World J Surg

DOI 10.1007/s00268-016-3416-2

ORIGINAL SCIENTIFIC REPORT

Delay Between Onset of Symptoms and Surgery in Acute

Appendicitis Increases Perioperative Morbidity: A Prospective Study
Sten Saar1 • Peep Talving1,2,3 • Juhan Laos1 • Taavi Põdramägi1,2 •

Maksim Sokirjanski1 • Thomas Lustenberger4 • Lydia Lam5 •

Urmas Lepner1,2,3

Ó Société Internationale de Chirurgie 2016

Abstract
Background Despite significant progress in surgery, controversy persists about timing of appendectomy. Objective
of this prospective observational study was to determine associations between time interval from onset of symptoms
in appendicitis to appendectomy and postoperative complications.
Methods After institutional review board approval, all adult consecutive patients subjected to emergency appen-
dectomy between 1/9/2013 and 1/12/2014 were prospectively enrolled. Data collection included demographics, open
vs. laparoscopic appendectomy, comprehensive complication index (CCI), and 30-day follow-up. To determine time-
dependent associations between delay of surgery and complications all patients were stratified into subgroups based
on 12-h time intervals from onset of abdominal pain to surgery. Primary outcome was complications per CCI in
correlation to delay from symptoms to appendectomy. Secondary outcomes included duration of surgery, hospital
length of stay (HLOS), and incidence of complication within 30-day follow-up.
Results A total of 266 patients with a mean age of 35.4 ± 14.8 years met inclusion criteria. Overall, 83.1 % of
patients were subjected to laparoscopic appendectomy. Delay to surgery in 12-h increments showed stepwise-
adjusted increase in complications per CCI (adj. P = 0.037). Also, delay to appendectomy increased significantly
duration of surgery and HLOS, respectively (adj. P \ 0.001 and adj. P \ 0.001). Overall, 5.7 % of patients
developed a surgical site infection after hospital discharge.
Conclusion Extended time interval from the onset of initial symptoms to appendectomy is associated with increased
complications per CCI, duration of surgery, and HLOS in acute appendicitis. Prompt appendectomy in acute
appendicitis is warranted.

Introduction
& Peep Talving
[email protected]
Appendectomy is the most frequently performed emergent
1
School of Medicine, University of Tartu, Puusepa 8, abdominal operation with a lifetime risk of appendicitis at
51014 Tartu, Estonia 9 % [1, 2]. Despite significant advancements in surgery and
2
Department of Surgery, Tartu University Hospital, antimicrobial therapy, many controversies in the manage-
Puusepa 1a, 50406 Tartu, Estonia ment of acute appendicitis persist.
3
Department of Surgery, School of Medicine, Many studies have observed that the risk of perforation
University of Tartu, Puusepa 8, 51014 Tartu, Estonia is time-dependent and extended time to surgery results in
4
Division of Trauma, Hand and Reconstructive Surgery, poor outcomes [3, 4]. However, other investigations have
Goethe University Hospital, Frankfurt/Main, Germany reported that spontaneous resolution of low-grade appen-
5
Division of Acute Care Surgery, Los Angeles dicitis is common and nonoperative management in these
County ? University of Southern California Medical Center, instances may result in good outcomes [5, 6]. Given the
Los Angeles, CA, USA

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 World J Surg

paucity of data, we set out to determine prospectively the was administered at the discretion of treating physician.
relationship between time interval from onset of symptoms Decision for drainage was made by attending surgeon and
to surgery and incidence of complications while comparing was utilized in general peritonitis, periappendicular
disease severity per histology in all specimens. abscess, or when highly contaminated surgical field was
encountered.
All surgical specimens were subjected to histology.
Methods and patients Based on the histological diagnosis, patients were stratified
into five subgroups using disease severity score (DSS):
Following institutional review board approval, all consec- grade 1 (G1), inflamed; grade 2 (G2), gangrenous; grade 3
utive patients C18 years of age subjected to emergency (G3), perforated with localized free fluid; grade 4 (G4),
appendectomy due to acute appendicitis between 1/9/2013 perforated with regional abscess and grade 5 (G5), perfo-
and 1/12/2014 were prospectively enrolled. Informed rated with diffuse peritonitis [10].
consent was obtained from all patients. Patients subjected Follow-up at 30 days after discharge included compli-
to nonoperative management were excluded. Data collec- cations per CD classification and CCI. All complications
tion included demographics, time of onset of abdominal and readmissions within 30 days after discharge were
pain, antibiotic administration, radiological investigations, documented.
surgical approach, post-operative complications, histology The P values for categorical variables were derived from
reports, hospital length of stay (HLOS), and follow-up the Chi-square or 2-sided Fisher’s exact test and for con-
within 30-day. tinuous variables the Student’s t test or the Mann–Whitney
To determine time-dependent associations between tests were deployed. Logistic regression analysis was used
delay of surgery and complications all patients were to compare the CCI, complications, antimicrobial therapy,
stratified into subgroups of 12-h time increments from duration of surgery, conversion rate, placement of a drain,
onset of abdominal pain to surgery. Primary outcome was HLOS, readmission rate, and the rate of SSI between
complications per comprehensive complication index subgroups. Values are reported as mean ± standard devi-
(CCI) [7] in correlation with time from onset of the ation (SD) for continuous variables and as percentages for
abdominal pain to appendectomy. CCI is a recently pub- categorical variables. P values \ 0.05 were set as statisti-
lished postsurgical morbidity assessment scale based on cal significance level. All analyses were performed using
Clavien-Dindo (CD) classification [8]. While the CD scale the Statistical Package for Social Sciences (SPSS for
includes only the most severe surgical complication, the MacÓ), version 16.0 (SPSS Inc., Chicago, IL).
CCI includes all surgical complications in a scale ranging
from 0 to 100. The CCI score of zero means no compli-
cations and a score of 100 is translated into a complication Results
burden that results in patient’s death. All complications are
weighted for their severity per CCI. Overall, during the 15-month study period, 270 appen-
Complication in this investigation was defined as any dectomies were performed and 266 (98.5 %) of patients
deviation from normal postoperative course with 30-day were included. Four patients declined to participate in the
follow-up included. Secondary outcomes were duration of study.
operation, HLOS, and incidence of complications within Table 1 depicts demographic and clinical characteristics
30-day follow-up after hospital discharge. of the cohort. The sole significant difference in demo-
Definitions of surgical site infections were based on the graphic profile was the mean age of the study groups that
CDC definitions [9]. Wound infection was defined as a was entered into logistic regression model. The mean in-
surgical site infection (SSI) divided into a superficial hospital time to surgery was 6.3 ± 5.7 hours and did not
incisional SSI involving skin and subcutaneous tissue and a differ significantly between the groups.
deep SSI involving deep soft tissues of the incision. Intra- Mean WBC on admission was 13.1 ± 3.9 9 109/L and
abdominal infection was defined as an organ/space SSI mean CRP was 47.8 ± 71.9 mg/L. Overall, 88.6 % of
involving any part of the body deeper than fascial/muscle patients were undergoing ultrasound investigation and
layers. 20.1 % computed tomography scan, respectively, before
All imaging studies and surgical interventions, laparo- the operation.
scopic or open appendectomy, were performed at the dis- A total of 95.1 % of patients received perioperative
cretion of an attending surgeon. Blood samples including intravenous antibiotics at the discretion of the treating
C-reactive protein (CRP) and white blood cell count physician. Overall, 4.9 % (n = 13) of patients did not
(WBC) were obtained in all the patients after admission to receive perioperative antibiotics. Two out of 13 cases
Emergency Department. Perioperative antibiotic therapy (15 %) of patients not receiving perioperative antibiotics

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World J Surg

Table 1 Demographic and clinical characteristics of all patients

Time from onset of abdominal Total 0–12 h 13–24 h 25–36 h 37–48 h [48 h P
pain to surgery n = 266 (n = 28) (n = 101) (n = 58) (n = 26) (n = 53)

Age (years) 35.4 ± 14.8 33.1 ± 14.0 32.4 ± 14.4 36.3 ± 13.8 40.6 ± 14.8 39.0 ± 15.9 0.020
BMI 25.4 ± 4.5 24.4 ± 4.9 25.3 ± 4.6 25.9 ± 4.5 25.0 ± 5.1 25.6 ± 3.9 0.661
Male 51.1 % (136) 67.9 % (19) 49.5 % (50) 55.2 % (32) 42.3 % (11) 45.3 % (24) 0.272
Previous IA surgery 9.8 % (26) 7.1 % (2) 7.9 % (8) 8.6 % (5) 3.8 % (1) 18.9 % (10) 0.152
Perioperative AB 95.1 % (252) 100 % (27) 96.0 % (97) 96.6 % (56) 96.2 % (25) 88.7 % (47) 0.159
In-hospital delay 6.3 ± 5.7 4.6 ± 1.7 6.3 ± 3.3 5.8 ± 3.1 6.4 ± 3.0 8.0 ± 11.1 0.107
Pre-hospital delay 27.1 ± 26.9 4.9 ± 2.4 11.3 ± 4.3 22.7 ± 4.1 36.4 ± 4.3 69.7 ± 31.7 <0.001
Abbreviations: hrs hours, n number of patients, BMI body mass index, IA intra-abdominal, AB antibiotic

developed one superficial SSI and one intra-abdominal subgroup compared to the \12 h subgroup. The follow-up
infection. demonstrated no significant outcome differences between
Surgical interventions are depicted in Table 2. Most the subgroups (Table 5).
patients were subjected to laparoscopic appendectomy at
83.1 %. Duration of operation and intraoperative place-
ment of a drain increased significantly with longer time Discussion
intervals to surgery (adj. P \ 0.001). Three patients
required conversion from laparoscopy to open midline We hypothesized that delayed presentation with an extended
laparotomy due to severe intra-abdominal adhesions. All time interval from onset of abdominal pain to surgery may
the primarily performed midline laparotomies were per- increase post-appendectomy complications. The present
formed due to general peritonitis. study proved our hypothesis and demonstrated that post-
Histology findings based on DSS are shown in Table 3. appendectomy complications are associated with extended
In patients with G4 and G5 acute appendicitis, the overall overall time interval from the very first symptoms to surgery.
time interval from onset of symptoms to operation was Also, all the advanced DSS cases (G4 and G5) were found in
beyond 36 hours (P \ 0.001 for G4 and P = 0.01 for G5). the subgroups of patients with appendicitis subjected to
For G1 cases, time interval was mostly \24 h (P \ 0.001). appendectomy beyond 36 h from the onset of symptoms.
In 1.1 % (n = 3) of patients histology revealed malignancy Multiple previous investigations have evaluated the
(carcinoids) and in 8.3 % non-inflamed appendix was impact of time interval from hospital admission to surgery
encountered. on outcomes in patients with acute appendicitis [11–20].
A detailed description of post-appendectomy compli- Busch et al. observed that an in-hospital delay [12 h
cations and antibiotic therapy are presented in Table 4. The increased considerably the risk of perforation and adverse
prevalence of postoperative complications and need for events [11]. Also, Teixeira and colleagues in an analysis of
antimicrobial therapy correlated with extended time inter- 4529 appendectomies noted that in-hospital delay [6 h
val to surgery. All the patients with DSS [2 received independently increased the risk of surgical site infections
intravenous antibiotics post-appendectomy. [12]. Likewise, in a study by Udgiri et al., an in-hospital
Complications per CD classification did not show sta- delay to surgery beyond 10 hours significantly increased
tistically significant correlation with prolonged time inter- incidence of complications [13]. Nevertheless, some stud-
val to surgery. However, CCI experienced a stepwise- ies have found contrary results. In a study by Shin and co-
adjusted increase in complications with delays from authors, no significant difference in outcomes was noted
symptoms to surgery (adj. P = 0.037) (Figure 1). Overall, between the subgroups waiting for operation less than 8
grade I and grade II type of CD complications predomi- hours versus more than 8 hours [14]. In another large study
nated. A total of 7.1 % (n = 19) of patients developed a by Drake and colleagues, no associations between in-hos-
SSI during hospital stay (20 %) or post-discharge (80 %), pital time prior to surgery and appendiceal perforations
respectively. Intra-abdominal infections, at 80 % (n = 8), were detected [15]. Some other studies have found an in-
were the predominant cause of all readmissions (n = 10) in hospital delay \24 h being a safe practice [16–19].
addition to one Clostridium difficile colitis and one deep Our study documented prospectively the entire time
SSI. No mortalities occurred. segment from the onset of very first symptoms prior to
HLOS was significantly longer with increasing time to hospital admission to the subsequent surgery. Very few
surgery and was about three-fold higher in the [48 h previous studies have evaluated the total time interval from

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Table 2 Duration of operation and surgical interventions of all patients
Time from onset of abdominal pain to surgery Total (n = 266) 0–12 h (n = 28) 13–24 h (n = 101) 25–36 h (n = 58) 37–48 h (n = 26) [48 hrs (n = 53) P adj. P*

Duration of OP (min) 41.2 ± 18.3 33.1 ± 11.9 36.6 ± 16.5 41.3 ± 16.8 46.4 ± 21.0 51.2 ± 20.1 <0.001 <0.001

Operations
Open 13.9 % (37) 17.9 % (5) 9.9 % (10) 15.5 % (9) 11.5 % (3) 18.9 % (10) 0.549 0.297
Laparoscopic 83.1 % (221) 82.1 % (23) 90.1 % (91) 84.5 % (49) 76.9 % (20) 71.7 % (38) 0.056 0.019
Conversion 1.1 % (3) 0 % (0) 0 % (0) 0 % (0) 11.5 % (3) 0 % (0) <0.001 0.273
ML 1.9 % (5) 0 % (0) 0 % (0) 0 % (0) 0 % (0) 9.4 % (5) <0.001 0.989
Drain placement 22.2 % (59) 3.6 % (1) 7.9 % (8) 20.7 % (12) 42.3 % (11) 50.9 % (27) <0.001 <0.001
Abbreviations: hrs hours, n number of patients, OP operation, min minutes, Conversion conversion from laparoscopic to midline laparotomy, ML midline laparotomy
*Adjusted for age

Table 3 Histology findings and distribution by disease severity score (G1–G5) of all patients
Time from onset of abdominal pain to surgery Total (n = 266) 0–12 h (n = 28) 13–24 h (n = 101) 25–36 h (n = 58) 37–48 h (n = 26) [48 h (n = 53) P

Normal appendix 8.3 % (22) 14.3 % (4) 9.9 % (10) 1.7 % (1) 3.8 % (1) 11.3 % (6) 0.179
G1 59.4 % (158) 71.4 % (20) 75.2 % (76) 58.6 % (34) 46.2 % (12) 30.2 % (16) <0.001
G2 13.9 % (37) 10.7 % (3) 11.9 % (12) 25.9 % (15) 7.7 % (2) 9.4 % (5) 0.056
G3 12.8 % (34) 3.6 % (1) 3.0 % (3) 13.8 % (8) 34.6 % (9) 24.5 % (13) <0.001
G4 2.6 % (7) 0 % (0) 0 % (0) 0 % (0) 3.8 % (1) 11.3 % (6) <0.001
G5 1.9 % (5) 0 % (0) 0 % (0) 0 % (0) 3.8 % (1) 7.5 % (4) 0.01
Carcinoid 1.1 % (3) 0 % (0) 0 % (0) 0 % (0) 0 % (0) 5.7 % (3) 0.016
Abbreviations: hrs hours, n number of patients, G1 grade 1 (inflamed), G2 grade 2 (gangrenous), G3 grade 3 (perforated with localized free fluid), G4 grade 4 (perforated with regional abscess),
G5 grade 5 (perforated with diffuse peritonitis)
World J Surg
World J Surg

Adj. P*
onset of symptoms to operation [3, 4, 21, 22]. A large

<0.001
0.002

0.374
0.270
0.254
0.992
0.963

0.037
retrospective study by Ditillo et al. demonstrated that the

–
–
severity of histology and complication rate was time-
dependent and delay of appendectomy was associated with
<0.001
<0.001
0.348
0.322
0.347
0.401
0.401

0.038
poor outcomes. These investigators noted that the risk of

–
–
P

advanced appendicular pathology increased 13-fold when

[48 h (n = 53)

the total time interval was greater than 71 h [21]. Two

6.09 ± 12.49
83.0 % (44)
28.3 % (15)

other retrospective studies analyzed the effects of delay in

13.2 % (7)
11.3 % (6)
1.9 % (1)
1.9 % (1)
1.9 % (1)

Abbreviations: hrs hours, n number of patients, post-OP postoperative, AB antibiotic, hosp hospital, CD Clavien-Dindo, CCI comprehensive complication index
surgery on outcomes [4, 22]. Sadot et al. found that a total

0 % (0)
0 % (0)
time interval beyond 48 hours significantly increased the
risk for perforation [22]. Likewise, Bickell et al. observed
similar results when overall interval from admission to
37–48 h (n = 26)

surgery was over 36 h [4]. Similarly, a prospective study

5.82 ± 10.03
80.8 % (21)

with, however, a small number of patients by Temple et al.

19.2 % (5)
11.5 % (3)
15.4 % (4)
3.8 % (1)
0 % (0)
0 % (0)
0 % (0)
0 % (0)

observed that a delay in presentation accounted for most of

the perforations [3]. Nevertheless, most of the studies
analyzing the total time interval are limited by retrospec-
25–36 h (n = 58)

tive design [4, 21, 22] nor did these studies analyze post-
operative adverse events [3, 22]. With regard to HLOS,
5.35 ± 9.91
65.5 % (38)
17.2 % (10)
12.1 % (7)
13.8 % (8)

many studies have indicated that longer interval or in-

3.4 % (2)
Table 4 Complications overall, per Clavien-Dindo classification and comprehensive complication index of all patients

0 % (0)
0 % (0)
0 % (0)
0 % (0)

hospital delay increased considerably the post-appendec-

tomy length of stay [13, 21].
Overall, our results are in coherence with the afore-
13–24 h (n = 101)

mentioned studies documenting poorer outcomes with an

extended time interval from admission to surgery. Most
2.60 ± 6.76
49.5 % (50)

9.9 % (10)

importantly, we utilized the CCI as a useful tool to evaluate

4.0 % (4)
5.0 % (5)

0 % (0)
0 % (0)
0 % (0)
0 % (0)
0 % (0)

post-appendectomy complications. In the present study,

CCI showed stepwise significant adjusted increase in
relation to the 12-h time increments from symptoms to
0–12 h (n = 28)

surgery. Moreover, post-appendectomy HLOS and dura-

tion of operation showed a significant increase with pro-
1.24 ± 3.10
64.3 % (18)

14.3 % (4)
3.6 % (1)

longed time to surgery. Likewise, with an increasing time

0 % (0)
0 % (0)
0 % (0)
0 % (0)
0 % (0)
0% (0)

to surgery, an intraoperative drain placement was per-

formed more frequently in the present study (adj.
P \ 0.001). However, placement of a drain is controversial
Total (n = 266)

and may be associated with prolonged HLOS [23].

64.3 % (171)

4.07 ± 9.09
13.2 % (35)

10.5 % (28)
9.8 % (26)

The 30-day follow-up revealed that 5.7 % of patients

1.5 % (4)
0.4 % (1)
0.4 % (1)
0 % (0)
0 % (0)

developed a SSI after discharge, which is considerably high

(Table 5).
The previous investigation by Garst et al. noted a DSS
Time from onset of abdominal pain to surgery

distribution G1 at 62.4 %, G2 at 13.0 %, G3 at 18.7 %, G4

at 4.4 %, and G5 at 1.5 % in their study cohort of 918
patients with appendicitis, which is comparable to our
study. In our study, a normal appendix was found in 8.3 %
Post-OP complications in-hosp

of cases and a similar incidence of normal appendicular

Post-OP AB therapy in- hosp

histology between 3.1 and 15.4 % has been reported in

many previous series [11, 15, 16, 21]. Thus, we believe that
the population of our study is representative for the general
*Adjusted for age

population with acute appendicitis.

Some studies have reported that spontaneous resolution
of appendicitis is common and a nonoperative management
CD IVb
CD IIIb
CD IVa
CD IIIa

CD V
CD II

may be prudent [5, 6]. However, our study showed that

CD I

CCI

most of the advanced grade cases of acute appendicitis

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Table 5 Hospital length of stay and 30-day follow-up of all patients

Time from onset of abdominal Total 0–12 h 13–24 h 25–36 h 37–48 h [48 h P Adj.
pain to surgery (n = 266) (n = 28) (n = 101) (n = 58) (n = 26) (n = 53) P*

HLOS (h) 61.5 ± 111.6 35.6 ± 23.6 40.5 ± 27.2 60.7 ± 50.9 71.9 ± 56.1 111.0 ± 231.6 0.003 <0.001
Post-discharge SSI 5.7 % (15) 3.6 % (1) 5.0 % (5) 10.3 % (6) 7.7 % (2) 2.0 % (1) 0.401 0.957
Readmission 3.8 % (10) 0 % (0) 4.0 % (4) 5.2 % (3) 3.8 % (1) 4.1 % (2) 0.842 0.551
Abbreviations: hrs hours, n number of patients, HLOS hospital length of stay, SSI surgical site infection
*Adjusted for age

subjected to antimicrobial treatment subsequently under-

7.00 went appendectomy at a follow-up within a 1-year period
adj. P = 0.037
6.00 [27]. Also, the Cochrane meta-analysis including five
5.00
prospective randomized studies of acute appendicitis sub-
jected to surgery versus antibiotic treatment concluded that
4.00
CCI

outcomes in cohorts treated with antibiotic therapy are

3.00 inconclusive [28]. Therefore, our institution still considers
2.00 appendectomy as the gold standard treatment for acute
1.00 appendicitis.
To the best of our knowledge this is the very first
0.00
Overall 0-12h 13-24h 25-36h 37-48h >48h prospective observational study investigating the entire
time interval from initial symptoms to 30-day postopera-
Fig. 1 Relationship between extended total time interval (x axis) tive follow-up. Nevertheless, our study is limited by
and comprehensive complication index (y axis). Abbreviations: CCI
number of patients resulting in a failure to demonstrate
comprehensive complication index
stepwise increase in complications per CD classification
among the time-stratified cohorts. Secondly, the antimi-
crobial therapy was administered at the discretion of
were in the extended time to surgery groups. Only four treating physician introducing a potential bias in outcomes;
perforated appendicitis (G3) were observed in a less than however, a single center setting functioning per principles
24 h subgroups and in all G4 and G5 cases, the time to of a sole antibiogram counterbalances the potential bias.
surgery was beyond 36 hours. Therefore, we suggest that Extended time interval from onset of symptoms to sur-
acute appendicitis may be a time-dependent process, gery is associated with increased duration of surgery, need
however, more prospective studies are warranted. of postoperative antibiotic therapy, surgical complications,
The overall incidence of malignancy in appendicular and HLOS. Prompt appendectomy in acute appendicitis is
specimens is reported to be about 1 % in the literature [24– warranted.
26]. Likewise, we observed an incidence of malignancy in
our appendicular specimens at 1.1 % (n = 3). Interest-
ingly, in only one out of the three cases, the attending
surgeon clinically suspected malignancy during operation. Disclosure All the authors declare that they have no conflict of
interest. There was no funding for the study. The paper has not been
Therefore, every appendicular specimen should be sent to presented before.
histology due to difficulties to differentiate benign and non-
benign specimens.
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