SURGICAL INFECTIONS

Volume 13, Number 2, 2012 Original Articles

Mary Ann Liebert, Inc.
DOI: 10.1089/sur.2011.058

Meta-Analysis of Randomized Trials Comparing Antibiotic

Therapy with Appendectomy for Acute Uncomplicated
(No Abscess or Phlegmon) Appendicitis

Rodney J. Mason, Ashkan Moazzez, Helen Sohn, and Namir Katkhouda

Abstract

Background: The objective was to conduct a meta-analysis of randomized controlled trials evaluating the efficacy
and morbidity of the management of acute uncomplicated (no abscess or phlegmon) appendicitis by antibiotics
versus appendectomy.
Methods: Appropriate trials were identified. The seven outcome variables were overall complication rate,
treatment failure rate for index hospital admission, overall treatment failure rate, length of stay (LOS), utilization
of pain medication, duration of pain, and sick leave. Both fixed and random effects meta-analyses were per-
formed using odds ratios (ORs) and weighted or standardized mean differences (WMDs or SMDs, respectively).
Results: Five trials totaling 980 patients (antibiotics = 510, appendectomy = 470) were analyzed. In three of the
seven outcome analyses, the summary point estimates favored antibiotics over appendectomy, with a 46%
reduction in the relative odds of complications (OR 0.54; 95% confidence interval [CI] 0.37, 0.78; p = 0.001); a
reduction in sick leave/disability (SMD - 0.19; CI - 0.33, - 0.06; p = 0.005), and decreased pain medication
utilization (SMD - 1.55; CI - 1.96, - 1.14; p < 0.0001). For overall treatment failure, the summary point estimate
favored appendectomy, with a 40.2% failure rate for antibiotics versus 8.5% for appendectomy (OR 6.72; CI 0.08,
12.99; p < 0.001). Initial treatment failure, LOS, and pain duration were similar in the two groups.
Conclusions: Non-operative management of uncomplicated appendicitis with antibiotics was associated with
significantly fewer complications, better pain control, and shorter sick leave, but overall had inferior efficacy
because of the high rate of recurrence in comparison with appendectomy.

A ppendectomy is universally considered the gold stan-

dard treatment for acute uncomplicated appendicitis. In
1889 [1], 40 years before the advent of antibiotics, open ap-
a recent commentary [14], we illustrated how in five of these
studies, using a simple composite calculation, 62% (n = 315) of
510 patients treated with antibiotics alone did not need an
pendectomy was established as the standard treatment be- appendectomy. Therefore, it is appropriate that we re-examine
cause it saved lives. Since that time, the dictum that surgical this alternative approach for the treatment of acute uncompli-
removal of the appendix is necessary has been largely un- cated appendicitis.
challenged. Meanwhile, non-operative management with Several earlier retrospective studies [1523] implied that
antibiotics has been established for the treatment of compli- acute uncomplicated appendicitis can be treated successfully
cated appendicitis [2], uncomplicated diverticulitis [3], neo- with antibiotics alone, and an earlier meta-analysis of three
natal enterocolitis [4], salpingitis [5], and cholecystitis [6,7]. randomized controlled studies [24] showed a trend toward
Until recently, the only treatment option considered for pa- fewer complications in the patients treated non-operatively.
tients with acute appendicitis was surgery. Now, six ran- Individually, the results from the randomized trials are in-
domized studies [813] show that non-operative management consistent, with one trial [13] showing non-inferiority of an-
is a safe and feasible therapeutic option for patients with tibiotics to appendectomy, whereas the others were either
uncomplicated appendicitis. Furthermore, it is apparent that inconclusive or showed equivalence of appendectomy and
two thirds of patients can be spared an appendectomy [14]. In non-operative management with antibiotics [812].

Division of General and Laparoscopic Surgery, University of Southern California, Keck School of Medicine, Los Angeles, California.

74
ANTIBIOTICS VS. APPENDECTOMY 75

The objective of this review was to compare the study- treatment failure rate during the initial hospitalization was
related efficacy and morbidity of antibiotic therapy alone with determined from the absence of therapeutic efficacy. For an-
appendectomy in the treatment of patients with acute un- tibiotic treatment, success was defined as definite improve-
complicated appendicitis. Effectiveness outcomes were ther- ment without need for surgery and subsequent hospital
apeutic success during the index hospital admission, pain discharge without an operation. Efficacy for surgical treat-
control, length of hospital stay (LOS), time to return to work, ment was pathologically confirmed appendicitis after surgery
recurrence, and morbidity outcomes, namely, any complica- or another appropriate surgical indication for operation.
tion of either non-operative or operative management. The Thus, patients with a pathologically proved normal appendix
primary topic therefore was whether non-operative manage- were classified as treatment failures. Overall treatment failure
ment with antimicrobial therapy given to patients with a was determined during the followup period up to one year.
suspicion of appendicitis could be effective source control This included any patient in the antibiotic group who re-
without a need for appendectomy. quired an appendectomy because of recurrence of appendi-
citis after the initial hospitalization. Complications included
Patients and Methods any antibiotic-related or surgery-related morbidity. As stated
above, the data extractors were not blinded to the study hy-
Data sources
pothesis, and two of the outcome variables, namely, the initial
A systematic review of the literature was performed to and overall treatment failure rates, are subject to interpreta-
identify all randomized controlled trials (RCTs) in which tion bias. The other five outcome variables were objective
treatment with any antibiotic regimen was compared with outcomes and not subject to interpretation bias.
appendectomy in patients with suspected appendicitis.
Medline, Embase, the Cochrane Central Register of Con- Statistical analysis
trolled Trials, and relevant meeting abstracts published be-
All analyses were performed using RevMan 5.1 (The Nor-
tween January 1950 and May 2011 were searched using the
dic Cochrane Centre, The Cochrane Collaboration, Co-
following MeSH terms: appendectomy/; appendicectomy/;
penhagen, Denmark). The meta-analysis was performed
appendicitis/; non-operative/; conservative/; and antibiotic
according to the recommendations of The Cochrane Colla-
therapy.
boration and the Cochrane Handbook for Systematic Reviews of
Interventions [26].
Study selection criteria
Initial and overall treatment failures are reported using
Only RCTs comparing management with any antimicrobial odds ratios (ORs) with 95% confidence intervals (CIs). Study
regimen with appendectomy for appendicitis were included. heterogeneity was determined using the I2 statistic and the p
Two authors (R.J.M., A.M.) reviewed the citations for rele- value from the w2 test. Interpretation of the I2 statistic was
vance and extracted the data. The data captured were the based on the guidelines in the Cochrane Handbook in which 0%
method of diagnosis, antibiotic regimen, operative technique, to 40% may be unimportant heterogeneity and 30%60%
pathology findings, LOS, pain assessments, complications, indicates moderate, 50%90% indicates substantial, and 75%
and duration of followup. The data extractors were not blin- 100% indicates considerable heterogeneity [26]. Pooled ana-
ded to the study hypothesis. Disagreement between the re- lyses were performed with the MantelHaenszel method
viewers was resolved by a consensus meeting with a third using a random effects model because these outcomes are
reviewer (H.S.). Patients of any age and either sex with sus- influenced by the context of care. Length of hospital stay was
pected acute uncomplicated appendicitis based on clinical assessed using weighted mean differences (WMDs) with the
presentation with or without radiologic confirmation were 95% CI and a random effects model. Because the trials used
included. different types and dosages of pain medication and deter-
Given the nature of the interventions, blinding of the sur- mined duration of pain and sick leave/disability differently,
geon, patient, and outcome assessor was not possible and we assessed these outcomes using standardized mean dif-
therefore was not an exclusion criterion. There were no re- ferences (SMDs) with 95% CIs and a random effects model.
strictions on the type of antibiotic, duration of antibiotic, or Complication rates are reported using ORs with the 95% CIs.
the appendectomy technique (open or laparoscopic). Studies Morbidity after appendectomy and the side effects associated
enrolling patients with known complicated appendicitis at the with the antibiotics was uncommon. Pooled estimates of effect
time of randomization, including subjects with periappendi- therefore were calculated using Petos odds ratios, because
cular abscess or phlegmon, were excluded. simulation studies have shown that this measure is most ro-
bust when events are rare and the numbers of patients in the
Data extraction, quality appraisal, and outcomes control and the experimental groups are similar [27]. Funnel
of interest plots were assessed to provide a visual assessment of whether
treatment estimates were associated with study size and to
The studies were assessed for methodological quality using
detect publication and other biases. Significance was set at a
the Jadad scoring system [25] in which each study was as-
p value of 0.05.
signed a score between zero (lowest quality) and five (highest
quality) based on reporting of randomization and blinding
Sensitivity analysis
and description of withdrawals.
The seven outcome variables analyzed were: (1) Initial In the trial published by Hansson et al., only 52.5% of the
treatment failure rate; (2) overall treatment failure rate; (3) patients assigned to the antibiotic arm (106/202) and 92.2% of
overall complication rate; (4) duration of pain; (5) utilization patients assigned to the appendectomy arm (154/167) actu-
of pain medication; (6) LOS; and (7) duration of sick leave. The ally received the assigned treatment. In the main analysis, the
 Table 1. Descriptive Summary of Five Randomized Trials Analyzed

Eriksson and
Granstrom [8] Stryud et al. [9] Hansson et al. [10] Malik & Bari [11] Vons et al. [13]

Location Sweden Sweden Sweden India France

No. participants 40 252 369 80 243
Diagnosis Clinical; universal Clinical, CRP, suspicion of Clinical, selective Clinical with modified Clinical; universal CT scan
US and CRP perforation and US and CT Alvarado score;
CRP < 10 excluded universal US and CRP
Exclusions Children Children; women Children Children Children
Intention-to-treat analysis? Yes Yes Yes and per-protocol basis Yes Yes
Appendectomy technique Not stated Surgeon discretion; 6% Not stated; surgeon Not stated Surgeon discretion; 66%
(open vs. laparoscopic) (8/128) laparoscopic discretion (78/119) laparoscopic
Normal appendix in 3/20 (15) 4/124 (3.2) 25/167 (15) 4/40 (10) 4/119 (3)
appendectomy group (%)

76
Perforated appendix in 1/20 (5) 6/124 (5) 50/250 (20)a 2/40 (5) 21/120 (18)
appendectomy group (%)
Followup schedule (days) 6, 10, and 30 7, 42, and 365 Questionnaire 30 and 365 7, 12, 30, and 365 15, 30, 90, 180, and 365
Followup (months) Mean 7 12 12 12 12
Recurrence in antibiotic group 7/20 (35%) 16/128 (12.5%) 14/202 (6.9%) 4/40 (10%) 30 /120 (25%)
15/119 (12.6%)b
Time to recurrence (mos) Mean 7 (range 312) Mean 4 1/3 within Mean 8 (range 412) Median 4.2 (range 1.211.1)
(range 110) 10 days; 2/3
between 3 and 16 mos
Minimum required hospitalization
Antibiotic 2 days 2 days 24 h 2 days 48 h
Appendectomy No minimum No minimum Not stated No minimum Not stated
a
In the patients undergoing operation.
b
Recurrence using per-protocol analysis.
CRP = C-reactive protein; CT = computed tomography; US = ultrasonography.
ANTIBIOTICS VS. APPENDECTOMY 77

Table 2. Details of Interventions in Randomized Controlled Trials

Source Antibiotic group details Appendectomy group details

Eriksson and Granstrom [8] Cefotaxime 2 g q 12 h + tinidazole 80 mg q d intravenously Technique not stated (n = 20)
for 2 days; ofloxacin 200 mg q 12 h + tinidazole 500 mg q
12 h orally for 8 days (n = 20)
Styrud et al. [9] Cefotaxime 2 g q 12 h + tinidazole 80 mg q d intravenously Open or laparoscopic at
for 2 days; ofloxacin 200 mg q 12 h + tinidazole 500 mg q surgeons discretion (n = 124)
12 h orally for 8 days (n = 128)
Hansson et al. [10] Cefotaxime 1 g q 12 h + metronidazole 500 mg or 15 mg/kg Open or laparoscopic at surgeons
intravenously for 1 day; ciprofloxacin 500 mg q discretion (n = 167)
12 h + metronidazole 400 mg q 8 h orally. Total 10 days
(n = 202)
Malik & Bari [11] Ciprofloxacin 500 mg q 12 h + metronidazole 500 mg q Technique not stated (n = 40)
8 h intravenously for 2 days; ciprofloxacin 500 mg q
12 h + tinidazole 600 mg q 12 h for 5 days. Total
7 days (n = 40)
Vons et al. [13] Amoxicillin/clavulanic acid (3 g/day for patients Open or laparoscopic at surgeons
weighing < 90 kg; 4 g/day for patients > 90 kg), given discretion (n = 119)
intravenously to patients with nausea or vomiting
and orally to others. Total 8 days (n = 120)

crossover patients were analyzed in their assigned group eight full reports and excluded three more studies: Two be-
using an intention-to-treat method. In the sensitivity analysis, cause they enrolled patients with known complicated ap-
we analyzed the data first excluding the trial by Hansson et al. pendicitis and one [12] because there were no usable
[10] and then by calculating the statistic using a per-protocol secondary outcome data and because it did not truly ran-
analysis with the patients analyzed according to the treatment domize patients between antibiotic treatment and appen-
they actually received. This step was performed in an attempt dectomy. Five studies including 980 patients were included in
to replicate the real world result. our meta-analyses [811,13].

Results Description of the trials

The Medline and Embase literature search identified 306 A description and summary of each trials methodology is
potentially relevant papers. We excluded 298 studies, 214 shown in Table 1. All studies had only two arms, antibiotic or
because they were non-randomized, and 84 because they appendectomy, and the treatment strategy in all five was simi-
studied other treatments. We then retrieved and reviewed lar. Because of the nature of the treatment arms, none of the

Table 3. Reported Complications

Surgical site Organ/space Small bowel

infection (%) infection (%)a obstruction (%) Other (%)b

Eriksson and Granstrom [8]

Antibiotic NR NR NR NR
Appendectomy 1/ 20 (5.0) NR NR 1/ 20 ( 5.0)
Stryud et al. [9]
Antibiotic NR NR NR 4/128 ( 3.1)
Appendectomy NR NR NR 17/124 (13.7)c
Hansson et al. [10]
Antibiotic 13/202 (6.4) 5/202 ( 2.5) NR 33/202 (16.3)
Appendectomy 7/167 (4.2) 5/167 ( 3.0) 4/167 (2.4) 39/167 (23.4)
Malik & Bari [11]
Antibiotic NR NR NR NR
Appendectomy 3/ 40 (7.5) NR NR NR
Vons et al. [13]
Antibiotic 2/120 (1.7) 2/120 ( 1.7) 1/120 (0.8) NR
Appendectomy 1/119 (0.8) 2/119 (16.8) NR NR
a
Organ space infection occurs within 30 days after the operation or appendicitis and appears to be related to the operation or appendicitis.
It involves any part of the anatomy (e.g., organ or space) other than the appendix or the incision created or manipulated during an operation.
b
Other complications were enteritis, thrombophlebitis, rectus muscle hematoma, sensoric loss in leg, urticaria, scrotal edema, diarrhea,
reoperation, wound dehiscence, incisional hernia, ileocecal resection, caval vein thrombosis, ileus, bladder dysfunction, aspiration at
extubation, pulmonary embolism, postoperative cardiac problems, vaginal or anal fungal infections, clostridium infection, and tooth injury.
c
Specific details not provided but reported mostly as surgical site infections.
NR = not reported.
78 MASON ET AL.

Table 4. Jadads Scale Scores for Trials management was reported in all five studies [811,13], and
the rate ranged from 6.9%35% (Table 1), for a mean overall
Total recurrence rate of 13%. The mean time to recurrence ranged
Source score Randomization Blinding Withdrawal
from 48 mos. Complications were reported in all five studies
Eriksson & 1 1 0 0 (Table 3).
Granstrom [8]
Quality appraisal
Stryud et al. [9] 2 2 0 0
Hansson et al. [10] 1 0 0 0 The quality of the five studies ranged from poor to fair
Malik & Bari [11] 2 2 0 0 (mean Jadad score 1.8 of 5), with each study having some
Vons et al. [13] 3 2 0 1 methodologic flaws (Table 4). All studies reported random
allocation, although only three had an appropriate method of
randomization. None of the studies reported blinding of the
studies was blinded. Three of the groups of authors performed outcome assessors, as blinding is impossible. Only one paper
a sample size calculation to support enrollment numbers. Two described withdrawals and dropouts from the study.
of the studies had a sample size of < 50 per group [8,11]. The
age range of the patients was 17 to 94 years; all studies ex- Methodological quality
cluded children. Four of the studies [8,10,11,13] included both
Funnel plots (mean differences, SMDs, or log ORs) dem-
male and female patients, and one study included only men
onstrated asymmetry for initial and overall treatment failure,
[9]. Together, the five studies enrolled 671 male and 309 female
suggesting the presence of publication bias and study het-
patients. Selection of the patients in four of the studies was
erogeneity for these outcomes (Fig. 1). No points fell outside
mainly on clinical grounds. In one study, computed tomog-
the 95% CIs for complications, LOS, utilization of pain med-
raphy (CT) scans were obtained on every patient [13], two
ication, duration of sick leave, or pain, suggesting the absence
of the groups of investigators [8,11] used ultrasound scan-
of publication bias and heterogeneity for these outcomes.
ning routinely, and one study [10] used ultrasonography and
CT selectively to confirm the clinical suspicion of acute un-
Outcomes
complicated appendicitis. Four studies also utilized serum
C-reactive protein (CRP) to aid in screening. Data for initial treatment failure and LOS were analyzed in
There were differences in the choice of antibiotic, antibiotic all five trials. All trials reported data on complications and
dosage, and duration of antibiotic therapy. The antibiotics overall treatment failure, three trials had data for duration of
used were divided into nine major groups; the details are pain and sick leave/disability, and only two trials had usable
summarized in Table 2. data on pain medication (Table 5). In three of the outcomes,
In three studies, the technique of appendectomy, whether the summary point estimates favored antibiotic therapy over
open or laparoscopic, was defined poorly (Table 2). In the appendectomy. These studies reported: (1) A 46% reduction
study of Stryud et al. [9], 6% (8/128) and in the trial by Vons in the relative odds of any complication in patients treated
et al. [13], 66% (78/119) of the patients underwent laparo- non-operatively (antibiotic group 11.8%, appendectomy 18%;
scopic appendectomy. OR 0.54; 95% CI 0.370.78; p = 0.001; Fig. 2); (2) a reduction
Formal followup ranged from 7 mos1 yr. Recurrence of in the duration of sick leave or disability (SMD - 1.19; 95%
appendicitis later than 30 days after successful non-operative CI - 0.33, - 0.06; p = 0.005; Fig. 3) in the patients treated

FIG. 1. Funnel plots demonstrate asymmetry of initial treatment failure, overall treatment failure, and length of hospital
stay, suggesting presence of publication bias and heterogeneity. No points fall outside 95% confidence limits for any other
variable, suggesting absence of publication bias and heterogeneity.
ANTIBIOTICS VS. APPENDECTOMY 79

Table 5. Summary of Outcome Measures

Eriksson & Granstrom [8] Stryud et al. [9] Hansson et al. [10] Malik & Bari [11] Vons et al. [13]

Initial failure: index hospital admission (%)

Antibiotics 1/20 ( 5.0) 15/128 (11.7) 105/202 (52) 2/40 ( 5) 14/120 (11.7)
Appendectomy 3/20 (15) 4/124 ( 3.2) 25/167 (15.0) 4/40 (10) 4/119 ( 3.4)
Overall failure (%)
Antibiotics 8/20 (40) 31/128 (24.2) 116/202 (57.4) 6/40 (15) 44/120 (36.7)
Appendectomy 3/20 (15) 4/124 ( 3.2) 25/167 (15.0) 4/40 (10) 4/119 ( 3.4)
Complication rate (%)
Antibiotics 0/20 4/128 ( 3.1) 52/202 (25.7) 0/40 5/120 ( 4.2)
Appendectomy 2/20 (10) 17/124 (13.7) 58/167 (34.7) 3/40 ( 7.5) 3/119 ( 2.5)
Total mean hospital stay (days) (standard deviation)
Antibiotics 3.1 ( 0.3) 3 ( 1.4) 3 ( 1.42) 3.2 ( 3.2)a 4.0 ( 4.9)
Appendectomy 3.4 ( 1.9) 2.6 ( 1.2) 3 ( 3.87) 2.1 ( 2.1)a 3.0 ( 1.5)
a
Mean length of stay reported incorrectly in the original manuscript. Error corrected after personal communication with authors; however,
no standard deviation (SD) supplied, so we imputed the SD as the mean value.

non-operatively; and (3) decreased utilization of pain medi- all seven outcome measures were exactly the same as for the
cation in the antibiotic-treated group (SMD - 1.55; 95% main analysis in which we used an intention-to-treat analysis
CI - 1.96, - 1.14; p < 0.0001; Fig. 4). (Table 7). Summary estimates still favored antibiotics over ap-
The only outcome that favored the appendectomy group pendectomy for developing any complication, duration of sick
was overall treatment failure, which showed a 30% reduction leave, and utilization of pain medication. Overall treatment
in relative risk with appendectomy. The overall treatment failure was still better with appendectomy and initial treatment
failure rate in the antibiotic group was 40.2% versus 8.5% in failure, LOS, and pain duration were similar in the antibiotic and
the appendectomy group (OR 6.72; 95% CI 3.4812.99; appendectomy groups. In the second scenario, when we ex-
p < 0.00001; Fig. 5). cluded the data of Hansson et al. from the analysis, the summary
For the remaining three outcomes, there were no significant estimates were the same as those found in the main analysis for
differences between antibiotics and appendectomy. For the all the outcome measures except duration of sick leave, which no
initial hospitalization, the therapeutic failure rate for antibi- longer favored the antibiotic group but rather showed equiva-
otics was 26.8% and that for appendectomy 8.9% (OR 2.43; lence to the appendectomy group (Table 7).
95% CI 0.946.33; p = 0.07; Fig. 6). There was no significant
difference in the LOS (WMD 0.34; 95% CI - 0.060.73; p = 0.09; Discussion
Fig. 7) or duration of pain (WMD - 0.13; 95% CI - 0.28, 0.03;
In trials with both a surgical and a non-surgical arm,
p = 0.11; Fig. 8). Pooled summary statistics for the seven out-
comparisons between treatment groups inevitably are asso-
comes are shown in Table 6.
ciated with a bias for both investigators and patients. As
Significant heterogeneity, as evidenced by the values of the
pointed out by Jadad [25], when concealment in patient allo-
Q statistic and I2 index, was present for the initial treatment
cation is lacking, open assessment tends to yield a statistically
failure rate (Q = 13.00; p = 0.01; I2 69%). No heterogeneity was
significantly larger estimate of treatment effects. Thus, in
detected for any other outcome measure (Table 6).
summarizing the treatment outcomes in trials such as those
reviewed here, point estimates are likely to favor appendec-
Sensitivity analysis
tomy, as it has been considered the gold standard for the
The sensitivity analysis, in which we considered the real- treatment of acute appendicitis. Therefore, rather than fo-
world scenario and analyzed the data of Hansson et al. as cusing on whether appendectomy is superior or similar to
treatment received using a per-protocol analysis, the findings for antibiotic therapy, we should examine the safety of antibiotics

FIG. 2. Forest plot of antibiotics versus appendectomy for overall complications, depicted as Peto odds ratios. Diamond
represents overall treatment effects, and squares are treatment effects for individual studies, with 95% confidence intervals
indicated by horizontal lines. CI = confidence interval.
80 MASON ET AL.

FIG. 3. Forest plots of antibiotics vs. appendectomy for duration of sick leave or disability, depicted as standardized mean
differences using random effects model. Diamond represents overall treatment effects, and squares are treatment effects for
individual studies, with 95% confidence intervals indicated by horizontal lines. These data were not reported in three studies.
CI = confidence interval; SD = standard deviation.

and the reduction in surgically-related morbidity by using fatalities. The fact that no deaths were reported could be re-
antibiotics as the first-line treatment option for patients with lated to the close monitoring and mandatory period of hos-
uncomplicated appendicitis. This meta-analysis showed that pitalization to which the patients in these trials were
patients who underwent antibiotic therapy were at a signifi- subjected. By contrast, standardized mortality ratios have
cantly lower risk of any complication than those undergoing shown a seven-fold excess rate of deaths after appendectomy
appendectomy. This finding is in keeping with an earlier compared with the general population [28], and the excess
meta-analysis [24] that included only three studies and rates for patients with non-perforated and non-surgical ab-
showed a trend toward fewer complications with antibiot- dominal pain suggest that some of the deaths may be caused
ics. Thus, one advantage of non-operative management of by surgical trauma. The unanswered question is whether the
uncomplicated appendicitis is the absence of any surgery- standardized mortality ratios with non-operative treatment of
related morbidity, which appears to be more frequent after uncomplicated appendicitis using antibiotics only also is as-
appendectomy than antibiotic therapy. It is interesting that in sociated with an excess rate of deaths. Future large multi-
the pooled analysis, 37% (22) of the complications seen in the center trials are needed to answer this question.
60 antibiotic-treated patients actually were surgery-related. No difference in treatment efficacy was demonstrated be-
However, because all studies correctly used an intention-to- tween antibiotic therapy and appendectomy for the index
treat analysis, these complications were assigned to the orig- hospital admission for acute uncomplicated appendicitis.
inal randomization group. In addition to the absence of any There was a trend toward a lower risk of failure in the appen-
surgery-related complications, there is an absence of inci- dectomy-treated group. However, we believe that there are a
sional pain in the patients treated non-operatively. In the two number of caveats in interpreting this outcome. First, optimal
studies that reported analgesic consumption, both showed surgical therapy was not compared with optimal antibiotic
significantly less pain medication usage in the patients treated therapy in any of the studies. Amoxicillin-clavulanic acid was
with antibiotics than in those undergoing appendectomy. the antibiotic in two studies, and this combination has been
Furthermore, the meta-analysis showed a trend toward a associated with considerable Escherichia coli non-susceptibility,
shorter duration of pain in the antibiotic-treated group. with the rate of resistance to this antibiotic in Europe being as
As expected, reduced pain and decreased complications high as 66% [29,30]. Second, the technique of appendectomy,
were associated with a significantly shorter duration of sick whether laparoscopic or open, influences morbidity [31,32], and
leave/disability in the patients treated non-operatively. Al- in none of the studies was the operative technique standardized
though no difference was found in the LOS, this may have or reported accurately. The laparoscopic appendectomy tech-
been attributable to the protocol-driven nature of the trials nique has been associated with fewer post-operative compli-
that dictated a mandatory period of hospitalization in the cations [31,32], and in all but one of the studies in this meta-
antibiotic-treated group of patients and the initial uncertainty analysis, laparoscopy appeared to be the least-favored surgical
associated with an unproved therapeutic modality. technique. Third, the studies all included a high proportion of
There were no deaths in any of the studies. There has al- patients with either a perforated or a gangrenous appendix, the
ways been a concern that expectant management of patients rate ranging from 5% for perforation to 48% for gangrenous
with appendicitis would lead to serious complications or appendicitis [9,10]. Even in the study reported by Vons et al.

FIG. 4. Forest plots of antibiotics versus appendectomy for utilization of pain medication, depicted as standardized mean
differences using random effects model. Diamond represents overall treatment effects, and squares are treatment effects for
individual studies, with 95% confidence intervals indicated by horizontal lines. These data were reported in only two studies.
CI = confidence interval; SD = standard deviation.
ANTIBIOTICS VS. APPENDECTOMY 81

FIG. 5. Forest plots of antibiotics versus appendectomy for overall treatment failure, depicted as odds ratios using the
MantelHaenszel random effects model. Diamond represents overall treatment effects, and squares are treatment effects for
individual studies, with 95% confidence intervals indicated by horizontal lines. CI = confidence interval.

FIG. 6. Forest plots of antibiotics versus appendectomy for treatment failure for index hospital admission, depicted as odds
ratios using MantelHaenszel random effects model. Diamond represents overall treatment effects, and squares are treatment
effects for individual studies, with 95% confidence intervals indicated by horizontal lines. CI = confidence interval.

FIG. 7. Forest plots of antibiotics versus appendectomy for length of hospital stay, depicted as standardized mean dif-
ference using random effects model. Diamond represents overall treatment effects, and squares are treatment effects for
individual studies, with 95% confidence intervals indicated by horizontal lines. CI = confidence interval; SD = standard de-
viation.

FIG. 8. Forest plots of antibiotics versus appendectomy for duration of pain, depicted as standardized mean difference
using random effects model. Diamond represents overall treatment effects, and squares are treatment effects for individual
studies, with 95% confidence intervals indicated by horizontal lines. Duration of pain was not reported in three studies.
CI = confidence interval; SD = standard deviation.
82 MASON ET AL.

Table 6. Summary Statistics of Pooled Data Comparing Non-Operative Management and Appendectomy

Pooled odds ratio, Test for overall effect Test for heterogeneity
weighted or standard 2
mean difference (95% CI) Z P value Tau Q P value I2 (%)

Overall complications 0.54 ( 0.37, 0.78) 3.24 0.001 8.28 0.08 52

Duration of sick leave - 0.19 ( - 0.33, - 0.06) 2.79 0.005 0.00 1.91 0.39 0
Utilization of pain medication - 1.55 ( - 1.96, - 1.14) 7.38 < 0.0001 0.00 0.02 0.90 0
Treatment failure: initial 2.43 ( 0.94, 6.33) 1.82 0.07 0.74 13.00 0.01 69
hospitalization
Overall treatment failure 6.72 ( 3.48, 12.99) 5.67 < 0.001 0.28 8.28 0.08 52
Hospital stay (days) 0.34 ( - 0.06, 0.73) 1.67 0.09 0.08 6.64 0.16 40
Duration of pain - 0.13 ( - 0.28, 0.03) 1.62 0.11 0.00 2.03 0.36 2

CI = confidence interval.

[13], in which a CT scan was used routinely for diagnosis, the recurrence of appendicitis mandated appendectomy. An al-
perforation rate was extremely high at 21%. In none of the ternative would be to give another course of antibiotics, such
studies was the presence of an appendicolith a contraindication as is used for recurrent attacks of diverticulitis [33], or a dif-
to non-operative management, yet there is increasing evidence ferent antibiotic, as recurrence may be an indication of anti-
[13,22] that patients with an appendicolith have a high inci- biotic resistance. However, the recurrence rates described in
dence of failure with non-operative management, and these the present meta-analysis may not be representative of the
patients therefore should be excluded from this treatment. The true recurrence rates after antibiotic therapy because of the
fact that only one trial routinely used a CT scan to aid diagnosis relatively short followup for most of the patients, the lack of
is problematic, and not the U.S. standard of care [7]. Computed diagnostic definitions for recurrence, and the absence of uni-
tomography scanning is essential in all patients to exclude non- form selection criteria for patients with minimal appendicitis.
appendicitis and to identify perforated appendicitis or an ap- No trial looked at recurrence rates beyond 12 months, and
pendiceal abscess. Future trials need to exclude all patients there currently are no data available on the long-term risk of
with perforated appendicitis and compare the best antibiotic appendicitis after non-operative treatment.
therapy with the best surgical technique. Furthermore, routine There was bias in all the studies in that those patients
imaging should be used during followup to ensure that there is in the appendectomy group who were found at operation
no bias. to have perforation were treated with antibiotics post-
The overall therapeutic failure rate was significantly better operatively. Strictly speaking, these patients should be clas-
for the patients treated with appendectomy. However, in sified as treatment failures of appendectomy, that is, failure
nearly all the studies, the design protocol dictated that a of surgery to provide adequate source control. In contrast,

Table 7. Sensitivity Analysis Depicting Summary Statistic of Pooled Data Using Both a Per-Protocol
Analysis of Data from Hansson et al. [10] and Omitting Those Data

Pooled odds ratio, Test for overall effect Test for heterogeneity
weighted or standard
mean difference (95% CI) Z P value Tau2 Q P value I2 (%)

Overall complications
Per-protocol analysis 0.49 ( 0.33, 0.72) 3.56 0.0004 7.56 0.11 47
Hansson et al. trial omitted 0.36 ( 0.18, 0.72) 2.90 0.004 6.45 0.09 53
Duration of sick leave
Per-protocol analysis - 0.20 ( - 0.36, - 0.04) 2.44 0.01 0.01 2.75 0.25 27
Hansson et al. trial omitted - 0.12 ( - 0.29, 0.06) 1.29 0.20 0.00 0.29 0.59 0
Overall treatment failure
Per-protocol analysis 4.53 ( 1.70, 12.04) 3.03 0.002 0.92 17.12 0.002 77
Hansson et al. trial omitted 6.01 ( 2.16, 16.77) 3.43 0.0006 0.69 8.30 0.04 64
Treatment failure initial hospitalization
Per-protocol analysis 1.38 ( 0.53, 3.56) 0.66 0.51 0.70 11.19 0.02 64
Hansson et al. trial omitted 1.61 ( 0.49, 5.31) 0.79 0.43 0.86 7.63 0.05 61
Hospital stay (days)
Per-protocol analysis 0.15 ( - 0.66, 0.96) 0.37 0.71 0.70 36.10 < 0.0001 89
Hansson et al. trial omitted 0.44 ( - 0.4, 0.93) 1.78 0.07 0.11 5.23 0.16 43
Duration of pain
Per-protocol analysis - 0.11 ( - 0.27, 0.04] 1.43 0.15 0.00 1.71 0.42 0
Hansson et al. trial omitted - 0.02 ( - 0.24, 0.20) 0.18 0.86 0.00 0.34 0.56 0

Pain medication usage not shown, as this was not reported in the paper by Hansson et al.
CI = confidence interval.
ANTIBIOTICS VS. APPENDECTOMY 83

patients in the antibiotic group who needed to have surgery Acknowledgments

to provide adequate source control were all considered
We would like to acknowledge Jolene Moroney for writing
treatment failures. None of the trials addressed this bias, and
assistance.
the outcomes might have been different if patients in the
surgery arms of these studies had not been given this pref-
erential treatment. Author Disclosure Statement
There were design flaws in each of the studies reviewed, and
The authors have no conflict of interests to disclose.
two in particular are worthy of mention. In the study by Vons
et al. [13], complicated appendicitis with peritonitis identified
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