appendicitis. J Gastrointest Surg 2010;4:309–14.
20. Tanaka Y, Uchida H, Kawashima H, et al. Long-term out-
comes of operative versus nonoperative treatment for uncompli-
cated appendicitis. J Pediatr Surg 2015;50:1893–7.
21. Coward S, Kareemi H, Clement F, et al. Incidence of ap-
pendicitis over time: a comparative analysis of an administrative
healthcare database and a pathology-proven appendicitis registry.
PLoS One 2016;11:e0165161.
Reproduced with permission of copyright owner. Further reproduction
prohibited without permission.