Indication of conservative treatment by antibiotics for uncomplicated and complicated acute appendicitis

Abstract

BACKGROUND

Acute appendicitis is one of the most common emergency abdominal disease, and recent studies have evaluated conservative treatment using antibiotics for uncomplicated appendicitis. Although the efficacy of conservative treatment for uncomplicated appendicitis is known, its efficacy for complicated appendicitis remains unknown, so are risk factors for the conservative treatment of appendicitis. In our institution, conservative treatment has long been the first choice for most appendicitis cases, except for perforation. Therefore, this novel study investigated the outcomes of conservative treatment for uncomplicated and complicated acute appendicitis and the risk factors associated with conservative treatment.

AIM

To investigate the indication of conservative treatment by antibiotics for uncomplicated and complicated acute appendicitis

METHODS

We investigated 270 patients who received conservative treatment for acute appendicitis at the Nishitokyo Central General Hospital, between April 2011 and February 2022. Twenty-eight (10.3%) patients were resistant to conservative treatment and underwent surgery. We retrospectively investigated the outcomes of conservative treatment for appendicitis and the risk factors for resistance to conservative treatment using the receiver operating characteristic curves and Cox hazard model.

RESULTS

Two hundred and forty-two (89.7%) patients improved with conservative treatment. The significant and independent predictors of resistance to conservative treatment were body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid visible on computed tomography (CT). The rate of resistance to conservative treatment was 66.7% (6/9) for patients with the above three factors, 22.9% (8/35) for patients with two factors (appendicolith and body temperature ≥ 37.3 °C), 16.7% (2/12) for patients with two factors (Douglas sinus fluid and appendicolith) and 11.1% (1/9) for patients with two factors (Douglas sinus fluid and body temperature ≥ 37.3 °C).

CONCLUSION

A temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid on CT might be clinical risk factors of resistance to conservative treatment for acute appendicitis.

Key Words: Acute appendicitis; Conservative treatment; Antibiotics; Appendicolith; Uncomplicated appendicitis

Core Tip: This is a retrospective study to investigate the outcomes of conservative treatment for uncomplicated and complicated acute appendicitis. The success rate of conservative treatment of acute appendicitis was 89.7%. The significant and independent predictors of resistance to conservative treatment were body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid. The rate of resistance to conservative treatment was 66.7% for patients with the above three factors, therefore, surgical treatment should be recommended at the first visit. Body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid might be clinical risk factors for resistance to conservative treatment for acute appendicitis.

INTRODUCTION

Acute appendicitis is one of the most common emergency abdominal diseases, and appendectomy has long been the standard treatment. However, recent studies have evaluated conservative treatment using antibiotics for uncomplicated appendicitis[1-9]. In addition, international guidelines suggest that conservative treatment is effective and an alternative to surgery for uncomplicated appendicitis[10-13].

Coronavirus disease 2019 (COVID-19) was first reported in China in 2019 and has since spread worldwide. COVID-19 potentially increases surgical morbidity and mortality, therefore, emergency surgery is not recommended for COVID-19 patients[14,15]. Furthermore, surgery under general anesthesia increases the risk of COVID-19 infection for medical staff because of viral transmission via aerosolization. Therefore, the use of antibiotics alone for acute appendicitis has become more prevalent and paramount. However, International guidelines recommend conservative treatment for uncomplicated appendicitis but not for complicated appendicitis[10-12]. Although, complicated appendicitis is generally associated with perforation, abscess, appendicolith, etc.[8,10-12], there are no reports or guidelines with a clear definition of the difference between uncomplicated and complicated appendicitis. Therefore, at present, the kind of treatment to be selected for each case is not known, especially in complicated appendicitis.

In our institution, conservative treatment has long been the first choice for most appendicitis cases, except for perforation. Therefore, this novel study investigated the outcomes of conservative treatment for uncomplicated and complicated acute appendicitis and the risk factors associated with conservative treatment.

MATERIALS AND METHODS

Study design

We collected the data of 332 patients who were hospitalized at Nishitokyo Central General Hospital, because of acute appendicitis between April 2011 and February 2022. We retrospectively investigated the outcomes of conservative treatment for appendicitis and the risk factors for resistance to conservative treatment.

Nishitokyo Central General Hospital has its own Institutional Review Board (IRB). This study was approved for use in the hospital database for research by the IRB (Approval No. 2018-004).

Patient management

To diagnose acute appendicitis, computed tomography (CT) and laboratory tests were performed on all patients at the first visit. A diagnosis of acute appendicitis was made by comprehensive physical examination, increased inflammatory reaction [white blood cell (WBC), C-reactive protein (CRP)], and the presence of an enlarged appendix on CT. Patients who were strongly suspected of having a neoplasm through a CT scan at the first visit were excluded from this study. Patients with rebound pain in the entire abdomen (diffuse peritonitis), vital signs indicating shock, and perforation of the appendix (extraluminal air present) on CT were not suitable for conservative treatment. However, they were absolute indications for surgery. Furthermore, patients who wanted to undergo surgery were also not suitable for conservative treatment and hence, were a relative indication for surgery. Regardless of the level of inflammation, we performed the conservative treatment with antibiotics in all patients. All patients were hospitalized and managed by fasting, cooling the site of abdominal pain, and administering antibiotics. We basically administered intravenous flomoxef sodium. On the other hand, we administered meropenem hydrate for cases with severe abdominal pain, CRP ≥ 10, abscess, or appendix size ≥ 15mm. Laboratory and abdominal examinations were performed daily. When we judged that the condition had not improved due to persistent fever, no improvement in abdominal pain and in WBC and CRP, a CT scan was done to determine whether surgery was indicated.

Statistical analysis

All statistical analyses were performed using the chi-square test, Mann-Whitney U-test and SPSS for Windows (SPSS, Tokyo, Japan). Receiver operating characteristic (ROC) curves were used to determine the cutoff points for data concentrations that indicated resistance to conservative treatment. Significant factors were identified using univariate analysis and further examined using multivariate analysis. A multivariate regression analysis was performed using the Cox hazard model. A P value of less than 0.05 indicated a statistically significant difference between the two groups.

RESULTS

A total of 332 patients were diagnosed with appendicitis. Out of this, 28 patients had an absolute indication for surgery, and 34 patients had a relative indication for surgery. Therefore, 270 patients received conservative treatment for acute appendicitis. Twenty-eight (10.3%) patients were resistant to conservative treatment and underwent surgery (Figure 1). We compared the age and laboratory tests such as WBC count, CRP level, time taken to hospital, body temperature and size of the appendix on CT between the group that underwent surgery and the group that improved with conservative treatment (Table 1). Only body temperature was significantly higher in the surgery group, and there were no significant differences in WBC count, CRP level, and appendix size on CT.

Figure 1  Flow diagram showing the patient selection process.

Table 1 Patient characteristics and clinical data of patients underwent surgery and improved with conservative treatment.

	Surgery group, n = 28	Conservative group, n = 242	P value
Age	41.9 ± 19.8	44.8 ± 20.7	0.495
Time to visit hospital (hour)	38.6 ± 70.0	37.6 ± 66.1	0.453
Body temperature (°C)	37.8 ± 1.0	37.2 ± 0.8	< 0.001
WBC count (/μL)	13440.4 ± 4130.1	12489.8 ± 3986.3	0.325
CRP (mg/dL)	5.9 ± 7.3	4.2 ± 5.3	0.311
Size of appendix (mm)	14.0 ± 3.7	12.3 ± 4.1	0.014

CRP: C-reactive protein; WBC: White blood cell.

Cutoff points for resistance to conservative treatment

A ROC curve was constructed to determine the cut-off points for resistance to conservative treatment by the time taken to visit the hospital, body temperature, WBC count, CRP level and appendix size on CT. The optimal cut off points were defined as points plotted close to the point from the upper left corner of the ROC curve. The optimal cut-off points were 22 hours for the time to visit the hospital, 37.3 °C for body temperature, 15160 count/μL for WBC, 4.6 mg/dL for CRP and 12 mm for appendix (Table 2).

Table 2 Area under the curve and optimal cutoff values of clinical data as predictors of resistance to conservative treatment.

	Cutoff value	Area under the curve	FPF	TPF
Time to visit hospital (hour)	22	0.5432	0.434	0.571
Body temperature (°C)	37.3	0.6923	0.368	0.679
WBC count (/μL)	15160	0.5568	0.236	0.429
CRP (mg/dL)	4.6	0.5584	0.351	0.500
Size of appendix (mm)	12	0.6409	0.533	0.786

TPF: True-positive fraction; FPF: False-positive fraction; CRP: C-reactive protein; WBC: White blood cell.

Predictors of resistance to conservative treatment

To determine the predictors of resistance to conservative treatment, we examined 16 items: Age, sex, past history of appendicitis, the existence of rebound pain, time to visit the hospital, body temperature, WBC count, CRP, size of the appendix, stranding of the adjacent fat and periappendiceal fluid and air in the appendix. Additionally, abscess and appendicolith and Douglas sinus fluid on CT, and type of antibiotics were assessed (Table 3). Univariate analysis showed that the following 10 factors were associated with resistance to conservative treatment: Body temperature ≥ 37.3 °C (P = 0.001), WBC count ≥ 15160/μL (P = 0.027), appendix size ≥ 12 mm (P = 0.011), stranding of the adjacent fat (P = 0.020), the air in the appendix (P = 0.014), abscess (P = 0.048), appendicolith (P < 0.001), Douglas sinus fluid (P = 0.003), and broad-spectrum antibiotics (P = 0.009). Multivariate analysis showed that, body temperature ≥ 37.3 °C (P = 0.028), appendicolith (P = 0.008) and Douglas sinus fluid (P = 0.016) were significant and independent predictors of resistance to conservative treatment.

Table 3 Univariate and multivariate analysis of risk factors for resistance to conservative treatment, n (%).

	Surgery group, n = 28	Conservative group, n = 242	Univariate analysis, P value	Multivariate analysis, P value	Hazard ration
Age
< 75	26 (10.7)	216 (89.3)	0.554
≥ 75	2 (7.1)	26 (92.9)
Sex
Female	12 (11.1)	96 (88.9)	0.744
Male	16 (9.9)	146 (90.1)
Past history of appendicitis
(-)	25 (11.6)	190 (88.4)	0.180
(+)	3 (5.5)	52 (94.5)
Rebound pain
(-)	9 (7.8)	106 (92.2)	0.238
(+)	19 (12.3)	136 (87.7)
Time to visit hospital (hour)
< 22	12 (8.1)	137 (81.9)	0.166
≥ 22	16 (13.2)	105 (86.8)
Body temperature (°C)
< 37.3	9 (5.6)	153 (94.4)	0.001	0.028	2.945
≥ 37.3	19 (17.6)	89 (82.4)
WBC count (/μL)
< 15160	16 (8.0)	185 (92.0)	0.027	0.138
≥ 15160	12 (17.4)	57 (82.6)
CRP (mg/dL)
< 4.6	14 (8.2)	157 (91.8)	0.122
≥ 4.6	14 (14.1)	85 (85.9)
Size of appendix (mm)
< 12	6 (5.0)	113 (95.0)	0.011	0.600
≥ 12	22 (14.6)	129 (85.4)
Stranding of the adjacent fat
(-)	1 (1.3)	79 (98.7)	0.001	0.162
(+)	27 (16.6)	163 (83.4)
Periappendiceal fluid
(-)	19 (8.4)	206 (91.6)	0.020	0.892
(+)	9 (20.0)	36 (80.0)
Air in appendix
(-)	22 (8.9)	224 (81.1)	0.014	0.164
(+)	6 (25.0)	18 (75.0)
Abscess
(-)	24 (9.4)	230 (80.6)	0.048	0.083
(+)	4 (25.0)	12 (75.0)
Appendicolith
(-)	9 (5.1)	167 (94.9)	< 0.001	0.008	3.746
(+)	19 (20.2)	75 (79.8)
Douglas sinus fluid
(-)	17 (7.7)	203 (92.3)	0.003	0.016	3.580
(+)	11 (22.0)	39 (78.0)
Antibiotics
Second-generation cephems	14 (7.3)	178 (92.7)	0.009	0.260
Broad-spectrum	14 (17.9)	64 (82.1)

CRP: C-reactive protein; WBC: White blood cell.

Of the patients with three factors (body temperature ≥ 37.3 °C, existences of appendicolith and Douglas sinus fluid), six (66.7%) were resistant to conservative treatment. Among the patients with two factors, one patient (11.1%) with Douglas sinus fluid and body temperature ≥ 37.3 °C, two (16.7%) with Douglas sinus fluid and appendicolith, and eight (22.9%) with appendicolith and body temperature ≥ 37.3 °C were resistant to conservative treatment (Table 4).

Table 4 Probability of resistance to conservative treatment by number of risk factors, n (%).

Number of risk factors	Total number	Surgery
0 factor	92	2 (2.2)
1 factor
Body temperature ≥ 37.3 °C	55	4 (7.3)
Douglas sinus fluid	20	2 (10.0)
Appendicolith	38	3 (7.9)
2 factors
Douglas sinus fluid + body temperature ≥ 37.3 °C	9	1 (11.1)
Douglas sinus fluid + appendicolith	12	2 (16.7)
Appendicolith + body temperature ≥ 37.3 °C	35	8 (22.9)
3 factors	9	6 (66.7)

DISCUSSION

The purpose of this study was to determine whether patients with acute appendicitis were resistant to conservative treatment using data from their first visit to the hospital. In this study, the success rate of the conservative treatment was 89.7%. However, 28 (10.3%) patients were resistant to conservative treatment and underwent surgery. The significant and independent predictors of resistance to conservative treatment were body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid on CT. Generally, guidelines[10-12] defined complicated appendicitis as perforation, appendicolith, or abscess. Furthermore, these cases were excluded from the indications for conservative treatment for acute appendicitis in randomized control studies. At our institution, conservative treatment is administered for acute appendicitis, regardless of the data on inflammation, except for perforated cases. Therefore, we performed this study to identify factors associated with resistance for conservative treatment for acute appendicitis, including complicated appendicitis.

Although appendicolith and abscess are generally defined as risk factors for complicated appendicitis, in this study, appendicolith was indicated as a risk factor, and abscess was not indicated. On the other hand, although not defined, fever and Douglas sinus fluid were also indicated as factors associated with resistance to conservative treatment. Fever was not identified as a risk factor in some guidelines[8,10-12], however, it was indicated as an appendicitis severity score in some reports[15-17]. Recently, some studies reported percutaneous drainage of abscesses, followed by interval appendectomy[18,19]. We believe that abscess drainage is an effective procedure. However, there were no patients in whom abscess drainage was performed in this study owing to facility problems. In this study, 16 patients were diagnosed with abscesses, of whom four underwent surgery and 12 improved with conservative treatment. The median size of abscess in the 16 patients was 25 (5-45) mm, with the median size in the 4 and 12 patients being 25 (19-32) mm and 21 (5-45) mm, respectively, with no significant difference in size. In addition, we re-examined the CT scans of 16 patients with abscess; there were no cases in which abscess drainage was considered safe. We believe that abscess drainage is an effective procedure as part of conservative treatment for large abscesses that can be safely drained. However, even when the abscess cannot be drained, we believe that the condition can be improved with conservative treatment without abscess drainage.

Few studies have discussed the relationship between imaging findings and complicated acute appendicitis[17]. Similarly, in this study, we focused on following CT imaging such as the size of the appendix, stranding of the adjacent fat, periappendiceal fluid, air in appendix, abscess, appendicolith, and Douglas sinus fluid. Among these findings, only Douglas sinus fluid was indicated as a risk factor, except for appendicolith. Fujiwara et al[17] reported the imaging findings of stranding of the adjacent fat and periappendiceal fluid also indicated as a risk factor of complicated appendicitis[17]. However, this report defined complicated appendicitis as pathological appendicitis with gangrene, which might be different from clinically complicated appendicitis being resistant to conservative treatment as we think. Intraoperative findings included infected ascites in a few patients who underwent surgery and serous ascites in others. Douglas sines fluid was a risk factor even when these patients were included, and might represent the spread of inflammation.

The average length of hospital stay for conservative treatment was 10 days, which was longer than that in some reports. This attributed to the inclusion of all cases in which conservative treatment was indicated at the request of the patient despite the high inflammation level, and CT-detected appendicolith and abscess. These patients may require a relatively long time to improve. In addition, this was probably because all patients were managed by fasting until the data indicating inflammation improved. Moreover, they were hospitalized for several days after starting the diet. However, for patients who desire to avoid surgery, this length of hospital stay is considered acceptable if surgery can be avoided. Another problem is the long hospitalization period of 16 days for patients who underwent surgery. This is probably because 6 of 28 patients who underwent surgery underwent ileocecal resection.

There was also a risk that a neoplasm would be present in the patient with complicated appendicitis. Some reports have indicated that approximately 10% of neoplasms were found in interval appendectomy for complicated appendicitis[20,21]. In this study, 28 patients who were resistant to conservative treatment and underwent surgery had no neoplasms. However, we strongly recommended colonoscopy and CT after one month for all patients with findings such as appendicoliths and abscesses that improved with conservative treatment. There were no neoplasms among the patients who underwent CT and colonoscopy. However, it is uncertain whether this follow-up method is sufficient to rule out neoplasms.

This study has a limitation. There were no clear surgical criteria for patients whose conditions worsened after conservative treatment. The decision to perform surgery was left to the surgeons at the time. However, as the chief of our surgical team during this study did not change, we do not believe that the decision for surgery has changed significantly.

This study was a retrospective study conducted at a single institution. In the future, it may be desirable to conduct prospective studies for the patients with the above three or two factors; however, conducting such a study would be challenging. Therefore, we believe that it is necessary to present these results to patients with the above three or two risk factors and allow them to choose a treatment method. Furthermore, whether the results improve perioperative factors such as hospital stay and surgical complications should be examined.

CONCLUSION

In this study, the success rate of conservative treatment of acute appendicitis was 89.7%. The significant and independent predictors of resistance to conservative treatment were body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid on CT. The rate of resistance to conservative treatment was 66.7% for patients with the above three factors, therefore, surgical treatment should be recommended at the first visit. Body temperature ≥ 37.3 °C, appendicolith and Douglas sinus fluid on CT might be clinical risk factors for resistance to conservative treatment for acute appendicitis.