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. 2026 Feb 4;411(1):80. doi: 10.1007/s00423-026-03979-7

Outcomes following out-of-hours acute appendectomy: a systematic review and meta-analysis

Jing Hu 1, Tao Zhang 2, ChuWen Chen, Xiyang Chen 3,✉, Hankui Hu 3,✉
PMCID: PMC12901186  PMID: 41639283

Purpose

Appendicitis is one of the most common emergency diseases. Currently, it is unclear whether there are differences in performing appendectomy during in-hour (IH) versus out-of-hour (OH).

Methods

A comprehensive search for studies that compared IH and OH was conducted in Web of Science, PubMed and EMBASE. Data of including studies were subjected to meta-analysis. The study was registered on PROSPERO (CRD42023467592).

Result

The result indicated that the OH group had more complicated appendicitis (OH 25.1% vs. IH 24.5%, RD = 0.02; 95% CI, 0.00 to 0.05; p = 0.04, I2 = 72%), higher level of C-reactive reaction protein (OH 44.88 ± 16.14 vs. IH 41.19 ± 16.50, MD = 12.15; 95% CI, 2.28 to 22.01; p = 0.02, I2 = 100%) and higher rate of conversion to open surgery {OH 8.0% vs. IH 7.8%, RD = 0.02; 95% CI, 0.00 to 0.03; p = 0.02, I2 = 93%. 95% Predictive interval (PI), -0.04 to 0.08}. No significant differences were observed in operative time, length of hospital stay, surgical site infection rates, readmission, reintervention, or the distribution of Clavien-Dindo grades1-2 and3-4 complications. Thirty-day mortality and overall mortality were also comparable.

Conclusion

OH appendectomy does not affect perioperative complications or mortality in patients with appendicitis compared to IH. These results should be interpreted cautiously due to the limited number of available studies.

Keywords: Acute appendicitis, Laparoscopic, Open surgery, Out-of-hours, In-hour, Meta-analysis

Highlights

1. The out-of-hour appendectomy may not affect the perioperative complications and mortality of appendicitis patients compared with in-hour appendectomy.

2. Patients that accepted out-of-hour appendectomy have a higher level of CRP and a higher proportion of complicated appendicitis.

Introduction

Acute appendicitis is a very common abdominal surgical emergency, often due to obstruction of the appendix cavity or bacterial infection caused by inflammation [1]. Appendicitis is classified into complicated appendicitis and uncomplicated appendicitis based on the presence or absence of complications such as perforation, abscess formation, intestinal obstruction, and fistula formation. The main treatment [2–5] for acute appendicitis included anti-infection and surgery, such as open appendicectomy, laparoscopic appendicectomy and endoscopic retrograde appendicitis therapy. The guidelines recommend that an appendectomy be performed within 24 h without delay [6, 7]. And the society of American gastrointestinal and endoscopic surgeons recommend that adult and pediatric patients with uncomplicated appendicitis may undergo either delayed (> 12 h) or immediate operation (< 12 h) [1].

However, whether performing appendectomy during in-hours or out-of-hours will affect the prognosis of patients with appendicitis is still controversial. Fatigue that caused by sleep deprivation in the nighttime may worsen both individual physician and team performance [8–11], potentially leading to the occurrence of medical errors. It was also called “nighttime effect”. Additionally, out-of-hours include not only nighttime but also weekends, and studies have shown that patients undergoing surgery on weekends have higher mortality rates [12–16], that was called “weekend effect”. The reduced staffing ratio of medical personnel during out-of-hours [12, 13] periods may lead to lower efficiency in various stages of patient care [15]—including examinations, diagnosis, transfers, surgeries, and monitoring—compared to standard working hours.

And the availability of a sufficient number of skilled medical practitioners is also lower at out-of-hours [17, 18]. Several meta-analyses [19, 20] found no significant differences in postoperative mortality or complication rates between nighttime and daytime appendectomies. But nighttime appendectomy had higher conversion rates [20]. They did not record preoperative comorbidity status and limited their analysis to nighttime procedures, failing to provide complete statistical evaluation of all off-hour appendectomies (encompassing both nighttime and weekend surgeries). Consequently, we systematically reviewed existing evidence to assess differences in preoperative patient profiles and determine the prognostic impact of surgical timing (in-hours vs. out-of-hours) in appendicitis cases.

Materials and methods

This study followed the PRISMA guidelines [21] and was registered at PROSPERO with registration number CRD42023467592. Two independent researchers (Chuwen Chen, Guoxin Chen) systematically searched the PubMed, Web of Science, EMBASE, Cochrane Central Register, and ClinicalTrials.gov databases for published studies that compared working hours with nonworking hours for acute appendicitis before 30 April 2023. In cases of disputes or discrepancies between researchers, a third author (XiYang Chen) was consulted to give the final judgment and provide a consensus. The combinations of the following key terms were used: appendicitis, laparoscopic, appendectomy, and surgery. To find additional studies, the references of eligible studies were manually searched. In-hour hours were defined as daytime in weekday. The out-of-hour time was defined as nighttime or outside normal working hours (such as weekend or holidays).

Search strategy and study selection

Inclusion and exclusion criteria

Two researchers individually screened all titles and abstracts to find papers that met the following criteria: (1) studies focused on comparing in-hour (IH) and out-of-hour (OH) studies; (2) studies that included randomized controlled trials (RCTs), retrospective studies, cohort studies, and case‒control studies; and (3) articles published in English. The exclusion criteria were as follows: (1) non-English or experimental studies; (2) studies without sufficient data; and (3) the publication type was editorials, abstracts, letters, case reports, or expert opinions.

Data extraction and quality assessment

The original data from all the candidate articles were independently assessed and extracted by three reviewers by using a unified datasheet, which included the following: baseline characteristics (first author, country, publication year, research design, sample size, mean age, sex, and American Society of Anesthesiologists (ASA) grade) score of 1 (fit and well) to 4 (a patient with comorbidities that are a constant threat to life), complicated appendicitis, operative complications, operative time, conversion from laparoscopic to open surgery and postoperative outcomes (postoperative bleeding, hospital stay, Clavien–Dindo grade, rehospitalization, surgical site infection, white blood cell (WBC) count and Creative reaction protein (CRP), 30-day mortality and overall mortality. The Newcastle–Ottawa Scale (NOS) [22] was used to evaluate the quality of the included studies, and an NOS score ≥ 6 was considered a high-quality article.

Statistical analysis

Statistical analysis was performed by using Review Manager 5.3 software and Stata 19. The summary effect size and its 95% CI was estimated by using both fixed-effects and random-effects models. The method of converting medians with ranges into means with standard deviations was in accordance with a prior study carried out by Hozo et al. [23]. The Higgins I2 index was used to quantify the statistical heterogeneity [24]. When heterogeneity was low or moderate (I2 < 50%), the fixed-effects model (FEM) was adopted. In contrast, the random-effects model (REM) was adopted when the heterogeneity was high (I2 ≥ 50%). And the 95% prediction interval (PI) was further estimated accounts for between-study heterogeneity [25].

Results and outcomes

Search results and characteristics of the included studies

Our thorough literature search produced 5554 pertinent English publications in total (Fig. 1). Finally, 18 retrospective studies [15, 26–42] and 1 randomized controlled trial [43] involving 208,823 patients that compared the effects of surgery in-hour (IH, 143516 patients) and out-of-hour (OH, 65307 patients) were identified for further analysis. The general information and quality assessment are listed in Table 1.

Fig. 1.

Fig. 1

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Study selection flow diagram according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines

Table 1.

Characteristics of included studies

Author-Year Country Study Type Study Interval Samples Age (Mean ± SD year) Gender(male) NOS
In-hour Out-of-hour In-hour Out-of-hour In-hour Out-of-hour
Mean SD Mean SD Even Even
Yaghoubian-201026 USA RS 2003–2009 878 708 24 8.34 24 10.23 NA NA 8
Mathias-201227 USA RS 1999–2008 113,457 38,317 39.56 15.8 39.54 15.99 59,672 20,129 8
Meschino-201435 Canada RS 2014 548 957 54.1 19.28 50.68 19.32 245 441 8
Ferguson-201438 UK RS 2012 2444 872 NA NA NA NA 1236 465 7
Allaway-201741 Australia RS 2004–2013 558 1185 25.85 3.321 27.31 2.852 NA NA 8
Kohga-201837 Japan RS 2013–2018 65 84 43.2 19.9 45 20.1 37 52 8
Lane-201836 USA RS 1997–2012 13,187 13,022 NA NA NA NA 8137 8344 8
Singh-201828 UK RS 2012–2017 133 141 32.617 2.916 32.17 3.236 NA NA 7
Canal-201939 Switzerland RS 2010–2017 5118 4106 36.2 18.33 36.7 18.73 2843 2156 8
Ndegbu-201933 USA RS 2012–2015 161 106 38.7 18.3 37.8 17.6 94 73 7
Mönttinen-202134 Finland RS 2014–2017 776 422 34.3 14.11 33.59 15.31 403 237 8
Harriott-202240 Argentina RS 2006–2021 1849 344 35.75 11.62 38.15 12.38 957 176 7
Bom-202242 Netherlands RS 2014 1130 231 40.03 4.14 33.22 4.13 567 134 7
Shah-202229 Egypt RS 2017–2020 514 487 NA NA NA NA 356 358 8
Basilio-202330 Spain RS 2017–2021 1088 555 10.37 3.3 10.3 3.4 437 200 8
Nyström-202332 Sweden RS 2015–2022 1380 3570 33.34 0.31 32.03 0.54 793 1960 8
Pogoreli´c -202331 Croatia RS 2020–2022 171 132 11.04 0.93 11.05 1.35 115 81 8
Patel-202343 Canada RCT 2018–2022 59 68 42.2 17 38.9 16.7 26 34 8
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SD standard deviation, NOS newcastle ottawa scale, RS retrospective study

Preoperative characteristics

The baseline data revealed that the patients who underwent in-hour (IH) surgery were not different in terms of age [26–28, 30–33, 35, 37, 39–44] (IH 39.1 ± 16.0 vs. OH 38.8 ± 16.4, MD = − 0.68; 95% CI, -0.12 to 1.48; p = 0.09, I2 = 99%.) or gender [27, 29–40, 42, 43] (IH 53.3% vs. OH 55.2%, RD = -0.01; 95% CI, -0.02 to 0.01; p = 0.45, I2 = 69%. Table 2).

Table 2.

Pooled patient preoperative characteristics

Variables No. of
studies		 No. of
patients*		 95% CI (RD, R,
/ SMD, F)		 P value I2
Age, years26–28,30−33,35,37,39–44 15 178,297 0.68 [-0.12, 1.48] 0.09 99%
Gender27,29–40,42,43 15 205,220 -0.01 [-0.02, 0.01] 0.45 69%
CRP32,34,35,37,42 5 9173 12.15 [2.28, 22.01] 0.02 100%
WBC34,37,40,42,43 5 5028 0.22 [-0.23, 0.67] 0.33 97%
Delays before surgery29,30,32,34,37,41–43 8 13,364 2.91 [-1.72, 7.54] 0.22 100%
Complicated appendicitis27–30,32,34,40,42,43 9 164,521 1.15 [1.02, 1.30] 0.04 72%
ASA score I–II28,32,34,38–40,43 7 16,619 0.98 [0.85, 1.12] 0.74 65%
ASA score ≥ III28,32,34,38–40,43 7 21,282 1.14 [1.01, 1.30] 0.38 64%
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*: in each group; CI confidence interval, M-H mantel-haenszel, risk difference, M-H random, 95% CI/ mean difference, fixed, 95% CI

White blood cells and C-reactive reaction protein (CRP)

The results of five studies [34, 37, 40, 42, 43] revealed that white blood cells were lower in the IH group than in the OH group (IH 13.0 ± 3.8 vs. OH 13.6 ± 3.6, MD = 0.22; 95% CI, -0.23 to 0.67; p = 0.33, I2 = 97%). Five studies [32, 34, 35, 37, 42] described CRP, the result showed that the OH group had higher level of CRP than the IH groups (OH 44.88 ± 16.14 vs. IH 41.19 ± 16.50, MD = 12.15; 95% CI, 2.28 to 22.01; p = 0.02, I2 = 100%. Fig. 2. Table 2).

Fig. 2.

Fig. 2

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Forest plot of the meta-analysis for CRP

Delays before surgery

Eight studies [29, 30, 32, 34, 37, 41–43] analyzed the delay time from diagnosis to surgery. But no difference was found between the IH group and the OH group (OH 9.5 ± 7.1 vs. IH 13.0 ± 7.7, MD = 2.91; 95% CI, -1.72 to 7.54; p = 0.22, I2 = 100%. Table 2).

Complicated appendicitis

Complicated appendicitis was examined in nine studies [27–30, 32, 34, 40, 42, 43]. The pooled analysis revealed that the incidence of adverse outcomes in the non-working hours surgery group was 25.1%, which was higher than the 24.5% observed in the working hours surgery group. The risk difference between the two groups was 0.02 (95% CI: 0.00–0.05), and this difference was statistically significant (p = 0.04). However, a high degree of heterogeneity was observed among the included studies (I² = 72%). (OH 25.1% vs. IH 24.5%, RD = 0.02; 95% CI, 0.00 to 0.05; p = 0.04, I2 = 72%. Fig. 3. Table 2).

Fig. 3.

Fig. 3

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Forest plot of the meta-analysis for complicated appendicitis

American society of anesthesiologists (ASA) grade 1–2, 3–4

Seven studies [28, 32, 34, 38–40, 43]reported the ASA grade, and the results revealed that there was no difference between the two groups in ASA grades 1–2 (OH 92.6% vs. IH 94.1%, RD = 0.98; 95% CI, 0.85 to 1.12; p = 0.74, I2 = 65%.) and ASA grades 3–4 (OH 6.0% vs. IH 4.8%, RD = 1.14; 95% CI, 1.01 to 1.30; p = 0.38, I2 = 64%. Fig. 4. Table 2).

Fig. 4.

Fig. 4

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Forest plot of the meta-analysis for ASA grades ≥ 3

Peri-and post-operative outcomes

Operative time

Operative time was examined in ten studies [26, 28, 30, 32, 34, 37, 39, 40, 42, 43]. The pooled estimates revealed that the IH group had a shorter operation time than the OH group did (IH 58.1 ± 36.2 vs. OH 57.4 ± 31.7, MD = 0.52; 95% CI, -3.34 to 4.37; p = 0.79, I2 = 100%. PI, -3.82 to 2.95. Fig. 5. Table 3).

Fig. 5.

Fig. 5

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Forest plot of the meta-analysis for operative time

Table 3.

Comparison of patient outcomes between in-hour and out-of-hour groups

Variables No. of studies No. of
patients		 95% CI, RD,
M-H		 95% PI P I2
Operative time26,28,30,32,34,37,39,40,42,43 10 22,705 0.52 [-3.34, 4.37] (-3.82, 2.95) 0.79 100%
Hospital stays28–31,34,36,37,39–42 11 45,298 0.01 [-0.07, 0.08] (-0.22, 0.32) 0.86 82%
Conversion to open surgery26,27,29,31,32,34,37–40,43 11 175,580 0.02 [0.00, 0.03] (-0.04, 0.08) 0.02 93%
Clavien–Dindo I–II31,33–42 11 175,707 0.00 [-0.00, 0.00] (-0.01, 0.01) 0.56 32%
Clavien–Dindo III–IV31,33–42 11 175,707 -0.01 [-0.02, 0.01] (-0.01, 0.02) 0.42 22%
Surgical site infection26,27,30,34,36–38,40 8 188,068 1.00 [0.92, 1.09] (-0.02, 0.02) 0.63 77%
Readmission29–32,37,40–43 9 13,469 0.00 [-0.01, 0.01] (-002, 0.01) 0.72 19%
Reintervention27,29,31,33,37,42 6 154,855 0.00 [-0.01, 0.01] (-0.02, 0.02) 0.64 37%
Overall complication26–36,38−42 16 208,547 0.00 [-0.00, 0.00] (-0.01, 0.01) 0.86 26%
Overall mortality26,27,32–34,36 6 185,984 0.00 [-0.00, 0.00] (-0.00, 0.00) 0.36 0%
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*: in each group; CI confidence interval, M-H mantel-haenszel, risk difference, M-H random, PI, prediction interval

Conversion from laparoscopic to open surgery

Conversion from laparoscopic to open surgery was reported in eleven studies [26, 27, 29, 31, 32, 34, 37–40, 43].This result indicated that fewer conversion occurred in the IH group than in the OH group (OH 8.0% vs. IH 7.8%, RD = 0.02; 95% CI, 0.00 to 0.03; p = 0.02, I2 = 93%. 95% PI, -0.04 to 0.08. Fig. 6. Table 3).

Fig. 6.

Fig. 6

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Forest plot of the meta-analysis for conversion from laparoscopic to open surgery

Calvien-Dindo 1–2, 3–4

The results of eleven studies [31, 33–42] revealed no difference in the Calvien-Dindo 1–2 score between the two groups (OH 7.6% vs. IH 5.4%, RD = 0.00; 95% CI, -0.00 to 0.00; p = 0.56, I2 = 32%. 95% PI, -0.01 to 0.01. Table 3). Similarly, the pooled data from eleven studies indicated no difference in the Calvien-Dindo 3–4 score (OH 12.0% vs. OH 12.4%, RD = 0.00; 95% CI, -0.00 to 0.00; p = 0.42, I2 = 22%. 95% PI, -0.01 to 0.02. Table 3).

Hospital stays

Eleven studies [28–31, 34, 36, 37, 39–42] analyzed the length of hospital stays, and the results revealed no difference between the two groups (IH 4.5 ± 3.6 vs. OH 4.9 ± 3.7, MD = 0.01; 95% CI, -0.07 to 0.08; p = 0.86, I2 = 82%. 95% PI, -0.22 to 0.32. Fig. 7. Table 3).

Fig. 7.

Fig. 7

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Forest plot of the meta-analysis for hospital stays

Surgical site infection

The rate of superficial surgical site infection reported in eight studies [26, 27, 30, 34, 36–38, 40] was lower in the OH group than in the IH group (IH 0.7% vs. OH 1.2%, RD = 1.00; 95% CI, 0.92 to 1.09; p = 0.71, I2 = 37%. 95% PI, -0.02 to 0.02. Table 3).

Readmission

The results of nine studies [29–32, 37, 40–43] revealed that the rate of readmission was also no different (OH 3.4% vs. IH 3.7%, RD = 0.00; 95% CI, -0.00 to 0.01; p = 0.72, I2 = 19%. 95% PI, -0.02 to 0.01. Table 3).

Reintervention

There was no difference in reintervention rate between in-hour and out-of-hour according to the pooled data of six studies [27, 29, 31, 33, 37, 42] (IH 0.11% vs. OH 0.11%, RD = 0.00; 95% CI, -0.01 to 0.01; p = 0.64, I2 = 37%. 95% PI, -0.02 to 0.02. Table 3).

Overall mortality

The pooled data of six studies [26, 27, 32–34, 36] indicated that the overall complication had no difference between the two groups (OH 0.09% vs. IH 0.08%, RD = 0.00; 95% CI, -0.00 to 0.00; p = 0.36, I2 = 0%. 95% PI, -0.00 to 0.00. Table 3).

Overall complication

The pooled data of sixteen studies [26–36, 38–42] indicated that the overall complication had also no difference between the two groups (OH 7.58% vs. IH 7.54%, RD = 0.00; 95% CI, -0.00 to 0.00; p = 0.86, I2 = 26%. 95% PI, -0.01 to 0.01. Fig. 8; Table 3).

Fig. 8.

Fig. 8

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Forest plot of the meta-analysis for overall complication

Discussion

Appendicitis is one of the most common acute abdominal problems, but the guidelines do not make a clear recommendation on whether appendicitis should be treated as an emergency or non-emergency. However, significant controversy persists regarding how surgical timing (working vs. non-working hours) affects clinical outcomes in appendectomy cases.

Operation during working in-hour and out-of-hour has always been a topic of concern, elective surgery and emergency surgery, and even different clinical subspecialties have such problems. Sleep deprivation may frequently occur during night surgery but also weekends. And weekend health care within numerous medical disciplines has been associated with poorer outcomes relative to care provided during regular weekday hours [12], that was called to “weekend effect”. Postoperative mortality rises as the day of the week of elective surgery approaches the weekend, and is higher after admission for urgent/emergent surgery on the weekend compared with weekdays (OR = 1.27) [16]. Several reviews [14, 45–49] have been performed looking into the existence of a weekend effect for different conditions, with a higher out of hours mortality rate being established for ST segment elevation myocardial infarction, acute epiglottitis, pulmonary embolism, and ruptured abdominal aortic aneurysm. In terms of the weekdays and weekends, the pooled data in our study does not suggest they are associated with the perioperative complications and mortality of appendectomy.

Our findings align with prior meta-analyses [17–20], yet these earlier studies were limited by smaller sample sizes and lacked comprehensive analysis of patient baseline characteristics. This meta-analysis valued the appendicitis patient’s condition, and assess the impact of in-hour and out-of-hour surgery on appendectomy. The results indicated that the patients that accepted out-of-hour appendectomy had a higher level of CRP, higher rate of conversion to open surgery, and more complicated appendicitis. This finding is clinically plausible, as elevated values of these indicators typically correlate with more severe symptomatology, necessitating more aggressive therapeutic interventions that inherently increase anesthesia risk in emergency settings. It should be noted that this difference was only of borderline statistical significance regarding the conversion-to-open rate and the incidence of more complex appendicitis. Although the risk of conversion to open surgery during non-working hours showed a slight increase, the absolute difference was minimal (0.6%) and the prediction interval crossed zero (95% PI: -0.04–0.08), indicating that the effect is unstable. Therefore, it is of profound importance to explore how to ensure consistent surgical quality around the clock through systematic optimization of healthcare resource allocation and scheduling.

Additionally, there is no difference in operation time, hospital stays, surgery site infection, and readmission, reintervention. This result was consistent with Shen et al. [19]. But the conversion from laparoscopic to open surgery was relatively high in OH group that was consistent with Tang et al’s [20]. The higher conversion rate in procedures performed during non-working hours could potentially stem from three interrelated factors: greater incidence of complex appendicitis, advanced disease severity, and exacerbated local inflammatory reactions. Regrettably, the current evidence base is insufficient to permit a stratified analysis identifying the precise determinants of this phenomenon.

How to reduce surgery-related complications and improve the prognosis is a problem that doctors always pay attention to. The concentration of doctors during in-hour and out-of-hour, the allocation of medical resources, and the availability of skilled doctors may lead to different complications or different outcomes for the same type of surgery [17]. The smooth operation of an operation is not only the surgical skill of the surgeon, but also the assistance and cooperation of the anesthesia and nursing community. Existing research has shown that sleep deprivation could have a negative impact on the performance of surgeons and anesthesiologists [8–11], possibly resulting in a decrease in surgical dexterity [11] and a slower reaction time for anesthesiologists [9]. However, the implementation of advanced hospital management protocols has progressively mitigated these confounding factors. Furthermore, patient-specific variables, including preexisting comorbidities and baseline clinical status at the time of surgery, remain significant determinants of outcomes. Ultimately, the potential association between off-hours appendectomy and adverse clinical events continues to be an active area of investigation.

The studies included in this study were all retrospective studies with significant heterogeneity. Owing to the limited literature, we did not conduct comprehensive subgroup analyses for different time periods. Moreover, different articles also have different definitions of working time and non-working time, and patients’ baseline differences also varied. Moreover, the included studies exhibited a broad age range, spanning from adolescents to middle-aged and older adults. Furthermore, given the retrospective nature of the included studies and the ongoing debate regarding the necessity of immediate surgery for uncomplicated appendicitis [1], the possibility that appendectomies were deferred until regular work hours cannot be excluded, thereby increasing the heterogeneity of the study.

Conclusion

Our results suggest that the out-of-hour appendectomy may not affect the perioperative complications and mortality of appendicitis patients compared with in-hour appendectomy, although patients that accepted out-of-hour appendectomy have a higher level of CRP and more complicated appendicitis. But the results indicating that the higher rate of conversion to open surgery in the out-of-hour require prudent interpretation based on the limited studies. Higher-quality perspective studies are still needed to explore the impact of the time of surgery on the outcomes of appendicitis.

Acknowledgements

None.

Author contributions

Jing Hu and Tao Zhang were responsible for data analysis and draft writing and the literature screening and data extraction. Jing Hu was responsible for data summary and completion. Chuwen Chen and Xiyang Chen was responsible for the study conception and design and for the literature retrieval. Xiyang, Chen and Hankui Hu were responsible for the final judgment and provided a consensus and the final judgment and decision of the final draft.

Funding

This study was funded by the Sichuan Province Science and technology Department social development key projects (No. 2024YFFK0241) and the postdoctor research fund of West China Hospital, SiChuan University (No. 2025HXBH067).

Data availability

The author confirms that all data generated or analysed during this study are included in this published article.

Declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jing Hu and Tao Zhang contributed equally to this work and are co-first authors.

Contributor Information

Xiyang Chen, Email: xiyangchen@wchscu.cn.

Hankui Hu, Email: huhankui@126.com.

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