The Safety of Minimally Invasive and Open Cholecystectomy in Elderly Patients With Acute Cholecystitis: A Systematic Review

Elderly patients with acute cholecystitis (AC) often receive no surgical treatment due to a high number of comorbidities and a high risk of operations. With an increasingly aged population worldwide, this systematic review aims to review the safety of minimally invasive cholecystectomy and open cholecystectomy in this population compared to younger patients. A systematic search was conducted on PubMed, PubMed Central, and Google Scholar databases on July 2, 2022. Articles in the English language published in the last five years with free full text and involving elderly patients with AC treated with minimally invasive and open cholecystectomy were selected. Moreover, a quality assessment was carried out by using each study's most commonly used assessment tools. Initially, the search yielded 1,252 potentially relevant articles. After the final selection process, 11 studies were included: one cross-sectional study, eight cohort studies, one case-control study, and one systematic review with meta-analyses. These studies involved a total of 378,986 participants, with 375,623 elderly patients. In the elderly, cholecystitis severity, decreased physical status, and multiple comorbidities increase the risk of complications with cholecystectomy. In addition, the elderly had more complications, open surgery conversions, biliary tract injuries, leaks, postoperative mortality, and hospital length of stay than younger patients. Nevertheless, minimally invasive cholecystectomy is a viable treatment option for elderly patients when performing a thorough perioperative assessment.

The references of all the articles were grouped and organized in alphabetic order using Excel 2021. Then, two authors removed the duplicates, they also reviewed the titles and abstracts independently and excluded any irrelevant articles. Then the complete articles of the studies identified were retrieved and reviewed. The investigators decided to exclude conference papers, abstracts, guidelines, and case reports due to the lack of analysis required for this study. They included the sole systematic review conducted in the field so far.

Risk of Bias in Individual Studies
The remaining full articles were assessed by two independents authors for quality assessment and risk bias using different tools depending on the type of study: cross-sectional studies, Joanna Briggs Institute (JBI) critical appraisal checklist; cohort and case-control studies, the Newcastle-Ottawa Scale (NOS); systematic review and meta-analyses, assessment of multiple systematic reviews 2 (AMSTAR 2) [10][11][12]. The assessment tools had their criteria and different scoring. When the tool scores "YES," "PARTIAL YES," or "1," a point is given. When "2" is indicated, two points are given. A minimum of 70% score for each assessment tool was accepted ( Table 2).  (1) Were the criteria for inclusion in the sample clearly defined? (2) Were the study subjects and the setting described in detail? (3) Was the exposure measured validly and reliably? (4) Were objective, standard criteria used to measure the condition? (5) Were confounding factors identified? (6) Were strategies to deal with confounding factors stated? (7) Were the outcomes measured validly and reliably? (8)

Data Collection and Analysis
Two authors extracted the data independently. Due to the varying measures of observer variability between the studies, such as heterogeneity of participants, intervention, and outcome measures, this systematic review describes these studies based on their outcomes in a narrative synthesis. Complete articles were analyzed and tabulated into a table. The data collected for each study include first author, year of publication, study type, country of origin, number of patients, the definition of elderly or age ranges, indications of surgery, type of surgery, preoperative evaluation of the anesthetic-surgical risk based on the American Society of Anesthesiology Physical Status (ASA PS), comorbidity, and the results.

Study Outcome
The outcomes analyzed were the overall complications reported, the rate of conversion to open surgery, bile leaks and biliary tract injury, postoperative mortality, and hospital stay duration.

Evaluation of Study Selection and Quality
The database search yielded a total of 1,252 potentially relevant titles. Google Scholar automatically deleted one title. The removal of duplicates was also done, with 952 records retained. A total of 30 articles remained when the titles and abstracts of these records were screened based on this review's PIO elements and eligibility criteria; these articles were retrieved, and conference papers, abstracts, guidelines, and case reports were excluded (18 articles). Finally, the quality assessment for each article was done, and 11 studies with a score of greater than 70% were accepted for the review. These included one cross-sectional study, eight cohort studies, one case-control study, and one systematic review with meta-analyses. No other resources were added. We followed the PRISMA 2020 guidelines for screening and study selection. Figure 1 shows the PRISMA flow diagram illustrating the process [9]. Each study was evaluated with the appropriate quality assessment tool for each study type, and the results were tabulated. For example, the only cross-sectional study in the review was assessed using the JBI tool. This study scored 7/8, with item 6 recorded as "NO" because the strategies to deal with confounding factors were not stated. This information is shown in Table 3 below.  NOS tool was used in assessing all the cohort studies, and most of the accepted cohort studies had a score of "1" for each item; two studies used multiple controls for the confounding factor in the analysis scoring "2" in item 5. Most studies fail to assess the adequacy of the follow-ups, scoring 0 in item 8. One study that scored 6 (<70% of quality) was excluded from the review. The summary of the assessment is presented in

TABLE 4: Review authors' summary of the coding manual for cohort studies
The case-control study was assessed using the NOS tool, and the accepted study had a score of "1" for each item, with a total of 8/9 ( Table 5).

TABLE 5: Result summary of coding manual for the case-control study by review authors
One study was a systematic review with meta-analysis. Upon scoring using AMSTAR 2 tool, the accepted reviews had "NO" in items 3 and "Partial Yes" in items 4 and 8. These items discussed the explanation of the selection of the study designs, literature search, and studies description, respectively, as presented in Table  6.

Study Characteristics
The key traits of the cohorts, case-control study, cross-sectional analyses, and the systematic review with meta-analysis in the review are presented in chronological order in Tables 7-8   The cut-off ages utilized to designate elderly populations varied significantly, with age 60 (n=3 studies), 65 (n=3 studies), 70 (n=1 research), 75 (n=1 study), and 80 (n=3 studies) being the most common. The features and outcomes of the studies were described using the age groups established by each study. There were a total of 375,623 elderly patients in the 11 studies.
The systematic review and meta-analysis was the study with a significant population of 326,517 elderly patients (>60 years old) receiving laparoscopic cholecystectomy. Also, this study mainly emphasized the perioperative results of the surgery. In contrast, the rest of the studies reported the patients' physical status and comorbidities before the surgical intervention.

Outcomes
The authors analyzed all the studies in search of the overall complications reported, the rate of conversion to open surgery, bile leaks and biliary tract injury, postoperative mortality, and length of hospital stay. Unfortunately, some of the secondary results were not reported due to the different methods used in the study design. The resumed studies' outcomes are presented in Table 9. The mortality (5.4%) and morbidity rate in group A were more significant (14.3% vs.  [13] stay due to organ failure, with 10 (6.5%) of them being under the age of 65 and nine (4.8%) being over that age and nine patients (12 [14]. Also, Escartín et al. reported increased use of conservative treatment with increased age [18]. However, the rest of the studies did not note differences in the treatment received.
When comparing the type of surgery, half of the studies reported a laparoscopic procedure as the preferred course of treatment [15,17,20,22,23]. In contrast, in the rest of the studies, the number of open approaches was minimum. Due to this, a proper comparison between the open and laparoscopic procedures could not be made because the open procedure was not a first-line surgical treatment option regardless of the patient's age [13,16,18,19,21]. Furthermore, none of the studies uses robotic-assisted cholecystectomy.
In the case of preoperative physical status (ASA), elderly patients have higher score distribution; this was reported by Serban et al. and supported by the linear-by-linear association test [21]. Furthermore, ASA III and higher were more significant in the elderly group in most studies, showing an increased surgical risk. However, according to the same research, surgery is safe if an adequate preoperative assessment is performed on the elderly [13,[15][16][17][18][19][20][21].
Elderly patients have a higher burden of comorbidity when compared to their younger counterparts, which results in a higher frequency of complications [26]. This is evidenced by a significantly higher CCI in elderly groups [13,14]. Cardiovascular illness, lung disease, and diabetes were the most prevalent concomitant diseases [15][16][17][18]. Consequently, Wiggins et al. reported fewer comorbidities in patients who underwent emergency cholecystectomy [14].

Overall Complications
In general, an increase in age has been substantially linked to higher risks of surgical complications. Most of the studies in this review reported an increase in overall complications associated with the increasing age of the patients. However, the age of cut-off varies in the studies. For example, Serban et al. reported an increased rate of postoperative complications in patients over 50 and an increase in age-related cardiovascular postoperative complications [21]. In the same way, Bass et al. and Kamarajah et al. reported higher postoperative problems in patients over 65 [13,23]. However, Escartín et al. report increased complications with the increase in AC severity. Serious complications are more frequent in patients with grade III AC, independent of the treatment [18]. Also, Loozen et al. discovered that severe AC was linked to higher comorbidity [16].

Conversion to Open Surgery
The probability of converting to an open cholecystectomy rose considerably with age. This was consistently reported by the majority of the studies [13,15,16,19,20]. These results contrast with the study conducted by Shin et al., where no significant differences in conversion rate were discovered [17]. Also, the effect of advancing age on conversion to open cholecystectomy was documented in 53 studies with 59,173 patients, forming part of the systematic review and meta-analysis by Kamarajah et al. [23]. This result is consistent with the literature, which shows that advanced age increases the risk of converting to an open procedure [27].

Bile Leaks and Biliary Tract Injury
There was a significant correlation between age and bile leakage [13,16,19]. Similarly, Kamarajah et al. reported that the effect of aging on bile leakage was documented in 30 studies involving 42,765 patients [23]. In the same way, biliary tract injury was reported more frequently in elderly patients [15,16]. However, Shin et al. did not find a difference in the incidence of biliary tract injury between old and young groups [17].

Postoperative Mortality
Aging was substantially linked to higher postoperative mortality rates [13,15,16,[18][19][20]. Likewise, Kamarajah et al. reported that the effect of aging on postoperative mortality was observed in 50 studies with 78,404 patients [23]. Moreover, Wiggins et al. stated that in the case of elderly patients undergoing emergency cholecystectomy, the mortality rate can be as high as 11.6%. However, one of the major flaws of this research was that it did not consider the associated comorbidities and their impact on the outcomes [14]. In contrast with these findings, Antoniou [28].

Overall Outcomes
In elderly patients with mild to moderate AC, minimally invasive therapy appears to be a practical and effective therapeutic option. Conservative treatment is deemed ineffective based on existing research [14,18,29,30]. Comorbidities, however, should be kept in mind since they may complicate the procedure and the postoperative recovery period [15,16,18,19,21]. Complication and conversion rates are comparable across age groups when adequate preoperative assessment and therapy are carried out [17]. The severity of the disease (grade III AC), poor physical condition, and/or comorbidities rather than age per se can limit the therapeutic options available to older AC patients [13,18,20,21]. Also, reduced readmission rates and oneyear mortality are two potential advantages of emergency cholecystectomy in very elderly patients reported [14]. However, Kamarajah et al., in their meta-analysis of 99 studies, support prior assumptions that older patients undergoing cholecystectomy face increased risks and reported a seven-fold rise in perioperative mortality, which rises to 10-fold in patients over the age of 80 years. Furthermore, they recommended surgery selection on a patient-by-patient basis [23].

Limitations
This review restricted the included studies to those in the English language and those with a free full text published in three databases between 2018 and 2022. Gray literature and other databases were not used. In addition, the majority of the studies that the search yielded were cohort studies. Furthermore, the review was limited by the heterogeneity of the studies. For example, the studies vary in patient age, preoperative evaluations, and treatment options. No randomized controlled clinical trials (RCTs) or studies involving robotic-assisted cholecystectomy in the elderly with AC were found.
There was no extensive follow-up in the patients; most of the studies focused on the immediate postoperative results instead of preoperative management. Therefore, we recommend observational studies with longer follow-ups after surgery and adequate preoperative preparations as well as RCTs to find out which procedures or treatments provide the most significant benefits to elderly patients.

Conclusions
The studies included in this review demonstrate that in the elderly, compared with younger patients, the surgical treatment of AC is a challenging decision. The severity of this condition, the diminished physical status, and multiple comorbidities increase the risk of operative and postoperative complications in the older group of patients. Even though there is no consensus on the surgical treatment of AC in elderly patients, the laparoscopic approach is the preferred procedure for cholecystectomies. It can be safely performed in older patients and the conservative approach is not recommended.
The overall complications, open surgery conversions, biliary tract injury, leaks, postoperative mortality, and hospital length of stay increase considerably with age. Nevertheless, minimally invasive cholecystectomy is a feasible treatment option for elderly patients suffering from mild to moderate AC when a comprehensive perioperative assessment is conducted. Most complications reported in old patients who underwent cholecystectomy were related to the burden of comorbidities and cholecystitis severity than to the age or surgical procedure. That being the case, a thorough optimization of elderly patients with severe cholecystitis or severe comorbidities is required to determine the optimal treatment. Furthermore, extensive observational studies and RCTs need to be conducted and guidelines regarding associated diseases, physiological status, and age have to be devised and published.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.