What is the main problem in the conservative management of complicated appendicitis? A meta-analysis

Background: As one of the classied groups of appendicitis, complicated appendicitis has no standardized treatment methods for adults. Method: The ecacy of surgical treatment and conservative treatment for complicated appendicitis was evaluated based on the literatures systematically searched on PubMed, Cochrane and Web of Science. A focus was given to important aspects, such as the outcomes of the length of stay, operation time, postoperative complications and unplanned additional interventions. Result: A total of 14 studies were involved in the meta-analysis, which included 845 patients in the immediate operation group (IO) and 756 patients in the conservative management group (CM). The total hospitalization time for patients with surgical treatment was decreased by 1 day (WMD= -1.29, 95% CI [-2.42, -0.16], P= 0.03< 0.05) compared to that of patients with conservative treatment. The incidence of unplanned additional interventions in patients who underwent emergency surgery is lower than that of patients with conservative treatment (OR=0.18, 95%CI [0.11, 0.30], P<0.00001). Compared to patients with conservative treatment, patients who received surgery are more likely to develop complications such as wound infection (OR=2.41, 95%CI [1.08, 5.38], P=0.03<0.05) and intestinal obstruction (OR=4.14, 95%CI [2.21, 7.75], P<0.00001). The incidence of abdominal abscess in patients with surgery treatment was lower than that of patients with conservative treatment, but the difference was not statistically signicant (OR=0.9, 95%CI [0.54, 1.47], P=0.66>0.05). Conclusion: In treating complicated appendicitis, patients who received immediate operation, when compared to patients managed under conservative treatment, have shorter hospitalization time and less unplanned interventions; hence signicantly reduce the likelihood of readmission. This can decrease the requirements for follow-up treatments and ultimately lower the consumption of medical resources.


Background
As the most common form of acute abdomen in ammation that, affec about 7-8 % of adults 1 , appendicitis is categorized into two groups: uncomplicated appendicitis and complicated appendicitis. Accounting for about 3.8-5.0 % of acute appendicitis 1 , complicated appendicitis is often related to the rapid development of acute appendicitis or the improper and untimely treatment 2 . The development of exudates, necroses and perforations in the appendix leads to the accumulation of in ammatory factors in the surrounding tissues of the appendix, which then causes the retina and the nearby small intestine to form an appendiceal wrapping of an in ammatory mass or localized abscess containing pus 3 .
For uncomplicated appendicitis, recent meta-analyses 4 have reported that antibiotic therapy could represent a feasible treatment option. Although the success rates of complication-free treatment generally are higher than those with surgical treatment, some studies have suggested that non-operative Page 3/23 management for uncomplicated appendicitis does not statistically increase the perforation rates in adults and in pediatric patients receiving antibiotic treatment 5,6 .
However, there are still contradicting views on the treatment of complicated appendicitis. Some studies have shown that patients with complicated appendicitis receiving immediate operation (IO) have shorter hospitalization time and lower recurrence rates compared with those receiving early conservative treatments, such as anti-infection interventions and interval surgical resections 7,8 . Consistently, recent published meta-analysis studies indicate that postoperative complications in patients with early surgery were signi cantly higher than those receiving of conservative surgery 7,9 . However, most studies have not focused on abdominal abscess appendicitis, as well as the short-term recurrence after early treatment. Recent advancements in the development of antibiotics and medical technology have enabled the use of new operation procedures, such as, laparoscopic and percutaneous puncture drainage for treating complicated appendicitis 10,11 . The improved treatment methods for complicated appendicitis have changed the recovery rates and the occurrences of complications in patients 12 . This study aims to compare patients with complicated appendicitis treated by surgical treatment with those receiving conservative treatment through meta-analysis using the data from recent related studies.

Research data acquisition
Target studies were screened through by two researchers (author 1 and 2) independently in accordance to the guidelines outlined in the Cochrane Handbook 13 as well as using uni ed literature standards.
Relevant effect indexes selected for the study, such as author, year, research purpose and sample size and relevant effect indexes selected for the study were sorted out respectively. Collected data were reviewed and discussed by the study organizer. Controversial materials were either selected or excluded as deemed appropriate by the study organizer.

Research selection and exclusion criteria
Our analyses only included studies that compare surgical methods (laparoscopic or open) and  conservative methods (anti-infection interventions or procedures involving early drainage and selective   appendectomy).
Eligible studies with the scores higher than 6 according to NOS 14 scoring system were de ned as highquality studies. The evidence quality in randomized controlled studies was evaluated using the method recommended by Cochrane Handbook 13 .
Selected studies ful lled the following criteria: 6. Randomized controlled studies or retrospective study were include.
The following studies were excluded in our analyses: 1. Studies with unful lled selection criteria; 2. Studies with incomplete important outcome data, and without reporting on the results of the two treatments; 3. Studies that only included patients with uncomplicated appendicitis; 4. Studies with inaccessible required data for meta-analysis through public channels; 5. Studies that failed to accurately deduce the outcome.

Outcomes and de nitions
The immediate operation group (IO) included patients with complicated appendicitis who underwent emergency surgical treatment and/or exploration. The conservative management group (CM) included patients with complicated appendicitis who failed early conservative treatment, those who had emergency surgical treatment or elective surgery after early conservative treatment, and those without undergoing surgery at all. The outcomes used to differentiate the IO group and the CM group were as follows 1. The length of hospital stay included the duration of the rst stay, the average length of stay, the postoperation length of stay and the total length of stay with readmission; 2. The duration of antibiotics application included the time of intravenous antibiotics during the rst hospitalization and the time after the development of recurrent appendicitis and other complications; 3. The overall complications referred to the number of complications caused by complicated appendicitis during the whole treatment period including follow-ups. The wound is closed afterwards to prevent the formation of an abscess caused by infections on the surface or deep layer of the skin.
Abdominal abscess and ileus obstruction were identi ed during the whole treatment process as diagnosed by imaging diagnosis or recognized during emergency surgery or interval appendectomy.
4. The unplanned additional interventions referred to unplanned medical interventions such as repeated surgery, emergency surgery and puncture drainage, etc) for recurrent appendicitis, abdominal abscess and other complications. that occurred during the treatment and follow-up period.

Data analyses and processing
Statistical analyses were performed using the Revman 5.3 software provided by the Cochrane collaboration and the Stata 15.0. For continuous variables, Weighted Mean Difference (WMD) and Standardized Mean Difference (SMD) were used for analysis to calculate the 95% con dence interval. For continuous variables that were di cult to calculate, the formulas described from the Cochrane Handbook 13 ,Hozo 17 Luo 18 and Wan 19 were used. The odds ratio (OR) was employed to analyze the dichotomous variables in the study. An OR value of < 1 was considered to be bene cial to the IO group.
The OR value was considered to be statistically signi cant with P < 0.05. A c 2 test was used to analyze inter-study heterogeneity. Whilst a xed effect model was used for homogeneous study P>0.05,I 2 <50% , a random effect model was used for heterogeneous study P<0.05,I 2 >50% . To analyze the publication bias in heterogeneous studies Stata 15.0 was used, with Egger method set at P< 0.1. The effects of publication bias on the robustness of our meta-analysis was evaluated by metatrim method 20

Overall complications
A total of 8 studies [22][23][24][29][30][31][32][33] reported the total number of complications within the duration from the onset of the disease to the follow-up period (Figure 2), and a signi cant heterogeneity was found among the studies (P <0.05; I²>50%), Overall, patients in group IO had more overall complications, but the

Abdominal abscess
There were 11 studies 21,23,24,27-33 that reported the occurrence of abdominal abscess (Figure 3. B). In one study, patients with diffuse peritonitis that were classi ed by Brown 26 as abdominal abscess, which did not meet the requirements of this study and therefore not included in the meta-analysis. The remaining 10 studies showed homogeneity (P >0.05; I²< 50%), but the difference was not statistically signi cant (OR=0.9, 95%CI [0.54, 1.47], P=0.66>0.05).

Wound infections
A total of 12 studies reported the incision infection (Figure 4. D Figure 4. E).

Discussion
In this study, we demonstrated that the total duration of hospitalization for patients with surgical treatment was decreased by about 1 day compared with those receiving conservative treatment. Despite the high heterogeneity, the event outcome was not reversed according to after the estimation by metatrim method, indicating that our meta-analysis was robust. In agreement with a previous study 23 , the incidence of unplanned additional interventions in patients undergoing emergency surgery was lower than that of conservative treatment, showing that patients undergoing conservative treatment were more likely to have emergency surgery or readmission due to failure of conservative treatment, recurrent appendicitis, abdominal abscess and potential malignancy.
However, patients undergoing IO are more prone to complications, such as wound infections and intestinal obstructions than those receiving CM. This may be related to the non-sterile abdominal environment during emergency surgery, while the conservative treatment group has a selective drain of the abdominal abscess to improve the environment. Meta-analysis of abdominal abscess showed that the incidence of abdominal abscess is not statistically signi cant different between the two groups. However, due to the lack of rigorous RCT studies, and the variety of patients, it is di cult to accurately determine the merits of surgery compared to those of percutaneous drainage for abdominal abscess.
Although published guidelines recommend conservative treatment for complicated appendicitis 35 , there is currently no standard treatment for complicated appendicitis with localized perforation, abscess or mass formation. In some hospitals, IO for complicated appendicitis remains the preferred treatment method for many surgeons. In recent years, the e cacies of conservative treatment for complicated appendicitis and whether or not to perform interval surgeries have been questioned 27 . Some patients with complicated appendicitis underwent surgical treatment to remove tumors found in the ileocecal part after successful conservative treatment. A small percentage of patients with conservative treatment ended up having worse symptoms that lead to more surgical treatments. In addition, the patients were required to continue the treatment. The patients with failed conservative management were eventually excluded from the analysis, which may lead our data analysis to be more inclined to non-surgical treatment.
As the follow-ups after discharge became more detailed, there were some obvious issues caused by conservative treatment, such as recurrent appendicitis, missed potential malignancies and unconsolidated appendicitis progressing to appendiceal mass. This study clearly highlighted that conservative treatment resulted in more additional operations for patients through the summary of studies in the last 20 years. At the same time, through statistical reasoning, this meta-analysis demonstrated that surgical patients have a shorter duration of hospitalization.
Longer hospitalization, more antibiotic applications and more unplanned treatments often result in higher costs for patients. In addition, recurrent appendicitis and potential tumors require multiple imaging and laboratory tests. This not only increases the burden of patients, but also consumes a large amount of medical resources. Repeated admissions also tend to increase the cost of inpatient management. While the complications of emergency surgical treatment for complicated appendicitis often occur during the rst admission, some minor complications such as wound infection can be treated at lower-level medical institutions. Hence surgical treatment is obviously better than conservative treatment for complicated appendicitis..
The results of this study highlighted some of the limiting aspects. For instance, most studies did not report a clear application duration of intravenous antibiotics, therefore unable to be included in our evaluation. There are also differences in the organ development due to young age in children, which widens the biggish differences of the organ in preventing infection. This study only focused on patients over the age of 12. Although the heterogeneity of analysis results was low in some studies, it should be noted that the overall clinical status of patients in each group varied considerably. Even if there was statistical equivalence in some key results between the two groups, the utilization of medical resources and perioperative care remained inconsistent. Availability of data and materials All data in this article are derived from published articles, and the data generated or analysed during this study are included in this article.

Competing interests
The authors declare that they have no competing interests.

Funding
All nancial support in this study came from corresponding author sponsorship

Authors' contributions
Each author is responsible for the design of the study, the analysis of the data and the drafting and revision of the article, and ensure that questions related to the accuracy or integrity of any part of the work The Corresponding authors Peng Gao ensure that all listed authors have approved the manuscript before submission, including the names and order of authors, make it certain that no author on earlier versions have been removed or new authors added, and all data comply with the transparency and reproducibility standards of both the eld and journal.     Supplementary Files This is a list of supplementary les associated with this preprint. Click to download.