Early Appendectomy Shortens Antibiotic Course and Hospital Stay in Children with Early Perforated Appendicitis

Early Appendectomy Shortens Antibiotic Course and Hospital Stay in Children with Early Perforated Appendicitis Accepted Manuscript Early Appendectomy Shortens Antibiotic Course and Hospital Stay in Ch[.]

Early Appendectomy Shortens Antibiotic Course and Hospital Stay in Children with

Early Perforated Appendicitis

Hsin-Yu Tsai, MD, Hsun-Chin Chao, MD, Wan-Ju Yu, MD

DOI: 10.1016/j.pedneo.2016.09.001

To appear in: Pediatrics & Neonatology

Received Date: 23 June 2016

Revised Date: 10 August 2016

Accepted Date: 20 September 2016

Please cite this article as: Tsai H-Y, Chao H-C, Yu W-J, Early Appendectomy Shortens Antibiotic Course

and Hospital Stay in Children with Early Perforated Appendicitis, Pediatrics and Neonatology (2017), doi:

Background: The optimal management of perforated appendicitis in the pediatric population

has been controversial This study aimed to compare the therapeutic efficacy between

conservative treatment (CS) and early appendectomy (EA) in pediatric perforated appendicitis,

and to determine whether surgical intervention is an optimal treatment modality for early

perforated appendicitis in children

Methods: Patients treated between January 2012 and April 2014, aged 0-18 years with an

imaging-based diagnosis of perforated appendicitis were retrospectively reviewed Patients

were classified into non-abscess and abscess groups by image findings, and were further

categorized into CS and EA groups by treatment modality Early perforated appendicitis was

defined as having duration of symptoms (DOS) ≤ 7 days, C-reactive protein (CRP) level ≤

200mg/L, maximum abscess diameter ≤ 5 cm, and absence of general peritonitis and unstable

vital signs The clinical features and therapeutic outcomes were compared between CS and

EA in each group

Results: A total of 326 patients had confirmed appendicitis, including 116 patients with image

diagnosis of perforation The CS group had significantly longer DOS, larger abscess and

higher serum CRP levels at presentation (all p < 0.05) Patients in the EA group had shorter

antibiotic course and length of hospitalization (LOH), and a lower rate of antibiotic escalation

than those in CS group (p values < 0.001, < 0.001, and < 0.05 respectively) In patients with

early perforated appendicitis, the CS and EA groups showed no difference in baseline disease

severity Patients in the EA group also had a shorter antibiotic course and length of

hospitalization (LOH) than those in the CS group (p values < 0.001, and < 0.001

respectively)

Conclusion: Compared to conservative treatment, early appendectomy shortens the antibiotic

course and hospital stay in pediatric early perforated appendicitis, even in the presence of

small abscesses

Key Words: perforated appendicitis; conservative treatment; appendectomy; children; length

of stay

Acute appendicitis is one of the most common surgical abdominal diseases in the pediatric

population Appendicitis accounts for 1%-8% of the diagnosis in children visiting the

emergency department for acute abdominal pain.1,2 The perforation rate is high (up to 51%) in

pediatric appendicitis, especially in younger children.3 The image diagnosis of perforated

appendicitis could be accurately attained with abdominal ultrasonography or computed

tomography.4,5

Perforated appendicitis may result in complications leading to high medical expenses

Treatment for this condition is still controversial, and there is no consensus in the

management of pediatric perforated appendicitis Traditionally, conservative treatment (CS)

with interval appendectomy is preferred over early appendectomy (EA) in reducing

postoperative complications.6–10 However, recent opinions support the role of EA in

non-abscess patients.11,12

The current study presented a two-year experience (2012-2014) of pediatric perforated

appendicitis in a tertiary center in Taiwan The aim of this study is to compare the therapeutic

efficacy between CS and EA in children with early perforated appendicitis The demographic

information, laboratory values, therapeutic efficacy, complications, hospital duration, and

readmission rate were statistically analyzed

Between January 2012 and April 2014, patients from 0-18 years old, treated at Chang Gung

Children’s Medical Center with a diagnosis of acute appendicitis, were reviewed

retrospectively Only those patients with acute appendicitis confirmed through

ultrasonography (US), computed tomography (CT), or histology were included The US was

performed by a group of experienced pediatric gastroenterologists, and CT was interpreted by

experienced radiologists Presence of abscess, phlegmon, free ascites distant from the

appendix, extraluminal air or appendicolith, or appendiceal wall defect defines suspicious

perforation Patients having uncertain diagnosis, incomplete data, underlying systemic illness,

or secondary appendicitis were excluded Those with suspicious perforated appendicitis on

US and/or CT were enrolled for analysis

In our institution, the pediatrician routinely consulted the pediatric surgeon regarding the

option of surgical intervention in those patients with clinical presentations and imaging

findings consistent with appendicitis Considering our government’s case payment regulation

for pediatric patients receiving operation for acute appendicitis, the pediatric surgeon

performed the operation in cases of non-perforated, generalized peritonitis, or advanced

appendicitis with clinically ill-appearing or critical complications (intractable abdominal pain,

unstable vital signs, bowel obstruction), or cases with mark elevation of serum C-reactive

protein (CRP) (> 200 mg/L) There was no consensus of performing surgical intervention in

those patients with early perforated appendicitis Those patients with initial successful

non-operative treatment were assigned follow-up at outpatient department for the subsequent

interval appendectomy

Children with suspected perforated appendicitis were divided into two groups - abscess

(ABS) and non-abscess (NA) groups - according to the presence or absence of appendiceal

abscess or phlegmon Patients in each group were further classified based on two treatment

modalities: CS (ABS-CS and NA-CS) and EA (ABS-EA and NA-EA) Patients who received

antibiotic treatment, with or without CT-guided drainage, were classified as CS EA was

defined as appendectomy performed within 24 hours after acute appendicitis was diagnosed

Laparoscopic appendectomy was the standard operative method in our institution Those

patients with persistent high-spiking fever, or advanced conditions with critical complications

(intractable abdominal pain, unstable hemodynamics, bowel obstruction) underwent operation

beyond 24 hours of admission were excluded from the study

Data collection

Data collected from the medical records included demographic information, duration of

symptoms (DOS) before hospitalization, laboratory values (peripheral white blood cell (WBC)

counts, neutrophil counts, band-cell ratio, and serum CRP level), image findings, use of

parenteral nutrition, timing of appendectomy, operative results, the categories of initial

intravenous (IV) antibiotics, need of escalation, duration of IV and total (IV plus per-oral)

antibiotic treatment, length of hospitalization (LOH), and early readmission (within one

month after discharge from the hospital) The etiologies of early readmission included

adhesion ileus, residual abscess, recurrent appendicitis, and wound complications

Protocol of Antibiotic treatment

In our institution, the routine first-line IV antibiotics for acute appendicitis were ampicillin or

a first-generation cephalosporin, plus gentamicin and metronidazole Second-line parenteral

antibiotic regimens contained a third-generation cephalosporin Imipenem or

piperacillin-tazobactam was used for advanced conditions In EA group, the use of

postoperative antibiotic was determined by intraoperative findings and postoperative

complications Antibiotic escalation would be considered in patients who have no

improvement of clinical symptoms (peritoneal sign, abdominal pain, fever, or vomiting) or

laboratory parameters (WBC count, band-cell ratio, or CRP level) in 3 days of initial

antibiotic treatment After discharge, amoxicillin-clavulanate was the routinely prescribed oral

antibiotics

Definition of the early perforation group and subgrouping by serum CRP level

This group was defined as patients having DOS ≤ 7 days, serum CRP level ≤ 200mg/L, and

size of abscess or phlegmon ≤ 5cm Those patients with generalized peritonitis or severe

systemic manifestations (cardiopulmonary dysfunction, renal failure, septic shock, etc.) were

excluded in this group Serum CRP cutoff level was determined based on the observation that

all severe complications occurred in patients with a CRP level > 200mg/L; besides, only a

small proportion of patient with a CRP level >200mg/L received EA In our institution,

patients with abscesses > 5 cm were routinely evaluated for computed tomography-guided

drainage by radiologists; thus these patients were excluded from the early perforation group

For further analysis, patients in early perforation group were further divided into Group 1

(CRP ≤ 100 mg/L) and Group 2 (100 mg/L < CRP ≤ 200 mg/L) Children in each subgroup

with abscess formation were evaluated separately

Statistical analysis

Statistical analysis was performed with IBM SPSS Statistics version 22 Continuous variables

were analyzed with the Student’s t test Categorical data were analyzed with a Chi-square test

or Fisher’s exact test A p-value of < 0.05 was considered to be significant All tests were

two-tailed

Ethical considerations

The study was approved at our institution by the ethics committee of Chang Gung

Memorial Hospital with a waiver of informed consent (CGMH 103-1842B) However, all

patient records/information was anonymized and de-identified prior to analysis

Patient inclusion and grouping

During the 2-year study period, a total of 455 children were diagnosed with acute appendicitis

129 patients not fulfilling the inclusion criteria were excluded Of the remaining 326 patients

having either imaging or histological confirmation of acute appendicitis, 122 patients were

identified as having perforated appendicitis, using image diagnosis: 45 (36.9%) had

abdominal US alone, 37 (30.3%) had only CT and 40 (32.8%) patients had both US and CT

examinations 81 (66.4%) patients were identified as having appendiceal abscess or phlegmon

(ABS group), and 41 (33.6%) were not (NA group)

A total of 80 children received conservative management: 64 in the ABS group (ABS-CS)

and 16 in the NA group (NA-CS) EA was performed in 17 patients in ABS group (ABS-EA)

and 25 patients in NA group (NA-EA); most of these patients received laparoscopic

appendectomy, except one patient in ABS-EA group and two in NA-EA group The mean

latency from admission to operating room was 10.3 hours Intractable abdominal pain (36/42)

and bilious vomiting suggesting bowel obstruction (13/42) were two indications for EA Four

patients in NA-EA and two in ABS-EA groups were found to have non-perforated appendix

intra-operatively, and were therefore excluded from the analysis (Figure 1) Of the four

patients with non-perforated appendix in NA-EA group, all did not have gross appendiceal

perforation, but gangrenous change was observed in one of them Of the two patients in

ABS-EA group, they had gangrenous appendix but no gross appendiceal perforation

Patient characteristics

In 116 patients with perforated appendicitis, there were 68 male (58.6%) and 48 female

(41.4%) patients The mean age was 9.9 ± 3.9 years The mean duration of abdominal pain

before hospitalization was 3.4 ± 1.9 days In both ABS and NA groups, patients who were

treated conservatively had a significantly longer duration of abdominal pain (all p < 0.05)

Analysis of laboratory values revealed the mean peripheral WBC count was 16,690/µL,

with neutrophil count 13,966/µL, and band-cell ratio of 2.2% The mean serum CRP level was

significantly higher in patients with CS than with EA (186.8 mg/L vs 108.5 mg/L, p < 0.001)

32 patients (88.9%) in the EA group had a serum CRP level of ≤ 200 mg/L, while in the CS

group, 32 patients (40.0%) had a serum CRP level of > 200mg/L (Figure 2) Compared to EA

group, a significantly higher rate of patients with serum CRP level of > 200 mg/L was found

in CS group (p = 0.002, Chi-square analysis) In patients with a serum CRP level ≤ 100 mg/L,

55.6% (20/36) underwent EA However, in the group with a level between 100 mg/L and 200

mg/L, the EA rate declined to 27.3% (12/44) (Table 1) There was statistical difference of EA

rates between patients with serum CRP level ≤ 100 and patients with serum CRP level of

100-200 mg/L (p = 0.013, Chi-square analysis)

36 patients (45.0%) in the CS group and 28 patients (77.8%) in the EA group received

first-line IV antibiotics There were no surgical complications in the EA group The mean

duration of IV antibiotics was much longer in the CS group (14.7 ± 6.5 days vs 5.8 ± 2.1 days,

p < 0.001) Similarly, the total antibiotic duration was significantly longer for CS group (25.8

± 12.0 days vs 11.4 ± 5.4 days, p < 0.001) Escalation of IV antibiotics was required in 35

patients (43.8%) treated conservatively, but only in 2 patients (5.5%) in the EA groups (p <

0.001)

Overall, 9 of the 116 (7.8%) children received parenteral nutrition because they were

unable to eat for more than one week They all belonged to ABS-CS group The mean

duration of parenteral nutrition was 12.3 ± 5.9 days (range, 7.3-19.7 days) One patient

encountered catheter-related bacteremia Ten patients (15.6%) in the ABS-CS group were

treated with CT-guided drainage Two patients had life-threatening complications (one septic

shock and another pneumoperitoneum) requiring critical care in the intensive care unit (ICU)

All of these patients had an initial serum CRP level greater than 200mg/L

The mean length of hospitalization (LOH) was significantly longer in the CS group than in

the EA group (15.8 ± 6.9 days vs 6.4 ± 2.2 days, p < 0.001) Within one month, a total of 17

patients (14.7%) had readmission for complications associated with previous appendicitis

The readmission rate was similar in all modalities Ten patients (12.5%) treated conservatively

had recurrent appendicitis and eventually 59 (73.8%) received interval appendectomy (Table

1)

The early perforation group

When analyzing the early perforation group, the mean DOS, WBC count, and serum CRP

level were not significantly different between the CS and EA groups, in both Group 1 and 2,

indicating similar baseline severity in patients treated with the two modalities The mean IV

antibiotic duration and LOH were significantly longer in CS Group 1 and 2 (all p < 0.01) In

addition, the antibiotic escalation rate was significantly higher in CS Group 1 (42.7% vs 5%,

p = 0.02) There were also trends toward higher antibiotic escalation rates in CS Group 2, and

higher early readmission rates in both CS Group 1 and 2, although these were not statistically

significant (Table 2)

Patients with abscess formation fulfilling the early perforation criteria

Patients with abscess formation were evaluated separately; EA was performed in 43.8% (7/16)

patients in Group 1 and 17.6% (3/17) in Group 2 There was no significant difference in

parameters assessing baseline disease severity (i.e., DOS, WBC count, serum CRP level, and

presence of multiple abscesses) between patients receiving the two therapeutic modalities

The mean maximum abscess diameter was slightly larger in CS Group 1, but the significance

was borderline (3.9 ± 0.4 cm vs 3.1 ± 1.0 cm, p = 0.05) In Group 1, CS group had

significantly longer mean IV and total antibiotic duration, as well as longer LOH (p = 0.001, p

< 0.001, p = 0.001, respectively) Although the trends were similar for Group 2, there was

lack of statistical significance (Table 3)

Acute appendicitis is one of the most common surgical abdominal diseases in pediatric

population In children visiting the emergency department for acute abdominal pain,

appendicitis accounts for 1%-8% of the cases.1, 2 One epidemiologic study conducted in South

Korea revealed an overall perforated appendectomy rate in the general population at 21.47%

The incidence of perforation is second highest in patients younger than 14 years old.13 The

perforation rate also differs between pediatric age groups, with the highest (up to 51%) among

patients younger than 5 years of age, and lowest (up to 27%) in adolescents Younger children

have a higher risk of postoperative complications.3

The differentiation between non-perforated and perforated appendicitis is important

Abdominal US has been extensively performed as the first-line diagnostic tool for pediatric

appendicitis because of its inexpensiveness and lack of radiation exposure An US has a

sensitivity ranging from 19.3-100% and a specificity of 52.9-99% in detecting perforated

appendicitis.4 Compared to US, computed tomography has superior accuracy, the sensitivity

and specificity can reach up to 94.9% and 100%, respectively.5

In our institution, abdominal US was commonly performed to screen for appendicitis in

children Abdominal CT was indicated if emergent US is unavailable or non-diagnostic In the

current study, we used this step-wise image protocol; perforated appendicitis accounted for

35.6% of all appendicitis cases in patients under 18 years old The male-to-female ratio was

1.42 Compared with the histology results, our image protocol has a positive predictive value

(PPV) of 88.2% for appendiceal perforation in the ABS-EA group, and 84.0% in the NA-EA

group

There were six patients with false-positive perforated appendicitis based on image study

Two patients in ABS-EA group had gangrenous appendix but no gross appendiceal

perforation In NA-EA group, gross perforation was absent in four patients, but gangrenous

change was observed in one of them If these 6 patients were included, the statistic results

leaded to similar conclusion

There has been no consensus regarding the optimal treatment for pediatric perforated

appendicitis The decision is usually personalized, based on disease severity and predictors of

outcome Several papers discussing adult cases advocate the role of conservative treatment,

emphasizing its ability to limit sepsis, reduce acute inflammation, avoid morbidity after EA

and effectively treat abscess or phlegmon that had already formed They pointed out that

conservative treatment resulted in fewer complications with no change in LOH, and

consequently was a better choice for appendiceal abscess.6–10 Limited pediatric studies also

found an acceptable effectiveness of conservative treatment, barring a subset of patients with

extended LOH.14 Predictors for failure in conservative treatment have been identified as: lack