Preoperative C-reactive protein identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy

Preoperative C-reactive protein identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preoperative C-reactive protein identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy Christian Ballardo Medina, Jaime Matus Rojas, Paul Humberto Valdez Castillejo, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9257177/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Preoperative identification of patients at risk for severe operative difficulty during laparoscopic cholecystectomy remains clinically relevant. C-reactive protein (CRP) reflects systemic inflammatory burden and may predict intraoperative severity. This study evaluated the independent association between preoperative CRP levels and severe operative difficulty, and explored its performance in elective and emergency settings. Methods A retrospective cohort study of 304 patients undergoing laparoscopic cholecystectomy was performed. Severe operative difficulty was defined as Parkland grade IV–V. Multivariable logistic regression was used to assess independent predictors of severe operative difficulty, adjusting for urgency status, age, and sex. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Subgroup analyses were conducted for elective and emergency procedures. Results Severe operative difficulty occurred in 89 patients (29.3%). In multivariable analysis, preoperative CRP independently predicted severe operative difficulty (adjusted OR 1.06 per unit increase; 95% CI 1.04–1.09; p < 0.001). Emergency surgery (adjusted OR 3.46; 95% CI 1.92–6.21; p < 0.001) and male sex (adjusted OR 2.20; 95% CI 1.20–4.03; p = 0.011) were also independently associated. The multivariable model demonstrated good discrimination (AUC 0.82). CRP performance was more pronounced in emergency procedures compared to elective cases. Severe operative difficulty was significantly associated with increased postoperative complications and prolonged hospital stay. Conclusions Preoperative CRP independently identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy. Its predictive value is particularly relevant in emergency settings and may assist in preoperative risk stratification and operative planning. Laparoscopic cholecystectomy Acute calculous cholecystitis C-reactive protein Postoperative complications Parkland grading scale Figures Figure 1 Figure 2 Introduction Laparoscopic cholecystectomy is one of the most frequently performed surgical procedures worldwide and remains the standard treatment for symptomatic gallstone disease and chronic calculous cholecystitis. Although generally considered safe and minimally invasive, operative difficulty varies considerably and may be influenced by the degree of inflammatory changes and local anatomical distortion. 1,2 Severe inflammatory burden has been associated with increased operative complexity, higher conversion rates, and worse postoperative outcomes. However, reliable preoperative predictors of intraoperative severity remain limited. Identifying patients at risk for severe operative difficulty is clinically relevant for surgical planning, operative strategy, and allocation of resources, particularly in emergency settings where inflammatory activity may be more pronounced. 3 C-reactive protein (CRP), a well-established marker of systemic inflammation, has been investigated as a potential predictor of surgical complexity. Nevertheless, available evidence remains heterogeneous, often lacking standardized intraoperative severity grading and failing to evaluate performance across different clinical scenarios. 4–7 The aim of this study was to evaluate the independent association between preoperative CRP levels and severe operative difficulty during laparoscopic cholecystectomy, defined according to the Parkland grading scale. Additionally, we assessed its predictive performance in elective and emergency procedures, as well as its relationship with postoperative complications, conversion to open surgery, and length of hospital stay. Materials and Methods Study design and ethical approval A retrospective cohort study was conducted including consecutive adult patients who underwent laparoscopic cholecystectomy for gallstone-related disease between March 2022 and September 2025 at a tertiary referral center. The study was approved by the institutional review board in accordance with the Declaration of Helsinki. Due to the retrospective design and anonymized data collection, the requirement for informed consent was waived. Patient selection All patients undergoing elective or emergency laparoscopic cholecystectomy were eligible. Procedures converted to open surgery were included in the analysis to preserve real-world operative outcomes. Patients with missing preoperative CRP values or incomplete intraoperative grading data were excluded from multivariable modeling. Definitions and variables The primary outcome was severe operative difficulty, defined as Parkland grade IV–V according to the validated intraoperative grading system. Secondary outcomes included: Overall postoperative complications, classified according to the Clavien–Dindo system Major complications (Clavien grade ≥ III) Conversion to open surgery Prolonged hospital stay, defined a priori as ≥ 2 days. Preoperative CRP was analyzed both as a continuous variable and as a dichotomous variable using the optimal cut-off derived from ROC curve analysis for predicting severe operative difficulty. Procedures were categorized as elective or emergency based on admission indication. Statistical analysis Continuous variables were assessed for normality using the Shapiro–Wilk test and reported as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables were summarized as frequencies and percentages. Between-group comparisons were performed using the chi-square test or Fisher’s exact test for categorical variables, and Student’s t-test or Mann–Whitney U test for continuous variables. To identify independent predictors of severe operative difficulty, multivariable logistic regression analysis was performed. Variables were selected based on clinical relevance and prior evidence, including preoperative CRP, urgency status, age, and sex. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were reported. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). A simplified preoperative risk score was subsequently derived from independently associated variables by assigning one point to each significant predictor. Internal performance of the score was assessed using ROC analysis. All tests were two-sided, and a p-value < 0.05 was considered statistically significant. Statistical analyses were performed using Python (version 3.x). Results Patient characteristics A total of 304 patients underwent laparoscopic cholecystectomy during the study period and were included in the analysis. Severe operative difficulty (Parkland IV–V) occurred in 89 patients (29.3%). Emergency procedures accounted for a substantial proportion of severe operative cases. Patients with severe operative difficulty had significantly higher preoperative CRP levels compared with those with lower Parkland grades. Baseline demographic and clinical characteristics are summarized in Table 1 . Association between CRP and severe operative difficulty. In univariable analysis, elevated preoperative CRP was significantly associated with severe operative difficulty (p < 0.001). In multivariable logistic regression analysis adjusting for urgency status, age, and sex, CRP remained independently associated with severe operative difficulty (adjusted OR 1.06 per unit increase; 95% CI 1.04–1.09; p < 0.001). Emergency surgery (adjusted OR 3.46; 95% CI 1.92–6.21; p < 0.001) and male sex (adjusted OR 2.20; 95% CI 1.20–4.03; p = 0.011) were also independently associated predictors. Table 2 . The multivariable model demonstrated good discrimination with an AUC of 0.82 ( Fig. 1 ). Dichotomized CRP analysis: Using the optimal ROC-derived cut-off (CRP ≥ 2.48), elevated CRP was strongly associated with severe operative difficulty in multivariable analysis (adjusted OR 6.77; 95% CI 3.62–12.65; p < 0.001). The categorical model showed comparable discrimination (AUC 0.83) and improved model fit compared with the continuous model (lower AIC). Subgroup analysis: elective versus emergency procedures The predictive performance of CRP was more pronounced in emergency procedures compared with elective cases. In emergency surgeries, elevated CRP demonstrated higher sensitivity for severe operative difficulty, whereas discrimination was reduced in elective procedures. Postoperative outcomes: Severe operative difficulty was significantly associated with increased postoperative complications and prolonged hospital stay. Patients with Parkland IV–V had higher rates of overall complications and longer median hospitalization compared with those with lower grades. Conversion to open surgery occurred more frequently in patients with elevated CRP; however, due to the low event rate, estimates demonstrated wide confidence intervals. Development of a simplified preoperative risk score: A simplified additive score incorporating CRP ≥ 2.48, emergency status, and male sex was constructed. The score demonstrated good discriminatory performance (AUC 0.80). Risk of severe operative difficulty increased progressively with higher score values ( Table 3 & Fig. 2). Discussion In this cohort of 304 patients undergoing laparoscopic cholecystectomy, preoperative CRP levels were independently associated with severe operative difficulty (Parkland IV–V). This finding supports the concept that systemic inflammatory burden reflects advanced local inflammatory changes within the gallbladder and hepatocystic triangle, including fibrosis, wall thickening, and dense adhesions, which increase operative complexity. 8,9 Previous studies evaluating CRP as a predictor of difficult cholecystectomy have reported heterogeneous cut-off values and moderate discriminatory performance. 10–12 However, many lacked standardized intraoperative grading or multivariable adjustment. By incorporating the Parkland grading system and adjusted modeling, our findings strengthen the evidence supporting CRP as a preoperative risk stratification tool. Severe operative difficulty was significantly associated with postoperative morbidity and prolonged hospitalization, reinforcing the clinical validity of intraoperative grading beyond descriptive purposes. Increased operative complexity likely entails prolonged dissection, distorted anatomy, and greater tissue manipulation, which may contribute to adverse postoperative outcomes. 7,11,12 Although preoperative CRP was associated with overall postoperative complications, major complications were infrequent, limiting definitive conclusions regarding high-grade adverse events. Similarly, the low incidence of bile duct injury precluded advanced modeling for this outcome. 13–16 ROC analysis demonstrated good discriminatory performance of CRP for identifying severe operative difficulty. 7,9,15 The multivariable model achieved an AUC of 0.82, and the simplified additive score showed comparable performance, suggesting potential clinical applicability. Importantly, CRP is widely available, inexpensive, and objectively measurable, making it an attractive adjunct to clinical assessment. Subgroup analysis revealed stronger predictive performance in emergency procedures compared with elective cases, suggesting that CRP may better reflect operative severity in acute inflammatory settings. Although the difference in AUC did not reach statistical significance, the observed trend highlights the contextual value of CRP in urgent surgical scenarios. This study has limitations inherent to its retrospective, single-center design, which may affect generalizability. Despite the use of validated grading systems, intraoperative severity assessment may be subject to interobserver variability. External prospective validation is necessary before broad clinical implementation. Overall, preoperative quantitative CRP may serve as a complementary biomarker for identifying patients at risk of severe operative difficulty during laparoscopic cholecystectomy. When integrated with clinical evaluation and surgical expertise, it may facilitate improved operative planning and perioperative management. Conclusion Preoperative quantitative CRP was independently associated with severe operative difficulty during laparoscopic cholecystectomy and correlated with postoperative morbidity and prolonged hospitalization. Its discriminatory performance was particularly relevant in emergency procedures, where inflammatory burden is greter. Although CRP should not replace clinical judgment, its integration into preoperative assessment may enhance risk stratification and operative planning. Prospective multicenter studies are warranted to validate optimal thresholds and standardize its use within preoperative risk models. Declarations Ethical Approval This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Hospital Regional ISSSTE Dr. Manuel Cárdenas de la Vega (Protocol No. RIP.HRMCV.063.2025). Due to the retrospective nature of the study and anonymized data collection, the requirement for informed consent was waived. Informed Consent The requirement for informed consent was waived due to the retrospective design and anonymized data collection. Conflict of Interest The authors declare no conflict of interest. Funding No external funding was received for this study. Author Contributions Ballardo Medina Christian: Conceptualization, data curation, statistical analysis, manuscript drafting. Valdez Castillejo Paul Humberto: Data acquisition and data verification, critical revision of the manuscript. Luna Madrid Eduardo Esau : Methodological supervision and statistical validation, manuscript editing. Matus Rojas Jaime : Senior supervision, interpretation of results, final approval of the manuscript. Data Availability Statement The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Clinical Trial number Clinical trial number: not applicable References Warchałowski Ł, Łuszczki E, Bartosiewicz A, Dereń K, Warchałowska M, Oleksy Ł, Stolarczyk A, Podlasek R. The Analysis of Risk Factors in the Conversion from Laparoscopic to Open Cholecystectomy. Int J Environ Res Public Health. 2020 Oct 18;17(20):7571. doi: 10.3390/ijerph17207571. PMID: 33080991; PMCID: PMC7588875. Oddsdóttir m & hunter jg. Vesícula biliar y sistema biliar extrahepático. En: brunicardi fc. Schwartz manual de cirugía. 8a ed. Mexico; df. 2007. P 829-52. Yu S, Shi S, Zhu X. Clinical effect of laparoscopic cholecystectomy in the treatment of chronic cholecystitis with gallstones. Biotechnol Genet Eng Rev. 2024 Dec;40(4):4000-4012. doi: 10.1080/02648725.2023.2204710. Epub 2023 Apr 26. PMID: 37098886. Lee JW, Park S, Chung YH, Kim JG, Kim BW. Clinical significance of high C-reactive protein in predicting severity of acute cholecystitis. J Clin Med. 2020;9(7):2152. doi:10.3390/jcm9072152. Farahani PK, Nejat SK. Preoperative C-reactive protein as a predictor of conversion and complications in laparoscopic cholecystectomy for acute cholecystitis. BMC Surg. 2025 Oct 14;25(1):476. doi: 10.1186/s12893-025-03212-0. PMID: 41088047; PMCID: PMC12522728. Loccisano Matías H, Drago Martín, Todeschini Hernán, Sarotto Luis. Papel de la proteína C reactiva y la velocidad de sedimentación globular en la predicción de colecistectomía laparoscópica dificultosa: su aplicación en un programa de residencia universitario. Rev. argent. cir. [Internet]. 2020 Jun [citado 2026 Feb 15] ; 112( 2 ): 171-177. Disponible en: https://www.scielo.org.ar/scielo.php?script=sci_arttext&pid=S2250-639X2020000200012&lng=es. Bolívar-Rodríguez MA, Mendoza-Chang CR, Cázarez-Aguilar MA, et al. Predicción de colecistectomía difícil en colecistitis aguda con proteína C reactiva. Rev Med UAS. 2024;14(1):13-22. Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Safe cholecystectomy program guidelines [Internet]. Los Angeles (CA): SAGES; 2020. Available from: https://www.sages.org Elshaer M, Gravante G, Thomas K, Sorge R, Al-Hamali S, Ebdewi H. Subtotal cholecystectomy for "difficult gallbladders": systematic review and meta-analysis. JAMA Surg. 2015 Feb;150(2):159-68. doi: 10.1001/jamasurg.2014.1219. PMID: 25548894. Huang YC, Chung SD, Chien CW. Validation of the Parkland grading scale for predicting outcomes in acute cholecystitis. BMC Surg. 2020;20(1):29. doi:10.1186/s12893-020-00708-4. Wakabayashi G, Iwashita Y, Hibi T, Takada T, Strasberg SM, Asbun HJ & et al Tokyo Guidelines 2018: surgical management of acute cholecystitis: safe steps in laparoscopic cholecystectomy for acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25(1):73-86. doi: 10.1002/jhbp.517. Epub 2018 Jan 10. PMID: 29095575. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santibañes E & et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009 Aug;250(2):187-96. doi: 10.1097/SLA.0b013e3181b13ca2. PMID: 19638912. Sugrue M, Coccolini F, Bucholc M, Johnston A; Contributors from WSES. Intra-operative gallbladder scoring predicts conversion of laparoscopic to open cholecystectomy: a WSES prospective collaborative study. World J Emerg Surg. 2019 Mar 14;14:12. doi: 10.1186/s13017-019-0230-9. PMID: 30911325; PMCID: PMC6417130. Wu X, Li K, Kou S, Wu X, Zhang Z. The Accuracy of Point-of-Care Ultrasound in the Detection of Gallbladder Disease: A Meta-analysis. Acad Radiol. 2024 Apr;31(4):1336-1343. doi: 10.1016/j.acra.2023.09.029. Epub 2023 Oct 12. PMID: 37838525. Moreira Grecco Alejandro D., Zapata Gonzalo H., Montesinos María F., Morales Saifen Rodrigo, Flores Tomás A., Sarotto (h) Luis E.. Proteína C reactiva y su relación con las complicaciones posoperatorias en cirugía colorrectal electiva. Rev. argent. cir. [Internet]. 2022 Jun [citado 2026 Ene 31] ; 114( 2 ): 133-144. Disponible en: https://www.scielo.org.ar/scielo.php?script=sci_arttext&pid=S2250-639X2022000200133&lng=es. https://doi.org/10.25132/raac.v114.n2.1626. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Although generally considered safe and minimally invasive, operative difficulty varies considerably and may be influenced by the degree of inflammatory changes and local anatomical distortion.\u003csup\u003e1,2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSevere inflammatory burden has been associated with increased operative complexity, higher conversion rates, and worse postoperative outcomes. However, reliable preoperative predictors of intraoperative severity remain limited. Identifying patients at risk for severe operative difficulty is clinically relevant for surgical planning, operative strategy, and allocation of resources, particularly in emergency settings where inflammatory activity may be more pronounced.\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eC-reactive protein (CRP), a well-established marker of systemic inflammation, has been investigated as a potential predictor of surgical complexity. Nevertheless, available evidence remains heterogeneous, often lacking standardized intraoperative severity grading and failing to evaluate performance across different clinical scenarios.\u003csup\u003e4\u0026ndash;7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the independent association between preoperative CRP levels and severe operative difficulty during laparoscopic cholecystectomy, defined according to the Parkland grading scale. Additionally, we assessed its predictive performance in elective and emergency procedures, as well as its relationship with postoperative complications, conversion to open surgery, and length of hospital stay.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eStudy design and ethical approval\u003c/p\u003e \u003cp\u003eA retrospective cohort study was conducted including consecutive adult patients who underwent laparoscopic cholecystectomy for gallstone-related disease between March 2022 and September 2025 at a tertiary referral center. The study was approved by the institutional review board in accordance with the Declaration of Helsinki. Due to the retrospective design and anonymized data collection, the requirement for informed consent was waived.\u003c/p\u003e \u003cp\u003ePatient selection\u003c/p\u003e \u003cp\u003eAll patients undergoing elective or emergency laparoscopic cholecystectomy were eligible. Procedures converted to open surgery were included in the analysis to preserve real-world operative outcomes. Patients with missing preoperative CRP values or incomplete intraoperative grading data were excluded from multivariable modeling.\u003c/p\u003e \u003cp\u003eDefinitions and variables\u003c/p\u003e \u003cp\u003eThe primary outcome was severe operative difficulty, defined as Parkland grade IV\u0026ndash;V according to the validated intraoperative grading system.\u003c/p\u003e \u003cp\u003eSecondary outcomes included:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOverall postoperative complications, classified according to the Clavien\u0026ndash;Dindo system\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMajor complications (Clavien grade\u0026thinsp;\u0026ge;\u0026thinsp;III)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eConversion to open surgery\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eProlonged hospital stay, defined a priori as \u0026ge;\u0026thinsp;2 days.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003ePreoperative CRP was analyzed both as a continuous variable and as a dichotomous variable using the optimal cut-off derived from ROC curve analysis for predicting severe operative difficulty.\u003c/p\u003e \u003cp\u003eProcedures were categorized as elective or emergency based on admission indication.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were assessed for normality using the Shapiro\u0026ndash;Wilk test and reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range), as appropriate. Categorical variables were summarized as frequencies and percentages.\u003c/p\u003e \u003cp\u003eBetween-group comparisons were performed using the chi-square test or Fisher\u0026rsquo;s exact test for categorical variables, and Student\u0026rsquo;s t-test or Mann\u0026ndash;Whitney U test for continuous variables.\u003c/p\u003e \u003cp\u003eTo identify independent predictors of severe operative difficulty, multivariable logistic regression analysis was performed. Variables were selected based on clinical relevance and prior evidence, including preoperative CRP, urgency status, age, and sex. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were reported.\u003c/p\u003e \u003cp\u003eModel discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). A simplified preoperative risk score was subsequently derived from independently associated variables by assigning one point to each significant predictor. Internal performance of the score was assessed using ROC analysis.\u003c/p\u003e \u003cp\u003eAll tests were two-sided, and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using Python (version 3.x).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eA total of 304 patients underwent laparoscopic cholecystectomy during the study period and were included in the analysis. Severe operative difficulty (Parkland IV\u0026ndash;V) occurred in 89 patients (29.3%).\u003c/p\u003e\n\u003cp\u003eEmergency procedures accounted for a substantial proportion of severe operative cases. Patients with severe operative difficulty had significantly higher preoperative CRP levels compared with those with lower Parkland grades.\u003c/p\u003e\n\u003cp\u003eBaseline demographic and clinical characteristics are summarized in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eAssociation between CRP and severe operative difficulty.\u003c/p\u003e\n\u003cp\u003eIn univariable analysis, elevated preoperative CRP was significantly associated with severe operative difficulty (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cp\u003eIn multivariable logistic regression analysis adjusting for urgency status, age, and sex, CRP remained independently associated with severe operative difficulty (adjusted OR 1.06 per unit increase; 95% CI 1.04\u0026ndash;1.09; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Emergency surgery (adjusted OR 3.46; 95% CI 1.92\u0026ndash;6.21; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and male sex (adjusted OR 2.20; 95% CI 1.20\u0026ndash;4.03; p\u0026thinsp;=\u0026thinsp;0.011) were also independently associated predictors. Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThe multivariable model demonstrated good discrimination with an AUC of 0.82 \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDichotomized CRP analysis:\u003c/p\u003e\n\u003cp\u003eUsing the optimal ROC-derived cut-off (CRP\u0026thinsp;\u0026ge;\u0026thinsp;2.48), elevated CRP was strongly associated with severe operative difficulty in multivariable analysis (adjusted OR 6.77; 95% CI 3.62\u0026ndash;12.65; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cp\u003eThe categorical model showed comparable discrimination (AUC 0.83) and improved model fit compared with the continuous model (lower AIC).\u003c/p\u003e\n\u003cp\u003eSubgroup analysis: elective versus emergency procedures\u003c/p\u003e\n\u003cp\u003eThe predictive performance of CRP was more pronounced in emergency procedures compared with elective cases. In emergency surgeries, elevated CRP demonstrated higher sensitivity for severe operative difficulty, whereas discrimination was reduced in elective procedures.\u003c/p\u003e\n\u003cp\u003ePostoperative outcomes:\u003c/p\u003e\n\u003cp\u003eSevere operative difficulty was significantly associated with increased postoperative complications and prolonged hospital stay. Patients with Parkland IV\u0026ndash;V had higher rates of overall complications and longer median hospitalization compared with those with lower grades.\u003c/p\u003e\n\u003cp\u003eConversion to open surgery occurred more frequently in patients with elevated CRP; however, due to the low event rate, estimates demonstrated wide confidence intervals.\u003c/p\u003e\n\u003cp\u003eDevelopment of a simplified preoperative risk score:\u003c/p\u003e\n\u003cp\u003eA simplified additive score incorporating CRP\u0026thinsp;\u0026ge;\u0026thinsp;2.48, emergency status, and male sex was constructed. The score demonstrated good discriminatory performance (AUC 0.80).\u003c/p\u003e\n\u003cp\u003eRisk of severe operative difficulty increased progressively with higher score values \u003cstrong\u003e(\u003c/strong\u003eTable \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cstrong\u003e\u0026amp; Fig. 2).\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this cohort of 304 patients undergoing laparoscopic cholecystectomy, preoperative CRP levels were independently associated with severe operative difficulty (Parkland IV\u0026ndash;V). This finding supports the concept that systemic inflammatory burden reflects advanced local inflammatory changes within the gallbladder and hepatocystic triangle, including fibrosis, wall thickening, and dense adhesions, which increase operative complexity.\u003csup\u003e8,9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePrevious studies evaluating CRP as a predictor of difficult cholecystectomy have reported heterogeneous cut-off values and moderate discriminatory performance.\u003csup\u003e10\u0026ndash;12\u003c/sup\u003e However, many lacked standardized intraoperative grading or multivariable adjustment. By incorporating the Parkland grading system and adjusted modeling, our findings strengthen the evidence supporting CRP as a preoperative risk stratification tool.\u003c/p\u003e \u003cp\u003eSevere operative difficulty was significantly associated with postoperative morbidity and prolonged hospitalization, reinforcing the clinical validity of intraoperative grading beyond descriptive purposes. Increased operative complexity likely entails prolonged dissection, distorted anatomy, and greater tissue manipulation, which may contribute to adverse postoperative outcomes.\u003csup\u003e7,11,12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough preoperative CRP was associated with overall postoperative complications, major complications were infrequent, limiting definitive conclusions regarding high-grade adverse events. Similarly, the low incidence of bile duct injury precluded advanced modeling for this outcome.\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eROC analysis demonstrated good discriminatory performance of CRP for identifying severe operative difficulty.\u003csup\u003e7,9,15\u003c/sup\u003e The multivariable model achieved an AUC of 0.82, and the simplified additive score showed comparable performance, suggesting potential clinical applicability. Importantly, CRP is widely available, inexpensive, and objectively measurable, making it an attractive adjunct to clinical assessment.\u003c/p\u003e \u003cp\u003eSubgroup analysis revealed stronger predictive performance in emergency procedures compared with elective cases, suggesting that CRP may better reflect operative severity in acute inflammatory settings. Although the difference in AUC did not reach statistical significance, the observed trend highlights the contextual value of CRP in urgent surgical scenarios.\u003c/p\u003e \u003cp\u003eThis study has limitations inherent to its retrospective, single-center design, which may affect generalizability. Despite the use of validated grading systems, intraoperative severity assessment may be subject to interobserver variability. External prospective validation is necessary before broad clinical implementation.\u003c/p\u003e \u003cp\u003eOverall, preoperative quantitative CRP may serve as a complementary biomarker for identifying patients at risk of severe operative difficulty during laparoscopic cholecystectomy. When integrated with clinical evaluation and surgical expertise, it may facilitate improved operative planning and perioperative management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePreoperative quantitative CRP was independently associated with severe operative difficulty during laparoscopic cholecystectomy and correlated with postoperative morbidity and prolonged hospitalization. Its discriminatory performance was particularly relevant in emergency procedures, where inflammatory burden is greter.\u003c/p\u003e \u003cp\u003eAlthough CRP should not replace clinical judgment, its integration into preoperative assessment may enhance risk stratification and operative planning. Prospective multicenter studies are warranted to validate optimal thresholds and standardize its use within preoperative risk models.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Hospital Regional ISSSTE Dr. Manuel C\u0026aacute;rdenas de la Vega (Protocol No. RIP.HRMCV.063.2025). Due to the retrospective nature of the study and anonymized data collection, the requirement for informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for informed consent was waived due to the retrospective design and anonymized data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBallardo Medina Christian:\u0026nbsp;\u003c/strong\u003eConceptualization, data curation, statistical analysis, manuscript drafting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eValdez Castillejo Paul Humberto:\u003c/strong\u003e Data acquisition and data verification, critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLuna Madrid Eduardo Esau\u003c/strong\u003e: Methodological supervision and statistical validation, manuscript editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMatus Rojas Jaime\u003c/strong\u003e: Senior supervision, interpretation of results, final approval of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWarchałowski Ł, Łuszczki E, Bartosiewicz A, Dereń K, Warchałowska M, Oleksy Ł, Stolarczyk A, Podlasek R. The Analysis of Risk Factors in the Conversion from Laparoscopic to Open Cholecystectomy. Int J Environ Res Public Health. 2020 Oct 18;17(20):7571. doi: 10.3390/ijerph17207571. PMID: 33080991; PMCID: PMC7588875.\u003c/li\u003e\n\u003cli\u003eOddsd\u0026oacute;ttir m \u0026amp; hunter jg. Ves\u0026iacute;cula biliar y sistema biliar extrahep\u0026aacute;tico. En: brunicardi fc. Schwartz manual de cirug\u0026iacute;a. 8a ed. Mexico; df. 2007. P 829-52.\u003c/li\u003e\n\u003cli\u003eYu S, Shi S, Zhu X. Clinical effect of laparoscopic cholecystectomy in the treatment of chronic cholecystitis with gallstones. Biotechnol Genet Eng Rev. 2024 Dec;40(4):4000-4012. doi: 10.1080/02648725.2023.2204710. Epub 2023 Apr 26. PMID: 37098886.\u003c/li\u003e\n\u003cli\u003eLee JW, Park S, Chung YH, Kim JG, Kim BW. Clinical significance of high C-reactive protein in predicting severity of acute cholecystitis. J Clin Med. 2020;9(7):2152. doi:10.3390/jcm9072152.\u003c/li\u003e\n\u003cli\u003eFarahani PK, Nejat SK. Preoperative C-reactive protein as a predictor of conversion and complications in laparoscopic cholecystectomy for acute cholecystitis. BMC Surg. 2025 Oct 14;25(1):476. doi: 10.1186/s12893-025-03212-0. PMID: 41088047; PMCID: PMC12522728.\u003c/li\u003e\n\u003cli\u003eLoccisano Mat\u0026iacute;as H, Drago Mart\u0026iacute;n, Todeschini Hern\u0026aacute;n, Sarotto Luis. Papel de la prote\u0026iacute;na C reactiva y la velocidad de sedimentaci\u0026oacute;n globular en la predicci\u0026oacute;n de colecistectom\u0026iacute;a laparosc\u0026oacute;pica dificultosa: su aplicaci\u0026oacute;n en un programa de residencia universitario. Rev. argent. cir. [Internet]. 2020 Jun [citado 2026 Feb 15] ; 112( 2 ): 171-177. Disponible en: https://www.scielo.org.ar/scielo.php?script=sci_arttext\u0026amp;pid=S2250-639X2020000200012\u0026amp;lng=es.\u003c/li\u003e\n\u003cli\u003eBol\u0026iacute;var-Rodr\u0026iacute;guez MA, Mendoza-Chang CR, C\u0026aacute;zarez-Aguilar MA, et al. Predicci\u0026oacute;n de colecistectom\u0026iacute;a dif\u0026iacute;cil en colecistitis aguda con prote\u0026iacute;na C reactiva. Rev Med UAS. 2024;14(1):13-22.\u003c/li\u003e\n\u003cli\u003eSociety of American Gastrointestinal and Endoscopic Surgeons (SAGES). Safe cholecystectomy program guidelines [Internet]. Los Angeles (CA): SAGES; 2020. Available from: https://www.sages.org\u003c/li\u003e\n\u003cli\u003eElshaer M, Gravante G, Thomas K, Sorge R, Al-Hamali S, Ebdewi H. Subtotal cholecystectomy for \u0026quot;difficult gallbladders\u0026quot;: systematic review and meta-analysis. JAMA Surg. 2015 Feb;150(2):159-68. doi: 10.1001/jamasurg.2014.1219. PMID: 25548894.\u003c/li\u003e\n\u003cli\u003eHuang YC, Chung SD, Chien CW. Validation of the Parkland grading scale for predicting outcomes in acute cholecystitis. BMC Surg. 2020;20(1):29. doi:10.1186/s12893-020-00708-4.\u003c/li\u003e\n\u003cli\u003eWakabayashi G, Iwashita Y, Hibi T, Takada T, Strasberg SM, Asbun HJ \u0026amp; et al Tokyo Guidelines 2018: surgical management of acute cholecystitis: safe steps in laparoscopic cholecystectomy for acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25(1):73-86. doi: 10.1002/jhbp.517. Epub 2018 Jan 10. PMID: 29095575.\u003c/li\u003e\n\u003cli\u003eClavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santiba\u0026ntilde;es E \u0026amp; et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009 Aug;250(2):187-96. doi: 10.1097/SLA.0b013e3181b13ca2. PMID: 19638912.\u003c/li\u003e\n\u003cli\u003eSugrue M, Coccolini F, Bucholc M, Johnston A; Contributors from WSES. Intra-operative gallbladder scoring predicts conversion of laparoscopic to open cholecystectomy: a WSES prospective collaborative study. World J Emerg Surg. 2019 Mar 14;14:12. doi: 10.1186/s13017-019-0230-9. PMID: 30911325; PMCID: PMC6417130.\u003c/li\u003e\n\u003cli\u003eWu X, Li K, Kou S, Wu X, Zhang Z. The Accuracy of Point-of-Care Ultrasound in the Detection of Gallbladder Disease: A Meta-analysis. Acad Radiol. 2024 Apr;31(4):1336-1343. doi: 10.1016/j.acra.2023.09.029. Epub 2023 Oct 12. PMID: 37838525.\u003c/li\u003e\n\u003cli\u003eMoreira Grecco Alejandro D., Zapata Gonzalo H., Montesinos Mar\u0026iacute;a F., Morales Saifen Rodrigo, Flores Tom\u0026aacute;s A., Sarotto (h) Luis E.. Prote\u0026iacute;na C reactiva y su relaci\u0026oacute;n con las complicaciones posoperatorias en cirug\u0026iacute;a colorrectal electiva. Rev. argent. cir. [Internet]. 2022 Jun [citado 2026 Ene 31] ; 114( 2 ): 133-144. Disponible en: https://www.scielo.org.ar/scielo.php?script=sci_arttext\u0026amp;pid=S2250-639X2022000200133\u0026amp;lng=es. https://doi.org/10.25132/raac.v114.n2.1626.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Laparoscopic cholecystectomy, Acute calculous cholecystitis, C-reactive protein, Postoperative complications, Parkland grading scale","lastPublishedDoi":"10.21203/rs.3.rs-9257177/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9257177/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePreoperative identification of patients at risk for severe operative difficulty during laparoscopic cholecystectomy remains clinically relevant. C-reactive protein (CRP) reflects systemic inflammatory burden and may predict intraoperative severity. This study evaluated the independent association between preoperative CRP levels and severe operative difficulty, and explored its performance in elective and emergency settings.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective cohort study of 304 patients undergoing laparoscopic cholecystectomy was performed. Severe operative difficulty was defined as Parkland grade IV\u0026ndash;V. Multivariable logistic regression was used to assess independent predictors of severe operative difficulty, adjusting for urgency status, age, and sex. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Subgroup analyses were conducted for elective and emergency procedures.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSevere operative difficulty occurred in 89 patients (29.3%). In multivariable analysis, preoperative CRP independently predicted severe operative difficulty (adjusted OR 1.06 per unit increase; 95% CI 1.04\u0026ndash;1.09; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Emergency surgery (adjusted OR 3.46; 95% CI 1.92\u0026ndash;6.21; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and male sex (adjusted OR 2.20; 95% CI 1.20\u0026ndash;4.03; p\u0026thinsp;=\u0026thinsp;0.011) were also independently associated. The multivariable model demonstrated good discrimination (AUC 0.82). CRP performance was more pronounced in emergency procedures compared to elective cases. Severe operative difficulty was significantly associated with increased postoperative complications and prolonged hospital stay.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePreoperative CRP independently identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy. Its predictive value is particularly relevant in emergency settings and may assist in preoperative risk stratification and operative planning.\u003c/p\u003e","manuscriptTitle":"Preoperative C-reactive protein identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 14:52:31","doi":"10.21203/rs.3.rs-9257177/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f538ba5f-4c8d-4288-95a8-e3464f310487","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-06T08:24:31+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"38320773251723137231552241256279833970","date":"2026-05-05T11:45:56+00:00","index":28,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T09:58:37+00:00","index":27,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T11:52:55+00:00","index":25,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T08:42:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 14:52:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9257177","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9257177","identity":"rs-9257177","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}