ArticlePEDIATRICS Volume 140, number 1, July 2017:e20170048

Outcomes of Nonoperative Management of Uncomplicated AppendicitisRichard G. Bachur, MD, Susan C. Lipsett, MD, Michael C. Monuteaux, ScD

abstractBACKGROUND AND OBJECTIVES: Nonoperative management (NOM) of uncomplicated pediatric appendicitis has promise but remains poorly studied. NOM may lead to an increase in resource utilization. Our objective was to investigate the trends in NOM for uncomplicated appendicitis and study the relevant clinical outcomes including subsequent appendectomy, complications, and resource utilization.METHODS: Retrospective analysis of administrative data from 45 US pediatric hospitals. Patients <19 years of age presenting to the emergency department (ED) with appendicitis between 2010 and 2016 were studied. NOM was defined by an ED visit for uncomplicated appendicitis treated with antibiotics and the absence of appendectomy at the index encounter. The main outcomes included trends in NOM among children with uncomplicated appendicitis and frequency of subsequent diagnostic imaging, ED visits, hospitalizations, and appendectomy during 12-month follow-up.RESULTS: 99 001 children with appendicitis were identified, with a median age of 10.9 years. Sixty-six percent were diagnosed with nonperforated appendicitis, of which 4190 (6%) were managed nonoperatively. An increasing number of nonoperative cases were observed over 6 years (absolute difference, +20.4%). During the 12-month follow-up period, NOM patients were more likely to have the following: advanced imaging (+8.9% [95% confidence interval (CI) 7.6% to 10.3%]), ED visits (+11.2% [95% CI 9.3% to 13.2%]), and hospitalizations (+43.7% [95% CI 41.7% to 45.8%]). Among patients managed nonoperatively, 46% had a subsequent appendectomy.CONCLUSIONS: A significant increase in NOM of nonperforated appendicitis was observed over 6 years. Patients with NOM had more subsequent ED visits and hospitalizations compared with those managed operatively at the index visit. A substantial proportion of patients initially managed nonoperatively eventually had an appendectomy.

Division of Emergency Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Dr Bachur conceived and designed the study, analyzed and interpreted the data, and drafted and critically revised the manuscript; Dr Lipsett interpreted the data and drafted and critically revised the manuscript; Dr Monuteaux designed the study, acquired the data, analyzed and interpreted the data, and drafted and critically revised the manuscript; and all authors approved the final manuscript as submitted. Dr Monuteaux had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

DOI: https:// doi. org/ 10. 1542/ peds. 2017- 0048

Accepted for publication Apr 11, 2017

Address correspondence to Richard G. Bachur, MD, Division of Emergency Medicine, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: Richard.bachur@childrens.harvard.edu

To cite: Bachur RG, Lipsett SC, Monuteaux MC. Outcomes of Nonoperative Management of Uncomplicated Appendicitis. Pediatrics. 2017;140(1):e20170048

WhaT’s KnOWn On ThIs subjecT: Nonoperative management (NOM) of uncomplicated appendicitis has proven to be successful in select cases but remains poorly studied. Although success rates may approach 70% in limited prospective studies, premature adoption of NOM may have unintended consequences on subsequent resource utilization.

WhaT ThIs sTuDy aDDs: Among patients with uncomplicated appendicitis, NOM was associated with an increase in subsequent emergency department visits and hospitalizations compared with those managed operatively. During 1-year follow-up, 46% of those managed nonoperatively had a subsequent appendectomy.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

BACHUR et al

Appendectomy has been the standard practice for uncomplicated pediatric appendicitis across the United States. Although considered routine and safe, appendectomy has a recognized risk of complications including postoperative abdominal wall infections, intraperitoneal infections, and bowel obstruction secondary to adhesions.1, 2 For those with complicated appendicitis associated with abscess or phlegmon, initial antibiotic treatment with a delayed interval appendectomy has been shown to be effective, 3, 4 although the need for the subsequent appendectomy has been questioned.5 – 8

Nonoperative management (NOM) of acute appendicitis has been the subject of recent investigations and interest. Although previously practiced in remote locations and during wartime, 9 Coldrey10 in 1959 published the first large series of 471 adult patients treated conservatively with antibiotics alone. The more recent interest has grown from modern adult trials.11 –18 As demonstrated in a 2016 meta-analysis, 19 the 1-year success rate of NOM of acute appendicitis in adults is 63% without increased complications among treatment failures. Pediatric data are limited to a 4 retrospective studies, 20 –23 4 prospective case series, 24 – 27 4 prospective comparative pediatric studies, 28 – 31and 1 randomized trial32 with a reported 1-year success rate of 58% to 79%.

Despite the limited pediatric data, growing interest in medical management and the trend toward shared decision making with informed patients and parents has led to early, and potentially premature, adoption of nonoperative care. Herein, we sought to determine the frequency and outcomes of nonoperative treatment of uncomplicated appendicitis at major US pediatric institutions by using a large administrative database. We

hypothesize that patients managed nonoperatively will have increased rates of subsequent emergency department (ED) visits and hospitalizations as compared with those with primary appendectomy. As a consequence of the option for NOM, we also speculate that the diagnosis of appendicitis will increase in the absence of a histologic standard.

MeThODs

Data source and Design

This is a retrospective study using data obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, ED, ambulatory, and observation encounter–level data from 47 not-for-profit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children’s Hospital Association (Overland Park, KS). Data quality and reliability are assured through a joint effort between the Children’s Hospital Association and participating hospitals. For the purposes of external benchmarking, participating hospitals provide discharge or encounter data including demographics, diagnoses, and procedures. Forty-five of these hospitals also submit resource utilization data (eg, pharmaceuticals, imaging, and laboratory) into PHIS. Data are deidentified at the time of data submission.

We investigated all children <19 years of age with a primary diagnosis of appendicitis in association with an ED encounter from January 1, 2010, through June 30, 2016. An encounter was classified as an appendicitis case if any of the following International Classification of Diseases version 9 or 10 codes were assigned as the primary diagnosis from the ED visit: ICD-9 540.0, 540.1, 540.9, 541, or 542; ICD-10 K35.80, K35.89, K36, or K37. Perforated appendicitis was defined by diagnostic codes:

appendicitis with peritonitis or abscess (540.0, 540.1; K35.2, K35.3). Children with any chronic comorbidities were excluded.33

Data assumptions and Data Integrity

Without clinical information, we made the following assumptions: diagnostic studies ordered for ED patients were performed for the purpose of evaluation of the primary diagnosis. For evaluating the frequency and outcomes of NOM, we classified patients as receiving NOM when 3 conditions were satisfied: (1) the patient had an ED encounter with the primary diagnosis of appendicitis (nonperforated appendicitis diagnostic codes), (2) parenteral antibiotics were administered, and (3) no appendectomy procedure code was associated with the initial visit. To avoid the possibility of including patients with a recent complication of an appendectomy as an index case of newly diagnosed appendicitis, we removed any patients with a previous diagnosis of appendicitis or who had a previous appendectomy (on the basis of available data for a minimum of 12 months before their ED visit).

Data integrity was judged by testing the following conditions: (1) all patients with acute nonperforated appendicitis had an appendectomy procedure or were treated with parenteral antibiotics at the index visit (98.6%), and (2) all patients with perforated appendicitis were administered antibiotics (99.3%). Patients with acute appendicitis that were discharged from the ED without a parenteral dose of antibiotics would be missed from the analysis, although all the previous pediatric studies of NOM included at least a single dose of parental antibiotics before oral antibiotics.20, 21, 23 – 27, 29 – 32

analytic Plan

NOM Trends

The frequency of NOM was displayed over time as a proportion of nonperforated appendicitis cases.

2 by guest on March 22, 2020www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 140, number 1, July 2017

To test for trends of NOM, we estimated a multivariable logistic regression model of nonoperative care with 3-month time blocks as the independent variable. A robust variance estimator was used to accommodate the correlation resulting from the clustering of patients within hospitals.

We compared demographic variables, diagnostic imaging at the index visit, and duration of hospitalization among patients with nonperforated appendicitis managed with primary appendectomy and nonoperative care.

Frequency of the Diagnosis of Appendicitis

To assess the frequency of diagnosis, the number of patients with appendicitis was displayed over time and stratified by hospital utilization of NOM (based on 2016 data). We calculated the proportions of nonperforated cases managed with primary appendectomy, nonperforated cases managed nonoperatively, and cases of appendiceal perforation to identify any trends in diagnostic frequency.

Outcomes of NOM

To investigate relevant outcomes, we reviewed the fraction of patients having 12 months of follow-up available (index visit before July 2015). Five relevant outcomes were assessed among patients managed nonoperatively: (1) subsequent ED visits with a potentially related diagnosis (eg, appendicitis, abdominal pain, intestinal obstruction, vomiting, diarrhea, dehydration, colitis); (2) subsequent hospitalizations related to appendicitis; (3) advanced imaging studies of the abdomen after the index visit; (4) frequency of subsequent appendectomy after discharge from the index visit; (5) proportion of patients that converted from an initial nonperforated appendicitis diagnosis (index visit) to complicated appendicitis with

perforation (subsequent visit). Failure of antibiotics during the initial visit, defined in previous studies as lack of improvement or worsening signs during initial inpatient course, 19, 28 – 32 could not be studied with this data set since the exact time of the appendectomy during the initial hospitalization was not available. However, any patient with appendicitis that was discharged after the index visit (whether from ED or inpatient unit) but returned for appendectomy was considered a failure of NOM. We investigated predictors of having a subsequent appendectomy (among those with nonperforated appendicitis managed nonoperatively) by estimating a model with age, sex, race, initial length of stay (LOS), and total doses of parenteral antibiotics as covariates. Assuming that hospitals with more experience with NOM might have lower rates of perforation or subsequent appendectomy, we tested the correlation of these outcomes with the hospital-level rates of NOM.

General Considerations

All statistical tests were 2-tailed and α was set at .05. All analyses were conducted with the statistical software package Stata 13.1 (StataCorp, College Station, TX). The study was approved by the institutional review board and the administrators of the PHIS database. In accordance with PHIS policies, the identities of the institutions were not reported.

ResulTs

study sample

99 001 children with appendicitis were identified during the study period. Demographics and clinical characteristics are displayed in Table 1. The sample was predominantly male (60%) with a median age of 10.9 years. At the index visit, 65 712 (66%) were diagnosed with nonperforated

appendicitis, and of these, 4190 (6%) were managed nonoperatively (Fig 1). Trends in NOM over the study period are shown in Fig 2. NOM significantly increased over the study period (absolute difference +20.4%, test for linear trend odds ratio (OR) [95% confidence interval (CI)] = 1.13 [95% CI 1.04 to 1.23]).

During the study period, 54 958 children had 12 months of follow-up available and were included in the analysis of 1-year outcomes. There was an overall increase in the number of appendicitis cases as shown in Fig 3, stratified by hospital-level utilization of NOM; hospitals with >40% NOM had the largest increase in the diagnosis of appendicitis (+54.5%). Increases in NOM corresponded to decreases in primary appendectomy (Supplemental Fig 4). The frequencies of specific antibiotics administered during the initial NOM encounter are listed in Supplemental Table 4.

3

Table 1 Study Population (N = 99 001)

Age, y, median (interquartile range)

10.9 (8.1 to 13.8)

Sex (male) 59 818 (60.4)Race White 65 285 (65.9) African American 7467 (7.5) Asian American 2103 (2.1) Other 18 847 (19.0) Missing 5299 (5.4)Ethnicity Latino 34 049 (34.4) Not Latino 56 881 (57.5) Unknown 8071 (8.2)Index visit imaginga

Ultrasound 48 493 (49.0) CT 24 913 (25.2) MRI 768 (0.8)Diagnoses Perforated appendicitis 33 279 (33.6) Nonperforated

appendicitis65 712 (66.4)

Appendectomy at index visit

61 522 (93.6)

No appendectomy at index visit

4190 (6.4)

Values in table represent frequency (%) except where noted.a Restricted to imaging of the abdominal region.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

BACHUR et al

Operative Versus nonoperative Management among children With nonperforated appendicitis

The characteristics and outcomes of children managed with primary appendectomy and nonoperative care are displayed in Table 2. Both

groups have similar age and sex. Median LOS was 1 day for both. Nonoperative patients were more likely at the initial visit to have an ultrasound (+9.0% [95% CI 7.4% to 10.5%]) and computed tomography (CT) (+3.7% [95% CI 2.4 to 5.0])

but less likely to have a MRI (−0.3% [95% CI −0.5 to −0.1]).

During the 12 months after the index visit, nonoperative patients were more likely to have additional advanced imaging (absolute risk difference +8.9% [95% CI 7.6% to 10.3%]). Subsequent ED visits and hospitalizations occurred more frequently for those managed nonoperatively (+11.2% [95% CI 9.3% to 13.2%] and +43.7% [95% CI 41.7% to 45.8%], respectively). Among children managed nonoperatively, 46% had a subsequent appendectomy. The median time to subsequent appendectomy for NOM patients was 1 day (interquartile range 1–4 days); if the analysis is limited to NOM patients admitted to the hospital at the index visit (ie, removing patients that were discharged directly from the ED after parenteral antibiotics, n = 942), the median time to subsequent appendectomy was 52 days (interquartile range 33–94 days). Younger age, having a CT study at the initial visit, and more doses of parenteral antibiotics at the index visit were predictive of subsequent appendectomy (age in years OR 0.93 [95% CI 0.90 to 0.97], CT 3.87 [95% CI 1.91 to 7.86], antibiotic doses 1.58 [95% CI 1.03 to 2.44]), whereas an initial ultrasound at the index visit (OR 1.58 [95% CI 0.34 to 7.47]), male sex (OR 1.00 [95% CI 0.87 to 1.16]), and LOS at the initial visit (OR 0.41 [95% CI 0.16 to 1.08]) were not predictive of subsequent appendectomy. Additionally, rates of subsequent appendectomy or perforation did not correlate with the proportion of patients managed nonoperatively in a hospital-level analysis.

DIscussIOn

In this observational study based on administrative data, medical management of nonperforated appendicitis is increasing at large US

4

FIGuRe 1Study sample of appendicitis cases from 45 hospitals included in the PHIS database from 2010 to 2016.

FIGuRe 2Proportion of cases of appendicitis managed nonoperatively from 2010 to 2016 at 45 US pediatric hospitals.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 140, number 1, July 2017

pediatric hospitals, including nearly a quarter of cases in 2016. Outcomes included subsequent appendectomy in 46% of hospitals and appendiceal perforation in 14%. The short median time to subsequent appendectomy for NOM patients was influenced mostly by patients discharged from the ED after parenteral antibiotics. For those managed nonoperatively, there was a substantial rate of subsequent diagnostic imaging (absolute risk difference +8.9%), ED revisits (+11.2%), and subsequent hospitalization (+43.7%). Potentially as a consequence of the option for nonoperative care, the diagnosis of appendicitis is increasing among hospitals utilizing NOM.

For the last century, urgent appendectomy has been the standard of care for uncomplicated appendicitis because of concern for appendiceal rupture without prompt surgical treatment. Recent progress with the laparoscopic approach has reduced the length of hospitalizations and recovery time.34 –38 Despite the procedure being routine and safe, complications including surgical site infections, intraabdominal infections, and peritoneal adhesions occur in 3% of cases of nonperforated appendicitis.1, 39, 40 NOM of appendicitis is not new, but the surge in interest has grown from the success of antibiotic treatment of complicated appendicitis and other intraabdominal conditions, 41 – 44 the convenience of reliable diagnostic imaging to identify appendicitis and monitor for complications, and the availability of oral broad-spectrum antibiotics. Additionally, the invigorated focus on quality-of-life outcomes and cost has further driven the debate over nonoperative care versus automatic appendectomy.45

Nonoperative treatment of uncomplicated appendicitis in adults was summarized in a 2016 meta-analysis performed by Rollins et al.19 Five studies with 1430 subjects included 727 cases

with medical management. Overall treatment efficacy in the nonoperative group over 1 year of follow-up was 63%, with only 6.4% of patients developing complicated appendicitis. As stated by the authors, who used standard criteria for systematic reviews, each of the studies had “serious” risks of bias with overall “low” quality of evidence. All 5 studies were subject to enrollment bias. Three of the studies required diagnostic imaging for enrollment12, 15, 18 whereas imaging was optional in 2 studies13, 17; the authors acknowledge that the studies that did not require imaging would not properly identify complicated appendicitis or patients with an appendicolith, which are known to be risk factors for failure with nonoperative care.16, 18, 19 Rollins et al19 emphasized the 39% risk reduction for complications (defined by treatment arm) for nonoperative patients without any difference in LOS between the 2 groups. The observation that patients who failed nonoperative treatment had similar rates of complicated appendicitis as those treated with primary appendectomy was considered supportive of an initial nonoperative approach.

As compared with the adult literature, pediatric data are more limited, and a meta-analysis has not been possible because of the heterogeneity of the treatment strategies and study end points. Among the 5 prospective studies, 4 were nonrandomized comparative trials, 28 – 31 and 1 was a randomized trial by Svensson et al.32 The prospective pediatric trials are summarized in Table 3. Each study defined early treatment success differently, with varying duration of parenteral antibiotics and inconsistent determinants of treatment failure prompting appendectomy. For many studies, conversion to appendectomy was indicated by a lack of improvement or persistently elevated inflammatory markers, whereas others continued antibiotics in the absence of signs of peritonitis. One study used repeat ultrasounds to monitor for complications.31 All the comparative studies have significant risk of enrollment bias because of varying diagnostic criteria and treatment selection (often by parent or surgeon choice). The early treatment success of the prospective studies ranged from 58% to 99% for the nonrandomized trials and

5

FIGuRe 3Trends in the number of nonperforated appendicitis cases among PHIS hospitals over the study period. Hospitals are stratified by the proportion of cases with NOM (on the basis of the proportion of NOM cases in 2016).

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

BACHUR et al

92% for the randomized trial; this range of effectiveness likely reflects the variation in patient selection, varying treatment regimens, and the definition of treatment failure. The 1-year appendectomy rates among those studies ranged from 58% to 79%. In the randomized trial, 38% (9/24) of the nonoperative patients had a subsequent appendectomy; interestingly, 5 of the patients presented months after initial successful treatment with recurrent abdominal pain, and all had varying degrees of fibrosis without inflammation. In the current investigation, 46% of children managed with nonoperative care had a subsequent appendectomy; similar to the recently published comparative trial by Caruso et al (the largest in pediatrics), 31 failures occurred relatively early. We also noted that 14% of the current study patients were ultimately diagnosed with perforated appendicitis, which is higher than reported in the limited pediatric comparative studies that show a rate of 2.5% to 2.7%.28, 31 This increase in perforation rate may be related to the differences in patient selection at the onset or treatment, inadequate antibiotic treatment regimens, patient noncompliance, or limitations of measuring this outcome by using administrative data. In support of the possibility of inadequate treatment regimens, only 58% of NOM patients were admitted to the hospital (after parenteral antibiotics in the ED), and only 25% of cases had more than 2 doses of parenteral antibiotics.

The significant heterogeneity of the data for the nonoperative treatment demands well-designed comparative effectiveness trials that have clear diagnostic criteria, definitions for early failure, and a standardized response to recurrent episodes of abdominal pain. Although there are definitions for complications of operative care, each of the previous studies had various definitions for

complications of NOM. We have several concerns related to the observed increase in nonoperative care before more rigorous studies. First, without clear eligibility criteria or a diagnostic standard, we anticipate a less disciplined approach to the diagnosis of appendicitis, leading to the overuse of antibiotics for presumed appendicitis. Currently, ultrasound is the primary imaging modality despite its inferior performance to CT and high rate of equivocal results.46 With the convenient and low-risk option for medical management, clinicians faced with indeterminate ultrasounds may have a tendency to treat with antibiotics rather than admitting

for serial examinations, obtaining a CT, or proceeding with laparoscopy. Although we do not have enough clinical detail to fully understand our findings, we did observe an increase in patients with an appendicitis diagnosis, especially in hospitals utilizing NOM more frequently. As nonoperative treatment becomes more widespread, the consequences of treating a patient with suspected (but unproven) appendicitis with antibiotics would likely be considered more acceptable than a negative appendectomy. Second, although the preliminary (albeit biased) data indicates that 58% to 79% of children with uncomplicated appendicitis might be successfully

6

Table 2 Management and Outcomes of Children With Nonperforated Appendicitis (N = 65 712)

Operative: n = 61 522

Nonoperative: n = 4190 Δ, 95% CI

Index Visit Age, y 11.4 [8.8 to 14.2] 11.4 [8.6 to 14.2] −0.07 (−0.23 to 0.10) Sex (male) 37 657 (61.2) 2564 (61.2) −0.0 (−1.5 to 1.5) Admitted 61 522 (100) 2416 (57.7) −42.3 (−43.8 to −40.8) LOS, d 1.0 [1.0 to 2.0] 1.0 [1.0 to 1.0] Not estimated LOS (among admitted), d 1.0 [1.0 to 2.0] 1.0 [1.0 to 1.0] Not estimated Doses of parenteral

antibiotics2.0 [1.0 to 3.0] 2.0 [1.0 to 2.0] Not estimated

Ultrasound 29 871(48.6) 2411 (57.5) 9.0 (7.4 to 10.5) CT 12 066 (19.6) 976 (23.3) 3.7 (2.4 to 5.0) MRI 477 (0.8) 19 (0.5) −0.3 (−0.5 to −0.1)Follow-up period (12-mo period

after index visit)an = 52 731 n = 2227

Ultrasound 969 (1.8) 120 (5.4) 3.6 (2.6 to 4.5) CT 834 (1.6) 183 (8.2) 6.6 (5.5 to 7.8) MRI 30 (0.06) 5 (0.22) 0.17 (−0.03 to 0.37) No. diagnostic imaging

studies 0 51 143 (97.0) 1961 (88.1) −8.9 (−10.3 to −7.6) 1 1133 (2.2) 154 (6.9) 4.8 (3.7 to 5.8) ≥2 455 (0.9) 112 (5.0) 4.2 (3.3 to 5.1) No. ED visits 0 42 909 (81.4) 1562 (70.1) −11.2 (−13.2 to −9.3) 1 6791 (12.9) 489 (22.0) 9.1 (7.3 to 10.8) ≥2 3031 (5.8) 176 (7.9) 2.2 (1.0 to 3.3) No. hospitalizations 0 49 516 (93.9) 1117 (50.2) −43.7 (−45.8 to −41.7) 1 2721 (5.2) 1036 (46.5) 41.4 (39.3 to 43.4) ≥2 494 (0.9) 74 (3.3) 2.4 (1.6 to 3.1) Subsequent appendectomy NA 1032 (46) NA Time to appendectomy in

daysbNA 1 [1 to 4] NA

New diagnosis of perforation appendicitis

NA 313 (14.0) NA

Values in table represent frequency (percent) or median [interquartile range]. All imaging data are restricted to studies of the abdominal region. NA, not applicable.a Restricted to patients with an index visit on or before July 1, 2015, to allow for a full year of follow-up surveillance.b Calculated as number of days from initial admission date.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 140, number 1, July 2017 7

Tabl

e 3

Sum

mar

y of

Pro

spec

tive

Pedi

atri

c Tr

ials

for

NOM

of U

ncom

plic

ated

App

endi

citis

Year

Stud

yDe

sign

Patie

nt S

ampl

eNo

nope

rativ

e Pr

otoc

olPr

imar

y an

d Se

cond

ary

Outc

omes

Imm

edia

te

Succ

ess

Duri

ng

Initi

al T

reat

men

t W

ith N

OM, %

No a

ppen

dect

omy

at 1

-y fo

llow

-up,

%Se

cond

ary

Outc

omes

No

nope

rativ

e Ve

rsus

Ope

rativ

e Gr

oup

2015

Sven

sson

et a

l32Ra

ndom

ized

con

trol

led

tria

l24

non

oper

ativ

eM

inim

um

48 h

of I

V an

tibio

tic

follo

wed

by

8 d

ora

l an

tibio

tic

Reso

lutio

n of

sym

ptom

s w

ithou

t sig

nific

ant

com

plic

atio

ns; L

OS,

com

plic

atio

ns,

recu

rren

ce w

ithin

1 y

9262

Long

er L

OS (

med

ian

52 v

s 35

h)

Age

5–15

y, <

48 h

of p

ain,

no

nrup

ture

d ap

pend

iciti

s by

ul

tras

ound

or

CT, w

ith o

r w

ithou

t ap

pend

icol

ith

26 o

pera

tive

Low

er c

ost f

or in

itial

inpa

tient

st

ay (

tota

l cos

t sim

ilar

betw

een

grou

ps)

No s

igni

fican

t com

plic

atio

ns in

ei

ther

gro

up20

15Ta

naka

et a

l29No

nran

dom

ized

; car

egiv

er c

hoic

e Ag

e 5–

16 y

with

non

perf

orat

ed

appe

ndic

itis

by u

ltras

ound

or

CT,

with

or

with

out a

ppen

dico

lith

78 n

onop

erat

ive

IV a

ntib

iotic

s un

til C

RP

norm

aliz

ed

and

patie

nt

clin

ical

ly

impr

oved

; no

men

tion

of o

ral

antib

iotic

s

Succ

ess

rate

of

nono

pera

tive

care

dur

ing

initi

al

hosp

italiz

atio

n;

patie

nt s

atis

fact

ion

9979

Sim

ilar

LOS

(6.6

vs

6.5

d)86

ope

rativ

eLo

wer

ove

rall

satis

fact

ion

(4.4

vs

4.7

out o

f 5)

71%

man

aged

with

out

appe

ndec

tom

y w

ith e

xten

ded

follo

w-u

p

2016

Hart

wic

h et

al30

Nonr

ando

miz

ed; c

areg

iver

cho

ice

24 n

onop

erat

ive

Min

imum

of 2

do

ses

of IV

an

tibio

tics,

fo

llow

ed

by 7

d o

ral

antib

iotic

Prog

ress

ion

to

oper

ativ

e th

erap

y,

recu

rren

ce

8871

Low

er o

vera

ll co

st (

$277

1 vs

$4

130)

Age

5–18

y, <

48 h

of p

ain,

with

cl

inic

al d

iagn

osis

of a

cute

un

com

plic

ated

app

endi

citis

(al

l ul

tras

ound

), w

ith o

r w

ithou

t fe

calit

h, b

ut w

ith n

o co

ncer

n fo

r pe

rfor

atio

n or

abs

cess

50 o

pera

tive

Cost

-util

ity a

naly

sis

High

er u

tility

(0.

863–

0.88

4 qu

ality

-adj

uste

d lif

e m

onth

s vs

0.

854–

0.85

6)

2016

Min

neci

et a

l28No

nran

dom

ized

; car

egiv

er c

hoic

e37

non

oper

ativ

eM

inim

um

24 h

of I

V an

tibio

tic;

tota

l 10

d or

al

antib

iotic

30 d

suc

cess

rat

e;

disa

bilit

y da

ys,

mis

sed

scho

ol,

hosp

ital L

OS, q

ualit

y of

life

of p

atie

nt a

nd

pare

nt

9576

Few

er d

isab

ility

day

s (m

edia

n 8

vs

21 d

); re

turn

ed to

sch

ool f

aste

r (3

vs

5 d)

; sim

ilar

qual

ity o

f life

sc

ores

, inc

urre

d lo

nger

LOS

(m

edia

n 37

vs

20 h

)

Age

7–17

y, <

48 h

of p

ain,

WBC

co

unt <

18 0

00/m

m3 ,

nonr

uptu

red

appe

ndic

itis

by u

ltras

ound

or

CT,

no a

ppen

dico

lith

65 o

pera

tive

as

cont

rols

2016

Caru

so e

t al31

Nonr

ando

miz

ed; p

atie

nts

with

co

mpl

icat

ed a

ppen

dici

tis

unde

rwen

t ear

ly s

urge

ry, a

ll th

ose

with

unc

ompl

icat

ed

appe

ndic

itis

star

ted

nono

pera

tive

care

197

nono

pera

tive

(unc

ompl

icat

ed)

Min

imum

72

h o

f IV

antib

iotic

fo

llow

ed

by 5

d o

ral

antib

iotic

Earl

y su

cces

s at

1 w

k,

LOS,

com

plic

atio

ns58

58M

ean

LOS

shor

ter

for

cons

erva

tive

trea

tmen

t: 4.

9 vs

7.9

d

Diag

nosi

s of

app

endi

citis

: PAS

>

4, W

BC >

12 0

00/m

m3 (

>75%

ne

utro

phils

), CR

P >

3 m

g/dL

; ultr

asou

nd p

ositi

ve o

r no

nvis

ualiz

ed a

ppen

dix

165

oper

ativ

e (c

ompl

icat

ed)

CRP,

C-r

eact

ive

prot

ein;

IV, i

ntra

veno

us; P

AS, P

edia

tric

App

endi

citis

Sco

re; W

BC, w

hite

blo

od c

ell.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

BACHUR et al

treated without surgery, we have no knowledge about the cost and anxiety related to subsequent episodes of abdominal pain with associated medical visits, repeat diagnostic imaging, and repeated antibiotic treatments. Finally, without a standardized approach founded in structured prospective studies, we will be unable to optimally advise patients and caregivers on treatment options.

This investigation is limited by the use of administrative data to determine clinical management and outcomes. We relied on assumptions that diagnostic coding has an accurate clinical correlate. Previous investigations on appendicitis outcomes using this data source have been validated with medical record review.47 Additionally, the current study population mimics previous investigations with respect to age and sex distribution of appendicitis cohorts. The large data set allows trends to be observed, but patient-level data would be necessary to accurately determine reasons for specific management and better explain clinical causes of repeat visits, subsequent diagnostic imaging, or delayed appendectomies. Additionally, we acknowledge that the hospitals included in this analysis often serve as referral centers, and we cannot account for imaging or management before arrival at the ED; it is possible that patients had previous treatment

of appendicitis before care at the major pediatric hospital. However, we have no reason to suspect major shifts over the study period in types of referrals or care before transfer. The number of patients transferred to these institutions would generally be small and would not significantly influence the observed rate of subsequent appendectomy or the increase in repeat ED visits, diagnostic imaging, or hospitalizations seen with NOM patients. With regard to nonoperative treatment, early failures during initial hospitalization cannot be accurately distinguished from patients with a primary appendectomy (and potentially could underestimate the use of NOM and NOM failures). Similarly, although not standard practice and not previously described, patients could be theoretically discharged with a plan for a scheduled appendectomy, which would lead to the appearance of failure of conservative management. We assumed that NOM patients discharged and returning for an appendectomy would imply a treatment failure as described in a recently released article by Talan et al.48 Finally, the administrative data only tracks patients presenting to the same institution; therefore, subsequent visits or procedures may be missed, including non-ED ambulatory visits during which additional care may have been provided.

cOnclusIOns

By using administrative data from major pediatric institutions, we observed a significant increase in the number of patients with nonperforated appendicitis treated nonoperatively. Patients with NOM had more repeat ED visits and hospitalizations compared with those managed operatively at the index visit. Forty-six percent of those treated nonoperatively had a subsequent appendectomy within the first year. During the study period, the number of patients being diagnosed with appendicitis appears to be increasing, potentially as a consequence of the option of NOM. These findings have implications for the adoption of nonoperative treatment and should inform future studies. Finally, as this analysis relied on administrative data with assumptions about a clinical correlate, these conclusions will need further validation with large prospective clinical studies.

ReFeRences

1. Markar SR, Blackburn S, Cobb R, et al. Laparoscopic versus open appendectomy for complicated and uncomplicated appendicitis in children. J Gastrointest Surg. 2012;16(10):1993–2004

2. Masoomi H, Mills S, Dolich MO, et al. Comparison of outcomes of laparoscopic versus open appendectomy in children: data from the Nationwide Inpatient Sample (NIS), 2006-2008. World J Surg. 2012;36(3):573–578

3. Duggan EM, Marshall AP, Weaver KL, et al. A systematic review and individual patient data meta-analysis of published randomized clinical trials comparing early versus interval appendectomy for children with

8

abbReVIaTIOns

CI:  confidence intervalCT:  computed tomographyED:  emergency departmentLOS:  length of stayNOM:  nonoperative managementOR:  odds ratioPHIS:  Pediatric Health

Information System

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2017 by the American Academy of Pediatrics

FInancIal DIsclOsuRe: The authors have indicated they have no financial relationships relevant to this article to disclose.

FunDInG: No external funding.

POTenTIal cOnFlIcT OF InTeResT: Dr Bachur holds a patent for biomarkers of appendicitis (US 8535891 B2) and has had research support from Astute Medical, Inc (San Diego, CA); and Drs Lipsett and Monuteaux have indicated they have no potential conflicts of interest to disclose.

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 140, number 1, July 2017

perforated appendicitis. Pediatr Surg Int. 2016;32(7):649–655

4. Simillis C, Symeonides P, Shorthouse AJ, Tekkis PP. A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon). Surgery. 2010;147(6):818–829

5. Svensson JF, Johansson R, Kaiser S, Wester T. Recurrence of acute appendicitis after non-operative treatment of appendiceal abscess in children: a single-centre experience. Pediatr Surg Int. 2014;30(4):413–416

6. Ein SH, Shandling B. Is interval appendectomy necessary after rupture of an appendiceal mass? J Pediatr Surg. 1996;31(6):849–850

7. Puapong D, Lee SL, Haigh PI, Kaminski A, Liu IL, Applebaum H. Routine interval appendectomy in children is not indicated. J Pediatr Surg. 2007;42(9):1500–1503

8. Lee SL, Shekherdimian S, Chiu VY, Sydorak RM. Perforated appendicitis in children: equal access to care eliminates racial and socioeconomic disparities. J Pediatr Surg. 2010;45(6):1203–1207

9. Campbell MR, Johnston SL III, Marshburn T, Kane J, Lugg D. Nonoperative treatment of suspected appendicitis in remote medical care environments: implications for future spaceflight medical care. J Am Coll Surg. 2004;198(5):822–830

10. Coldrey E. Five years of conservative treatment of acute appendicitis. J Int Coll Surg. 1959;32(3):255–261

11. Di Saverio S, Sibilio A, Giorgini E, et al. The NOTA Study (Non Operative Treatment for Acute Appendicitis): prospective study on the efficacy and safety of antibiotics (amoxicillin and clavulanic acid) for treating patients with right lower quadrant abdominal pain and long-term follow-up of conservatively treated suspected appendicitis. Ann Surg. 2014;260(1):109–117

12. Eriksson S, Granström L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg. 1995;82(2):166–169

13. Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg. 2009;96(5):473–481

14. Hansson J, Körner U, Ludwigs K, Johnsson E, Jönsson C, Lundholm K. Antibiotics as first-line therapy for acute appendicitis: evidence for a change in clinical practice. World J Surg. 2012;36(9):2028–2036

15. 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(23):2340–2348

16. Shindoh J, Niwa H, Kawai K, et al. Predictive factors for negative outcomes in initial non-operative management of suspected appendicitis. J Gastrointest Surg. 2010;14(2):309–314

17. 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(6):1033–1037

18. 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(9777):1573–1579

19. Rollins KE, Varadhan KK, Neal KR, Lobo DN. Antibiotics versus appendicectomy for the treatment of uncomplicated acute appendicitis: an updated meta-analysis of randomised controlled trials. World J Surg. 2016;40(10):2305–2318

20. Abeş M, Petik B, Kazil S. Nonoperative treatment of acute appendicitis in children. J Pediatr Surg. 2007;42(8):1439–1442

21. Armstrong J, Merritt N, Jones S, Scott L, Bütter A. Non-operative management of early, acute appendicitis in children: is it safe and effective? J Pediatr Surg. 2014;49(5):782–785

22. Koike Y, Uchida K, Matsushita K, et al. Intraluminal appendiceal fluid is a predictive factor for recurrent

appendicitis after initial successful non-operative management of uncomplicated appendicitis in pediatric patients. J Pediatr Surg. 2014;49(7):1116–1121

23. Steiner Z, Buklan G, Stackievicz R, Gutermacher M, Erez I. A role for conservative antibiotic treatment in early appendicitis in children. J Pediatr Surg. 2015;50(9):1566–1568

24. Gorter RR, van der Lee JH, Cense HA, et al; APAC Study Group. Initial antibiotic treatment for acute simple appendicitis in children is safe: short-term results from a multicenter, prospective cohort study. Surgery. 2015;157(5):916–923

25. Kaneko K, Tsuda M. Ultrasound-based decision making in the treatment of acute appendicitis in children. J Pediatr Surg. 2004;39(9):1316–1320

26. Park HC, Kim MJ, Lee BH. The outcome of antibiotic therapy for uncomplicated appendicitis with diameters ≤10 mm. Int J Surg. 2014;12(9):897–900

27. Paudel GR, Agrawal CS, Regmi R, Agrawal S. Conservative treatment in acute appendicitis. JNMA J Nepal Med Assoc. 2010;50(180):295–299

28. Minneci PC, Mahida JB, Lodwick DL, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis. JAMA Surg. 2016;151(5):408–415

29. Tanaka Y, Uchida H, Kawashima H, et al. Long-term outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr Surg. 2015;50(11):1893–1897

30. Hartwich J, Luks FI, Watson-Smith D, et al. Nonoperative treatment of acute appendicitis in children: a feasibility study. J Pediatr Surg. 2016;51(1):111–116

31. Caruso AM, Pane A, Garau R, et al. Acute appendicitis in children: not only surgical treatment. J Pediatr Surg. 2017;52(3):444–448

32. Svensson JF, Patkova B, Almström M, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015;261(1):67–71

9 by guest on March 22, 2020www.aappublications.org/newsDownloaded from

BACHUR et al

33. Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatr. 2014;14:199

34. Aziz O, Athanasiou T, Tekkis PP, et al. Laparoscopic versus open appendectomy in children: a meta-analysis. Ann Surg. 2006;243(1):17–27

35. Jen HC, Shew SB. Laparoscopic versus open appendectomy in children: outcomes comparison based on a statewide analysis. J Surg Res. 2010;161(1):13–17

36. Li X, Zhang J, Sang L, et al. Laparoscopic versus conventional appendectomy–a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2010;10:129

37. Minutolo V, Licciardello A, Di Stefano B, Arena M, Arena G, Antonacci V. Outcomes and cost analysis of laparoscopic versus open appendectomy for treatment of acute appendicitis: 4-years experience in a district hospital. BMC Surg. 2014;14:14

38. Wang CC, Tu CC, Wang PC, Lin HC, Wei PL. Outcome comparison between laparoscopic and open appendectomy: evidence from a nationwide

population-based study. PLoS One. 2013;8(7):e68662

39. Masoomi H, Nguyen NT, Dolich MO, et al. Comparison of laparoscopic versus open appendectomy for acute nonperforated and perforated appendicitis in the obese population. Am J Surg. 2011;202(6):733–738, discussion 738–739

40. Boomer LA, Cooper JN, Anandalwar S, et al. Delaying appendectomy does not lead to higher rates of surgical site infections: a multi-institutional analysis of children with appendicitis. Ann Surg. 2016;264(1):164–168

41. Chan KW, Lee KH, Mou JW, Cheung ST, Sihoe JD, Tam YH. Evidence-based adjustment of antibiotic in pediatric complicated appendicitis in the era of antibiotic resistance. Pediatr Surg Int. 2010;26(2):157–160

42. Ehlers AP, Talan DA, Moran GJ, Flum DR, Davidson GH. Evidence for an antibiotics-first strategy for uncomplicated appendicitis in adults: a systematic review and gap analysis. J Am Coll Surg. 2016;222(3):309–314

43. McCafferty MH, Roth L, Jorden J. Current management of diverticulitis. Am Surg. 2008;74(11):1041–1049

44. Boermeester MA, Humes DJ, Velmahos GC, Søreide K. Contemporary review

of risk-stratified management in acute uncomplicated and complicated diverticulitis. World J Surg. 2016;40(10):2537–2545

45. Minneci PC, Sulkowski JP, Nacion KM, et al. Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children. J Am Coll Surg. 2014;219(2):272–279

46. Mittal MK, Dayan PS, Macias CG, et al; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Performance of ultrasound in the diagnosis of appendicitis in children in a multicenter cohort. Acad Emerg Med. 2013;20(7):697–702

47. Bachur RG, Levy JA, Callahan MJ, Rangel SJ, Monuteaux MC. Effect of reduction in the use of computed tomography on clinical outcomes of appendicitis. JAMA Pediatr. 2015;169(8):755–760

48. Talan DA, Saltzman DJ, Mower WR, et al. Antibiotics-first versus surgery for appendicitis: a US pilot randomized controlled trial allowing outpatient antibiotic management [published online ahead of print December 11, 2016]. Ann Emerg Med. doi: 10. 1016/ j. annemergmed. 2016. 08. 446

10 by guest on March 22, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2017-0048 originally published online June 2, 2017; 2017;140;Pediatrics 

Richard G. Bachur, Susan C. Lipsett and Michael C. MonuteauxOutcomes of Nonoperative Management of Uncomplicated Appendicitis

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/140/1/e20170048including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/140/1/e20170048#BIBLThis article cites 48 articles, 0 of which you can access for free at:

Subspecialty Collections

http://www.aappublications.org/cgi/collection/surgery_subSurgeryhttp://www.aappublications.org/cgi/collection/abdominal_pain_subAbdominal Painhttp://www.aappublications.org/cgi/collection/gastroenterology_subGastroenterologyfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on March 22, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2017-0048 originally published online June 2, 2017; 2017;140;Pediatrics 

Richard G. Bachur, Susan C. Lipsett and Michael C. MonuteauxOutcomes of Nonoperative Management of Uncomplicated Appendicitis

http://pediatrics.aappublications.org/content/140/1/e20170048located on the World Wide Web at:

The online version of this article, along with updated information and services, is

http://pediatrics.aappublications.org/content/suppl/2017/05/31/peds.2017-0048.DCSupplementalData Supplement at:

1073-0397. ISSN:60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print

the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on March 22, 2020www.aappublications.org/newsDownloaded from