Abstract
Background/Aim: The aim of this study was to identify predictors of conversion from laparoscopic to open cholecystectomy, and to determine whether pre-operative C-reactive protein-to-albumin ratio (CAR) can predict conversion from laparoscopic to open cholecystectomy, in patients with acute cholecystitis diagnosed according to the Tokyo Guidelines 2018. Patients and Methods: We retrospectively analysed 231 patients who underwent laparoscopic cholecystectomy for acute cholecystitis between January 2012 and March 2022. Two hundred and fifteen (93.1%) patients were included in the laparoscopic cholecystectomy group; sixteen (6.9%) patients were included in the conversion from laparoscopic to open cholecystectomy group. Results: In univariate analysis, significant predictors of conversion from laparoscopic to open cholecystectomy included the interval between symptom onset and surgery (>72 h), C-reactive protein (≥15.0 mg/l) and albumin (<3.5 mg/l) levels, pre-operative CAR (≥5.54), gallbladder wall thickness (≥5 mm), pericholecystic fluid collection, and pericholecystic fat hyperdensity. In multivariate analysis, elevated pre-operative CAR (≥5.54) and the interval between symptom onset and surgery (>72 h) were independent predictors of conversion from laparoscopic to open cholecystectomy. Conclusion: Pre-operative CAR as a predictor of conversion from laparoscopic to open cholecystectomy may be useful for pre-operative risk assessment and treatment planning.
- Conversion to open cholecystectomy
- C-reactive protein-to-albumin ratio
- laparoscopic cholecystectomy
- Tokyo Guidelines 2018
Laparoscopic cholecystectomy is the standard treatment for acute cholecystitis (1, 2). Laparoscopic cholecystectomy is advantageous, because it is associated with a shorter length of hospital stay, reduced wound pain, and fewer post-operative complications than open cholecystectomy (3). The Tokyo Guidelines 2018 (4) recommend that laparoscopic cholecystectomy for acute cholecystitis, especially severe acute cholecystitis, be performed carefully and in advanced laparoscopic surgery centres. The technical difficulties of laparoscopic cholecystectomy vary depending on the degree of inflammation and fibrotic changes in the gallbladder. These difficulties lead to conversion to open cholecystectomy in 1.8-15.0% of cases (5-7), increasing peri-operative times, complication rates, and the length of hospital stay (8). It is important to identify risk factors for conversion to open cholecystectomy to improve procedural safety and treatment planning.
Conversion to open cholecystectomy for acute cholecystitis is associated with male sex, older age, diabetes mellitus, elevated C-reactive protein (CRP) levels, hypoalbuminaemia, elevated white blood cell count, a history of upper abdominal surgery, and the experience of the surgeon (9-13). CRP and albumin levels are associated with the severity of acute cholecystitis, according to the Tokyo Guidelines 2018 (4). Low albumin levels indicate a weakened immune system, malnutrition, and poor prognosis. CRP and albumin levels can predict the severity of acute cholecystitis (14). The Glasgow Prognostic Score (GPS) is used to predict the severity of inflammatory diseases, such as acute cholecystitis (14). The pre-operative CRP-to-albumin ratio (CAR) was established as a novel inflammation-based prognostic score to identify patients with severe disease on admission (15). Ranzani et al. (16) reported that pre-operative CAR was associated with poor prognosis in patients with sepsis.
To our knowledge, few studies have examined predictors, including inflammatory markers, of conversion from laparoscopic to open cholecystectomy in acute cholecystitis. The aim of this study was to identify predictors of conversion from laparoscopic to open cholecystectomy, and to determine whether pre-operative CAR can predict conversion from laparoscopic to open cholecystectomy, in patients with acute cholecystitis diagnosed according to the Tokyo Guidelines 2018.
Patients and Methods
Ethical approval. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and adhered to the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects, effective 13th December 2001. The study design was approved by the Ethics Committee of the National Hospital Organization Fukuyama Medical Center (approval number: R3-9). The requirement for written informed consent was waived owing to the retrospective nature of the study.
Study design and setting. We conducted a retrospective cohort study of patients with acute cholecystitis diagnosed according to the Tokyo Guidelines 2018 who underwent laparoscopic cholecystectomy at the National Hospital Organization Fukuyama Medical Center between January 2012 and March 2022. Patients with common bile duct stones, cholangitis, or pancreatitis were excluded. Patients were categorised into two groups by surgical procedure: laparoscopic cholecystectomy and conversion from laparoscopic to open cholecystectomy.
Data collection and definitions. The following clinicopathological data were obtained retrospectively from medical records: sex, age at surgery, body mass index (demographic data), body temperature at diagnosis, the interval between symptom onset and surgery, Murphy’s sign (clinical data), serum CRP and albumin levels, platelet count, white blood cell count, amylase and creatinine levels (laboratory data), American Society of Anaesthesiologists physical status, intra-operative blood loss, operative time (operative data), length of hospital stay, and morbidity (surgical outcomes).
The following inflammatory markers were measured: CAR, GPS, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). The CAR was calculated by dividing the CRP level by the albumin level. The GPS was constructed as follows: patients with both an elevated CRP level (>1.0 mg/dl) and hypoalbuminaemia (<3.5 g/dl) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively (17). The NLR was calculated by dividing the neutrophil count by the lymphocyte count (18). The PLR was calculated by dividing the platelet count by the lymphocyte count (19).
Gallbladder wall thickness, cholecystolithiasis incarceration, pericholecystic fluid collection, and pericholecystic fat hyperdensity were measured by computed tomography. The severity of acute cholecystitis was defined according to the Tokyo Guidelines 2018 (20). Post-operative complications were classified according to the Clavien-Dindo classification (21).
Surgical procedure. Surgical residents and a board-certified surgeon of the Japan Surgical Society performed the surgery under general anaesthesia. Ports were inserted into the navel, upper medial abdomen, and right subcostal and lateral abdomen. Electrocautery was performed in all patients. In cases of severe inflammation, an ultrasonic coagulation-cutting device was used. The cystic duct and artery were clipped, and the gallbladder was excised. To avoid bile duct injury, we simultaneously identified Calot’s triangle and excised the cystic duct and artery (4, 22). Specimens were removed from the umbilical wound using an extraction bag. In cases of severe inflammation and bile leakage due to gallbladder perforation, a drainage tube was inserted. The tip of the tube was placed in the pouch of Morison. Since 2019, bailout surgery has been performed in cases of severe acute gangrene or difficulty in dissecting Calot’s triangle (4). A surgical resident began operating as the primary surgeon. In cases where the cystic duct and artery in Calot’s triangle could not be identified within 90 minutes, or the hepatic artery or bile duct was injured, the board-certified surgeon took over as the primary surgeon. The board-certified surgeon ensured the quality of the procedure.
Statistical analysis. Categorical data were presented as numbers and analysed using the chi-square test. Continuous data were presented as percentages and mean±SD and analysed using Student’s t-test or Mann-Whitney U-test, according to the Shapiro-Wilk test. Significant variables in the univariate analysis were included in the multivariate analysis. The results are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Significant variables in both the univariate and multivariate analyses were considered as predictors of conversion from laparoscopic to open cholecystectomy. Using conversion from laparoscopic to open cholecystectomy as an endpoint, we determined the optimal cut-off value, defined as the highest sum of sensitivity and specificity by receiver operating characteristic curve analysis. Diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC). All statistical analyses were conducted using JMP (version 11; SAS Institute, Cary, NC, USA). Statistical significance was set at p<0.05.
Results
Clinicopathological characteristics. Between January 2012 and March 2022, 231 patients with acute cholecystitis were included in this study. Conversion from laparoscopic to open cholecystectomy was necessary in 16 (6.9%) patients, with the following indications for conversion: inability to clearly define the anatomy of Calot’s triangle, due to local inflammation (n=13); severe adhesion around the gallbladder (n=3); duodenal injury (n=2); bleeding from the cystic artery or liver bed (n=2); common bile duct injury (n=1); and an inadequately created pneumoperitoneum (n=1), with some overlap. There was no injury to major vessels or peri-operative death.
Two hundred and fifteen (93.1%) patients were included in the laparoscopic cholecystectomy group and 16 (6.9%) patients were included in the conversion from laparoscopic to open cholecystectomy group. Between-group differences in pre-operative characteristics (demographic, clinical, and laboratory data; computed tomography findings; and Tokyo Guidelines 2018 severity grading) are shown in Table I. The interval between symptom onset and surgery was longer in the conversion from laparoscopic to open cholecystectomy group than in the laparoscopic cholecystectomy group. The conversion from laparoscopic to open cholecystectomy group had a significantly higher acute cholecystitis severity grade (Tokyo Guidelines 2018 Grade ≥II: 87.6% vs. 48.8%, respectively) and higher CRP and lower albumin levels than the laparoscopic cholecystectomy group. Pre-operative CAR was also significantly higher in the conversion from laparoscopic to open cholecystectomy group than in the laparoscopic cholecystectomy group.
Clinical characteristics.
Computed tomography findings showed that gallbladder wall thickness ≥5 mm, pericholecystic fat hyperdensity, and pericholecystic fluid collection were significantly more common in the conversion from laparoscopic to open cholecystectomy group than in the laparoscopic cholecystectomy group. The conversion from laparoscopic to open cholecystectomy group had greater intra-operative blood loss, longer operative times, and a longer length of hospital stay than the laparoscopic cholecystectomy group (Table II). Post-operative complications of Clavien-Dindo Grade ≥II were significantly more common in the conversion from laparoscopic to open cholecystectomy group than in the laparoscopic cholecystectomy group.
Operative findings and post-operative outcomes.
AUC analysis. The optimal cut-off values of pre-operative CAR and CRP and albumin levels were 5.54 (sensitivity, 75.0%; specificity, 76.3%), 16.24 (sensitivity, 81.2%; specificity, 68.4%), and 3.30 (sensitivity, 68.7%; specificity, 74.9%), respectively (Figure 1). The AUC values and 95%CIs of the diagnostic performance of pre-operative CAR, CRP, and albumin levels, NLR, PLR, and GPS were 0.787 (0.665-0.877), 0.765 (0.648-0.852), 0.742 (0.615-0.839), 0.449 (0.323-0.581), 0.473 (0.340-0.611), and 0.629 (0.489-0.749), respectively. Pre-operative CAR was superior to other inflammatory markers in predicting conversion from laparoscopic to open cholecystectomy in patients with acute cholecystitis.
Receiver operating characteristic curve of (A) pre-operative CRP-to-albumin ratio [cut-off value, 5.54 (arrowhead); AUC, 0.78; sensitivity, 75.0%; specificity, 76.3%], (B) albumin [cut-off value, 3.30 (arrowhead); AUC, 0.74; sensitivity, 68.7%; specificity, 74.9%], and (C) CRP [cut-off value, 16.24 (arrowhead); AUC, 0.76; sensitivity, 81.2%; specificity, 68.4%]. AUC: Area under the receiver operating characteristic curve; CRP: C-reactive protein.
Univariate and multivariate analysis. In univariate analysis, significant predictors of conversion from laparoscopic to open cholecystectomy included the interval between symptom onset and surgery (>72 h), CRP (≥15.0 mg/l) and albumin (<3.5 mg/l) levels, pre-operative CAR (≥5.54), gallbladder wall thickness (≥5 mm), pericholecystic fluid collection, and pericholecystic fat hyperdensity. In multivariate analysis, elevated pre-operative CAR (≥5.54) [OR=3.75 (95%CI=1.12-14.96); p=0.032] and the interval between symptom onset and surgery (>72 h) [OR=10.45 (95%CI=2.60-70.77); p<0.001] were independent predictors of conversion from laparoscopic to open cholecystectomy (Table III).
Univariate and multivariate analysis of risk factors for conversion from laparoscopic to open cholecystectomy.
Discussion
The Tokyo Guidelines 2018 proposed a severity grading system for acute cholecystitis and recommended best management practices (23). Surgeons can choose either early laparoscopic cholecystectomy or biliary drainage, according to the acute cholecystitis grade, American Society of Anaesthesiologists physical status, or Charlson Comorbidity Index. In patients with severe acute cholecystitis, the risk of vasculo-biliary injury increases significantly, because of severe edema and tissue adhesion (23). In these cases, the Tokyo Guidelines 2018 recommend conversion from laparoscopic to open cholecystectomy or bailout surgery (4). Therefore, it is important to identify risk factors for conversion from laparoscopic to open cholecystectomy.
In this study, pre-operative CAR was significantly elevated in the conversion from laparoscopic to open cholecystectomy group. Multivariate analysis identified pre-operative CAR as an independent predictor of conversion from laparoscopic to open cholecystectomy. Therefore, pre-operative CAR, which is accessible, objective, and non-invasive, may be a preferable predictive marker of conversion from laparoscopic to open cholecystectomy. The prognostic ability of pre-operative CAR was compared to that of other inflammatory markers. Pre-operative CAR had the highest AUC value with statistical significance. Pre-operative CAR was superior to other inflammatory markers in predicting conversion from laparoscopic to open cholecystectomy in patients with acute cholecystitis. To our knowledge, no study has identified pre-operative CAR as a risk factor for conversion from laparoscopic to open cholecystectomy.
In this study, most cases of conversion from laparoscopic to open cholecystectomy were caused by severe inflammation, consistent with a previous study showing that severe inflammation is the most common reason for conversion from laparoscopic to open cholecystectomy in patients with acute cholecystitis (24). Pre-operative CAR may reflect severe inflammation leading to conversion from laparoscopic to open cholecystectomy.
Several studies have reported that inflammatory markers, such as pre-operative CAR, GPS, PLR, and NLR, can predict disease severity in patients with acute cholecystitis (25, 26). Moreover, elevated pre-operative CAR has been identified as an independent risk factor for difficult laparoscopic cholecystectomy (27), suggesting that inflammatory markers, such as pre-operative CAR, are associated with severe inflammation, leading to conversion from laparoscopic to open cholecystectomy. These results are consistent with those of the present study.
The CRP level is a low-specificity marker that increases 12-18 hours after tissue damage caused by bacterial or viral infections. Elevated CRP levels in patients with acute cholecystitis may be attributed to an acute cholecystitis-induced systemic inflammatory response (24). The Tokyo Guidelines 2018 include CRP levels of ≥3 mg/dl as a diagnostic criterion for acute cholecystitis. However, CRP levels are not used to determine the severity of acute cholecystitis. Some studies have concluded that CRP levels reflect local inflammation and may be useful in predicting difficult laparoscopic cholecystectomy (13, 28). Serum albumin is involved in the systemic inflammatory response. Hypoalbuminaemia may reflect chronic inflammation caused by liver dysfunction and malnutrition (29). Thus, pre-operative CAR may reflect the systemic inflammatory response in patients with acute cholecystitis.
In this study, an interval of >72 h between symptom onset and surgery was identified as another independent predictor of conversion from laparoscopic to open cholecystectomy, consistent with a previous study (30). A randomised controlled trial showed that early laparoscopic cholecystectomy was associated with lower morbidity and a shorter length of hospital stay than delayed laparoscopic cholecystectomy in patients with acute cholecystitis, even when the interval between symptom onset and surgery was >72 h (31). According to the Tokyo Guidelines 2018 severity grading of acute cholecystitis, Grade II (moderate) is associated with an interval between symptom onset and surgery of >72 h (20). Therefore, the surgical procedure should be considered according to the interval between symptom onset and surgery.
Because pre-operative CAR, surgical procedure (open cholecystectomy vs. bailout surgery) and the experience of the surgeon are known before surgery, this information can be used for treatment planning, including the selection of the surgeon. Pre-operative CAR may be used in conjunction with the Tokyo Guidelines 2018 severity grade and Delphi score to predict difficult laparoscopic cholecystectomy in patients with acute cholecystitis (32). This would reduce intra- and post-operative complications and shorten the length of hospital stay.
This study has several limitations, including its retrospective, single-centre design, and small sample size, which restricted the number of variables in the multivariate analysis. Further validation in an independent, prospectively enrolled cohort of patients with acute cholecystitis is required.
In conclusion, we identified elevated pre-operative CAR (≥5.54) and the interval between symptom onset and surgery (>72 h) as independent predictors of conversion from laparoscopic to open cholecystectomy. Predictors of conversion from laparoscopic to open cholecystectomy may be useful for pre-operative risk assessment and treatment planning and may reduce complications and shorten the length of hospital stay.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
MU, KK, NT, KY, YS, RH, HM, YT, SO, and MI designed the study. MI, MU, NT, and KK treated and observed the patients. MU drafted the article and performed the literature search. MI critically revised the article for intellectual content. All Authors have read and approved the final article.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received January 19, 2023.
- Revision received January 31, 2023.
- Accepted February 2, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.