Laparoscopic Appendectomy Combined with an “Antimicrobial-Free” Strategy for Acute Uncomplicated Appendicitis

Abstract

Objective:

To explore the efficacy and safety of enhanced recovery protocol (ERP) combined with laparoscopic appendectomy (LA) in the treatment of acute uncomplicated appendicitis (AUA) without antibiotics.

Methods:

In this study, a total of 160 patients with AUA who underwent LA between January 2018 and December 2021 were included and divided into the antibiotic group (n = 80) or the no-antibiotic group (n = 80). The patients in the antibiotic group received the ERP combined with antimicrobials during the perioperative period, while those in the no-antibiotic group only received the ERP during the perioperative period. The clinical data of these patients were collected to compare the inflammation level and stress state before and after surgery. In addition, the incidence of postoperative complications and the recovery speed of the patients were compared between groups.

Results:

There were no significant differences in the inflammation level and stress state before or after surgery, the incidence of postoperative complications or the recovery speed between the antibiotic group and the no-antibiotic group (P > .05).

Conclusion:

The use of ERP combined with LA as an antimicrobial-free treatment scheme in the perioperative period was found to be safe and effective for patients with AUA. Therefore, this approach is clinically valuable.

Introduction

Appendectomy has been the standard surgical treatment for acute appendicitis for more than one century.¹ With the advancement of medical technology, laparoscopic appendectomy (LA) has become the main surgical method. Because this method of appendectomy is safe and has a shorter length of stay (LOS),² it has been regarded as one of the routine operations for junior surgeons. However, empirical medication therapy, excessive medication use, antimicrobial abuse, and nontargeted medication therapy pose challenges in the perioperative medication scheme. Among them, antimicrobial abuse is the most serious problem and may have a substantial impact on the long-term survival of patients after surgery.

In recent years, many researchers, including physicians, have explored therapies for acute appendicitis. Evidence shows that most patients with acute uncomplicated appendicitis (AUA) can be treated with antibiotics alone instead of surgery.^3–9 However, methods to consider for the failure of conservative treatment, recurrent appendicitis, and resistance to antimicrobials are debated. Some patients with AUA who are undergoing treatment with antibiotics have satisfactory short-term outcomes. However, early conservative treatment may still be ineffective in some patients, and the incidence of related complications is higher among patients treated with antibiotics.¹⁰ In addition, a previous study found that the recurrence rate of AUA is >39.1%,¹¹ and another study observed a sixfold increase in hospital readmissions within 1 year of enrolment among patients receiving antibiotic treatment.¹² Eventually, appendectomy may be required for these patients. It will most likely lead to a longer hospital stay and a heavier economic burden due to the recurrence of the disease.¹³

Therefore, there is a demand for an AUA treatment scheme that can alleviate pain in the short term, prevent disease recurrence in the long term, and reduce the use of antimicrobials. The focus of this study was to explore whether enhanced recovery protocol (ERP) combined with LA is safe and effective in AUA patients without the use of antibiotics.

Patients and Methods

Trial design

The trial was a parallel design, randomized clinical trial. All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients provided signed informed consent for participation in the study before initiation of the intervention.

Patient selection

Patients with AUA treated at The Fifth People's Hospital of Chongqing between January 2018 and December 2021 were eligible for the study. Clinical data of the patients were collected according to the inclusion criteria. Patients were randomly divided into two groups: a no-antibiotic group and an antibiotic group. Clinical data were collected and compared between the two groups, including information on age, sex, American Society of Anesthesiologists (ASA) grade, basic disease, and physiological index.

Inclusion criteria

The inclusion criteria were as follows: (1) age 14–80 years; (2) patients with AUA diagnosed preoperatively (diagnosis confirmed by computed tomography scan defined by the following criteria: appendiceal diameter is between 6 and 10 mm with thickened and enhanced wall and periappendiceal edema and/or minor fluid collection, and the absence of the criteria for complicated appendicitis) and confirmed by postoperative pathology; (3) treated with appendectomy by the same group of doctors and with the same surgical instruments; (4) first onset of the disease (the patient had not previously received conservative treatment for appendicitis, including antibiotics), and the time between onset and operation was >48 hours; (5) Nutrition Risk Screening 2002¹⁴ score <3 points; (6) the cardiopulmonary function of the patient met the requirements of general anesthesia; the patient's glomerular filtration rate was >20 mL/min; (7) no radiotherapy or chemotherapy; and (8) an anesthesia ASA score <4 points.

Exclusion criteria

The exclusion criteria were as follows: (1) patients for whom acute simple appendicitis was considered preoperatively, but postoperative pathology indicated acute suppurative appendicitis and acute gangrenous appendicitis; (2) patients older than 80 years or younger than 14 years; (3) patients with severe chronic and systemic diseases; (4) patients with septic shock, diffuse peritonitis, perforation of appendix or periappendiceal abscess; (5) patients with abdominal malignancy or serious complications found during surgery; or (6) patients who could not tolerate laparoscopic surgery (including patients with severe heart and lung dysfunction; severe abdominal distension; middle and late pregnancy; or a history of previous abdominal surgery); (7) allergy to contrast media or iodine; (8) allergy or contraindication to antibiotic therapy; and (9) inability to cooperate and give informed consent.

Treatment

For all patients, the time from diagnosis of AUA in the emergency department to emergency surgery was <6 hours. All patients underwent the usual examinations and preoperative preparations. All patients were treated by the same surgeon. The same laparoscopic instruments were used by the same group of doctors, and all patients underwent LA surgery according to their condition. All patients were hospitalized for observation within 36 hours after surgery and discharged when adequate pain relief was achieved using oral analgesics.

Based on our team's previous experience with ERP,¹⁵ the patients in the antibiotic group received the ERP combined with antimicrobials during the perioperative period, while those in the no-antibiotic group only received the ERP during the perioperative period. Patients in the antibiotic group received a single dose of prophylactic preoperative antibiotics intravenously, including Cefotaxime (1 gm) and Metronidazole (500 mg), at 30 minutes before skin incision for port placement. The patients were also given an additional dose of Cefotaxime (1 gm) and two additional doses of Metronidazole (500 mg) intravenously within 24 hours after surgery. The respective treatments are detailed in Table 1.

Table 1.

Comparison of Intervention Measures During the Perioperative Period Between the No Antibiotic and Antibiotic Groups

	Antibiotic	No antibiotic
Preoperative preparation
1. Propaganda and education	Before surgery, patients received treatment-related information, including surgical procedure description, risk of surgery, and corresponding treatment measures
2. Drug application	Antibiotics were administered 30 minutes before surgery	Simple intravenous fluid replacement, mainly with normal saline
Intraoperative operation
1. Body temperature management	Maintain normal body temperature (underarm 36.0°C–37.0°C) by, e.g., regulating room temperature, infusion heating device
2. Liquid management	Esophageal Doppler ultrasound was used to monitor the effects of fluid intake on cardiac output, and to monitor fluid perfusion during the procedure
Postoperative intervention
1. Drug application	Antibiotics, rehydration fluids, and analgesic treatment were administered	Antibiotics were not used; however, rehydration fluids and analgesic treatment were administered
2. Analgesia	Analgesia was achieved through continuous epidural analgesia, intravenous self-controlled analgesia pump, nonsteroidal anti-inflammatory drugs, and multimodal analgesia
3. Catheter indwelling	No nasogastric tube, urinary tube, or abdominal drainage tube remained after surgery
4. Early enteral nutrition	Eating was encouraged 4 hours after surgery if the patient's condition was stable; however, slow transition to fluid diet was encouraged based on gastrointestinal tolerance
5. Early activities	Patient is encouraged to get out of bed within 6 hours after surgery, under the guidance of the nursing staff, if the patient could withstand it

Observation index

All patient care data were obtained from medical records: 1.

Fasting peripheral blood was collected from all patients before surgery, and preoperative white blood cell (WBC), neutrophil percentage (N%), and neutrophil–lymphocyte ratio (NLR) were calculated. To assess the postoperative inflammatory response and stress state, fasting peripheral blood was drawn at 72 hours after surgery to calculate postoperative WBC, N%, and NLR.

Complications were observed in both groups during the course of treatment, including incision infection, abdominal infection, intestinal fistula, and intestinal obstruction. Unplanned reoperation and mortality were analyzed.

The time of first exhaust and first defecation after surgery were recorded for the two groups, and the total hospitalization time and total cost were compared between the two groups.

Statistical analysis

All collected information was analyzed using SPSS Statistics for Windows, version 22.0 (SPSS Inc., Chicago, IL, USA). Quantitative variables with a normal distribution are expressed as the mean and standard deviation. Differences between the two groups were compared using t tests, and qualitative data were analyzed using the chi-square tests. A P value <.05 indicated statistical significance.

Results

Patient information

A total of 160 patients were enrolled according to the inclusion and exclusion criteria. The patient characteristics are shown in Table 2. There was no significant difference in age, sex, body mass index, or anesthesia ASA score between the no-antibiotic group and the antibiotic group.

Table 2.

Comparison of Preoperative Clinical Data Between the Two Groups

Parameter	Antibiotic	No antibiotic	Statistics	P
Age, years	48.49 ± 12.37	45.95 ± 13.08	t = −1.571	.076
Sex, male/female	42/38	41/39	χ² = 0.025	.874
BMI, kg/m²	22.96 ± 3.37	24.19 ± 3.18	t = 1.078	.865
ASA score, n			χ² = 0.527	.768
I	50	48
II	28	31
III	2	1

Data are presented as the mean ± standard deviation or n.

ASA, American Society of Anesthesiologists; BMI, body mass index.

Perioperative laboratory data

Laboratory data for the two groups are presented in Table 3. There was no significant difference in the results of the two groups at all time points (P > .05).

Table 3.

Comparisons of White Blood Cells, Neutrophil Percentage, and Neutrophil–Lymphocyte Ratio Between the Two Groups

	Antibiotic	No antibiotic	Statistics	P
WBC ( × 10⁹/L)
Preoperative	6.77 ± 1.68	6.74 ± 1.66	0.098	.922
Postoperative 24 hours	8.36 ± 1.60	7.91 ± 1.61	1.905	.060
Postoperative 72 hours	6.59 ± 1.31	6.57 ± 1.26	0.109	.914
NEUT (%)
Preoperative	60.01 ± 5.76	61.26 ± 5.69	−1.300	.197
Postoperative 24 hours	70.99 ± 6.02	69.90 ± 5.69	1.250	.215
Postoperative 72 hours	60.31 ± 5.48	59.75 ± 5.45	0.681	.498
NLR
Preoperative	1.60 ± 0.25	1.59 ± 0.24	0.119	.905
Postoperative 24 hours	1.94 ± 0.28	1.92 ± 0.34	0.311	.756
Postoperative 72 hours	1.58 ± 0.25	1.59 ± 0.21	−0.253	.801

NEUT, neutrophil percentage; NLR, neutrophil–lymphocyte ratio; WBC, white blood cell.

Postoperative complications

No postoperative complications or serious adverse events occurred in any patient, including incision infection, abdominal infection, intestinal fistula, or intestinal obstruction. Unplanned reoperation and mortality were analyzed.

Postoperative recovery

Details of the postoperative recovery parameters are presented in Table 4. First exhaust time, first defecation time, and length of hospital stay were not significantly different between the two groups (P > .05). However, hospitalization costs were significantly lower in the no-antibiotic group than in the antibiotic group (P < .01).

Table 4.

Comparison of Postoperative Data Between the Two Groups

	Hospital stay (hours)	Hospitalization expenses (¥)	First exhaust time (hours)	First defecation time (hours)
Antibiotic	41.53 ± 3.50	5527.19 + 301.45	7.22 ± 1.60	21.94 ± 2.30
No antibiotic	42.35 ± 3.57	5042.04 ± 304.53	6.90 ± 1.76	22.19 ± 2.38
t Value	−1.589	11.238	1.180	−0.679
P value	.116	.000	.242	.499

Discussion

ERP can reduce the stress response in patients, reduce the physiological trauma caused by surgery, reduce the systemic inflammatory response, promote postoperative recovery, and reduce the occurrence of postoperative complications.^16–19 In recent years, the focus of several studies on ERP has been the perioperative period of emergency surgery. Related studies have emphasized that although ERP is commonly used in elective settings, it can lead to favorable outcomes in emergency settings.^20,21 In similar studies, researchers have noted that although some preoperative ERP cannot be performed in emergency settings (e.g., nutritional support, preoperative oral carbohydrate intake),^22–26 intraoperative and postoperative ERP can be performed in patients with AUA in the perioperative period (e.g., intraoperative body temperature control; strict restriction of perioperative fluid input; unconventional drainage tube placement; early postoperative feeding; early ambulation).

The laparoscopic technique was first published by Jacobs.²⁷ In the guidelines proposed by the Society of American Gastrointestinal and Endoscopic Surgeons, LA is recommended as the treatment of choice for adult patients with AUA and for pregnant women with suspected appendicitis.²⁸ A retrospective study of 198 patients with acute appendicitis showed that,²⁹ compared with open appendectomy (n = 105), laparoscopy (n = 93) was the preferred treatment for appendicitis because of the shorter hospital stay (2.6 versus 3.4 days, P < .01), earlier return to routine activity (14 versus 21 days, P < .02), shorter duration of parenteral analgesia (1.6 versus 2.2 days, P < .01), and lower rates of surgical site infection (SSI) (48%–70% decrease, P < .01). The purpose of the laparoscopic technique is to minimize the trauma caused by surgery and reduce the possible stress reaction in patients during surgery. This is highly consistent with the effect of ERP, so the advantages can be maximized by combining the two methods.

In our study, no postoperative complications or serious adverse events occurred in any of the patients, and the treatment effect was satisfactory with or without the use of antibiotics. Neutrophils, leukocytes, and NLR, which are helpful in diagnosing acute appendicitis and measuring severity,³⁰ are stable in the perioperative period, indicating a satisfactory treatment effect. After comparing our results to related studies,^31–33 we concluded that ERP combined with laparoscopy treatment is safe, has a low complication rate, and has the characteristics of the curative effect. Thus, applying this treatment can effectively improve patient conditions. In addition, a total of 12 patients withdrew from the study. Among them, 9 patients withdrew during the operation because they did not meet the diagnostic criteria for AUA. The 9 patients were given corresponding surgical treatment during the operation and received regular antibiotic therapy after the operation. Three patients were excluded after the operation due to pathology reports indicating suppurative appendicitis. We extended the stay of the 3 patients to 96 hours without antibiotics and conducted close observation.

Due to the short course of the disease, light abdominal cavity infection, and the use of laparoscopic techniques, the abdominal cavity can be thoroughly flushed, 12 patients recovered satisfactorily after surgery, and no complications occurred (including incision infection).

In recent years, scholars who supplement conservative treatment of AUA with antibiotics believe that conservative treatment will lead to a shorter LOS. In a large multicenter cohort study,³⁴ antibiotics were found to be an alternative first-line treatment for adult patients with acute appendicitis, in part, because conservative treatment with antibiotics was associated with a shorter median LOS for patients who underwent LA (2.5 versus 3 days). However, in our study, the LOS of patients who underwent the ERP was within 48 hours. In addition, due to regional differences in medical means, diagnosis, treatment, and management, some medical institutions^35,36 can discharge patients with AUAs on the same day of surgery, namely, day-case surgical patients. This suggests that surgical treatment better aligns with shorter LOS. A shorter LOS is associated with reduced medical costs and reduced risk of incision infection after surgery.^37,38

The main aim of prophylactic antibiotics is to lessen the occurrence of postoperative SSI.³⁹ SSI accounts for ∼15% of all nosocomial infections and usually develops when endogenous flora is translocated to a normally sterile site. Nevertheless, in AUA, the lesions are mainly concentrated in the mucosa or submucosa of the appendix, and there is no purulent coating covering. In other words, there is no bacterial translocation in the abdominal cavity before the operation begins. Adnan Aslan's findings support this idea: because no significant bacterial translocation frequency or tissue injury score was identified in children with noncomplicated acute appendicitis, antibiotic prophylaxis may be unnecessary in such patients.⁴⁰ In 1981, Amgwerd proposed through a prospective study that wound infection after appendectomy cannot be prevented by prophylactic use of antibiotics. Careful operation techniques with local protective steps are quite sufficient.⁴¹ It may have been difficult to accept at the time. However, we must consider the current status of LA.

First, LA reduces the incidence of SSIs, as demonstrated in Huseyin Ozgur Aytac's study,⁴² in Xiao's study⁴³ and in Alganabi's study.⁴⁴ Second, before the appendix is severed, the appendix is closed with a Hem-o-lok clip at each end of the proposed section to prevent the migration of bacteria from the appendiceal cavity into the abdominal cavity. Finally, the appendix is placed in a specimen retrieval bag immediately after it is severed, which can dramatically decrease the possibility of incision infection caused by the appendix in the process of specimen isolation. This value has also been reported in other studies.^45,46 These procedures are sufficient for the prevention of postoperative SSIs in patients with AUA. This was confirmed in our study; although all patients in the no-antibiotic group did not receive prophylactic antibiotics, compared with the antibiotic group, all patients had a good prognosis and did not develop any SSIs.

Conclusion

In our study, we were the first to perform ERP combined with laparoscopy to treat AUA without antibiotics during the perioperative period. The lesions can be removed in surgery to avoid the progressive aggravation of the disease. The combined treatment is effective and safe, leads to favorable postoperative recovery, eliminates the risk of appendicitis recurrence, and reduces the use of antimicrobials. However, our study also has certain limitations. As a single-center research project, the results need to be further confirmed. Moreover, there is a lack of long-term follow-up data, which may have a certain impact on the conclusions of this study.

Footnotes

Authors' Contributions

M.X. and X.L. conceived and designed the research. M.X. carried out experiments and analyzed the data. M.X. and X.L. wrote the main article. All authors discussed the results and commented on the article. All authors read and approved the final article.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon request.

Ethics Approval

This study was approved by the Ethics Committee of The Fifth People's Hospital of Chongqing from January 2018 (Identifier: LCT20180017).

Consent

All patients or their authorized clients agreed to participate in the study and signed the informed consent form.

Disclosure Statement

The authors declare that there are no conflicts of interest.

Funding Information

This study is supported by grants from the Medical Research Program of Chongqing Health and Family Planning Commission (Grant No. 2022QNXM011).

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