Author Affiliations: Internal Medicine Department (de Miguel-Yanes JM) and Surgery Department (Turegano F), Hospital General Universitario “Gregorio Maranon”, 46, Doctor Esquerdo, 28007, Madrid, Spain; Internal Medicine Department, Hospital Clínico San Carlos, Calle Profesor Martín Lagos, 28040, Madrid, Spain (Mendez-Bailon M); Preventive Medicine and Public Health Department, Health Sciences Faculty, Rey Juan Carlos University, Avenida de Atenas, Alcorcón, 28292, Madrid, Spain (Jimenez-García R, Hernandez-Barrera V and Lopez-de-Andres A); Spanish Agency of Alimentary Safety and Nutrition, Ministry of Health, Social Policy and Equality, 56, Alcala, 28071, Madrid, Spain (Perez-Farinos N); and Internal Medicine Department, Hospital Infanta Leonor, 80, Avenida Gran Vía del Este, 28031, Madrid, Spain (Munoz-Rivas N)

Corresponding Author: Dr. Jose M de Miguel-Yanes, Servicio de Medicina Interna, Hospital Gregorio Maranon, 46, Doctor Esquerdo, 28007, Madrid, Spain (Tel: +34915868522; Email: josemaria.demiguel@salud.madrid.org)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60091-7

Published online May 9, 2016.

 

 

Acknowledgements: We thank the Spanish Ministry of Health, Social Policy and Equality for providing the data of the MBDS.

Contributors: DJM researched the data and wrote the manuscript. MM, JR, PN, MN and LA researched the data and edited the manuscript. TF edited the manuscript and provided expertise in the topic. HV researched the data, did the statistical analyses and edited the manuscript. All authors contributed to the design and interpretation of the study and to further drafts. DJM is the guarantor.

Funding: Dr. Ana López-de-Andrés is the recipient of a Fondo de Investigaciones Sanitarias on behalf of the Spanish Ministry of Health, Social Policy and Equality, 2013 (PI13/00118).

Ethical approval: This study was approved by the Rey Juan Carlos University ethics committee (PI13/00118).

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: This study aimed to compare the rates of open and laparoscopic cholecystectomies and outcomes in patients with or without type 2 diabetes mellitus (T2DM) in Spain from 2003 to 2013.

 

METHODS: We collected all cases of open and laparoscopic cholecystectomies using national hospital discharge data and evaluated the annual cholecystectomy rates stratified by T2DM status. We analyzed tendency for in-hospital mortality (IHM). We also analyzed the impact of T2DM on IHM in patients who underwent cholecystectomies.

 

RESULTS: We identified 611 533 cholecystectomies (71.3% laparoscopic) in the patients, in whom 78 227 (12.8%) patients had T2DM. The rates of open cholecystectomies were 3-fold higher (130.0/10⁵ vs 41.1/10⁵) in patients with T2DM than in those without T2DM, and the rate of laparoscopic cholecystectomies was almost 2-fold higher (195.2/10⁵ vs 111.8/10⁵) in patients with T2DM. The annual rate of laparoscopic procedures showed an 11-year relative increase of 88.3% (from 117.0/10⁵ to 220.3/10⁵) in T2DM and 49.2% (from 79.2/10⁵ to 118.2/10⁵) in patients without T2DM (P<0.001), whereas the rate of open procedures showed an 11-year relative decrease of 27.6% in patients with T2DM and 37.9% in those without T2DM (P<0.001). The rate of emergency laparoscopic cholecystectomy was increased in the 11 years, whereas the rate of emergency open cholecystectomies was decreased (both P<0.001). Multivariate analysis revealed that older age, higher comorbidity and emergency cholecystectomy were associated with a higher IHM. Compared with patients without T2DM, patients with T2DM demonstrated a lower IHM after open cholecystectomy [OR=0.82 (0.78-0.87)], but a higher IHM after laparoscopic cholecystectomy [OR=1.18 (1.03-1.35)]. Time-trend analyses showed a significant reduction in IHM in patients with or without T2DM after the two procedures.

 

CONCLUSION: The rate of cholecystectomy was higher in patients with T2DM, and laparoscopic cholecystectomy was popularized in the past 11 years both in selective and emergency cholecystectomies.

 

(Hepatobiliary Pancreat Dis Int 2016;15:525-532)

 

KEY WORDS: diabetes mellitus; cholecystectomy; mortality; in-hospital mortality

Cholecystectomy is an optimal treatment of many gallbladder diseases. Laparoscopic cholecystectomy is recommended because of lower in-hospital mortality (IHM), decreased disability, less discomfort and shorter length of hospital stay (LOS), compared with open cholecystectomy.^[1] For the past years, the number of procedures has increased in most developed countries, largely driven by the increasing rate of laparoscopic procedure.^[2-6]

 

Gallstones are frequently seen in diabetic patients and their presence has also been associated with older age, obesity and a family history of gallstones.^[7] A previous study^[8] demonstrated a higher rate of complications, a higher rate of conversion from laparoscopic to open cholecystectomies, and a higher mortality rate in patients with type 2 diabetes mellitus (T2DM). Yet, Paajanen et al^[9] reported 2600 patients (9% of them had diabetes), who were operated on at a single institution.

 

Diabetes is a prevalent chronic disease.^{[10, 11]} If we could detect that such a large population is differentially exposed to a lower rate of laparoscopic procedures or associated with a higher mortality risk after cholecystectomy, this would add evidence to design specific strategies to increase the rate of less invasive procedures and to improve the outcomes in patients with T2DM. Using national hospital discharge data, we compared the rates and outcomes (LOS and IHM) of open and laparoscopic cholecystectomies performed in patients with or without T2DM in Spain between 2003 and 2013.

 

 

This cohort-based, retrospective, observational study was based on the Spanish National Hospital Database (Minimum Basic Data Set, MBDS). The database is managed by the Spanish Ministry of Health, Social Policy and Equality and consists of all the public and private hospital data, covering more than 95% of hospital discharges.^[12] The MBDS includes patient-related variables (gender, date of birth), date of admission, emergency vs regular admission, and date of discharge. The data included up to 14 discharge diagnoses, up to 20 procedures, and if the patient died during the hospitalization. The Spanish Ministry of Health, Social Policy and Equality sets standards for registration and performs periodic audits. We analyzed the data of 11 years between January 1, 2003 and December 31, 2013.

 

We chose the disease and procedure criteria of the International Classification Diseases-Ninth Revision, Clinical Modification (ICD-9-CM),^[13] which is used in the Spanish MBDS. We selected all patients for open cholecystectomy (ICD-9-CM codes 51.21 and 51.22) and laparoscopic cholecystectomy (codes 51.23 and 51.24), based on any procedural field. We grouped discharge diabetes status as follows: patients with no diabetes vs those with T2DM. We identified T2DM with the ICD-9-CM codes: 250.x0 and 250.x2. We excluded patients with type 1 diabetes mellitus (ICD-9-CM codes: 250.x1 and 250.x3) and those younger than 18 years old. Clinical characteristics included information on overall comorbidity at the time of diagnosis based on the Charlson comorbidity index (CCI).^{[14, 15]} The index applied to 17 disease categories whose scores were totaled to obtain an overall score for each patient. The index was subsequently categorized into three levels: 0, no disease; 1, one or two diseases; and 2, three or more than three diseases. We used 16 disease categories after excluding diabetes to calculate our modified CCI.

 

We considered other risk factors in the data analysis: obesity (ICD-9-CM codes: 278.0, 278.0x, 278.1 and 278.8), a diagnosis of gallbladder or pancreas cancer (ICD-9-CM codes: 156.x and 157.x, respectively), whether or not the procedure was performed during an emergency admission and conversion from laparoscopic to open cholecystectomy due to the technical infeasibility of the former (ICD-9-CM diagnosis code: V64.41; only available since 2006). The outcomes of interest included the proportion of patients who died during the admission defined as IHM and LOS.

 

We maintained data confidentiality at all times according to Spanish legislation. Participants’ identifiers were deleted before the database was provided to the authors in order to keep patients anonymous. Given the anonymous and mandatory nature of the dataset, it was deemed not necessary to obtain informed consent.

 

We estimated the rates of open and laparoscopic cholecystectomies for the patients with or without T2DM per 100 000 inhabitants. We calculated the age-, gender-specific incidence rates for diabetic patients by dividing the number of patients per year, gender, and age group and the corresponding estimated number of patients in the population group with diabetes according to data from the Spanish National Institute of Statistics, as reported on December 31 each year.^[16] The estimated prevalence of diabetes for gender and age groups was obtained from data from the Spanish Di@bet.es Study and the National Health Surveys conducted in April 2003, July 2006, October 2009, and December 2011.^{[11, 17]} In a similar fashion, we also calculated the age-, gender-specific incidence rates for non-T2DM patients by dividing the number of patients per year, gender, and age group and by the corresponding number of patients in the population group without diabetes according to the same sources.

 

We obtained the values for the variables as proportions or rates, means with standard deviations or medians with interquartile ranges, as was the case for LOS. We conducted bivariate analyses of the variables according to the year using binary logistic regression (proportions), ANOVA (means) and Kruskall-Wallis test (medians) as appropriate. In order to test the time trend for IHM adjusted by potential confounding variables, we performed logistic regression analyses with mortality as a binary outcome, entering year of discharge, gender, age, obesity, CCI and emergency admission procedure as independent variables. We generated models for subjects with or without diabetes and for the entire population in order to compare the IHM between those with or without the disease. In a sensitivity analysis, we additionally accounted for conversion to open cholecystectomy (coded since 2006) in the multivariate model only including data from the period of 2006-2013. We performed the statistical analyses using Stata version 10.1 (Stata, College Station, TX, USA). Nominal statistical significance was set at P<0.05 (two-tailed).

 

 

A total of 611 533 patients underwent a cholecystectomy in a period of 11 years. Among them, 78 227 (12.8%) patients had T2DM. Laparoscopic procedures accounted for 71.3% of the cholecystectomies. The characteristics of patients after open (Table 1) and laparoscopic (Table 2) cholecystectomies were categorized by T2DM status in Spain from January 2003 to December 2013.

 

Tables 1 and 2 show that the overall rates of open and laparoscopic cholecystectomies were higher in patients with T2DM than in those without T2DM in the years analyzed. The open cholecystectomy rate was three times higher (130.0/10⁵ vs 41.1/10⁵) and the rate of laparoscopic cholecystectomies was almost twice higher (195.2/10⁵ vs 111.8/10⁵) in patients with T2DM than in those without T2DM. The overall number of laparoscopic cholecystectomies was increased year by year during the 11-year period and the annual cholecystectomy rate was higher in the patients with T2DM. Specifically, the cholecystectomy rate raised from 117.0/10⁵ to 220.3/10⁵ (88.3% increase) in the 11 years in patients with T2DM and from 79.2/10⁵ to 118.2/10⁵ (49.2% increase) in those without T2DM (P<0.001). Reciprocally, the annual rate of open cholecystectomy showed in the 11 years a decrease of 27.6% in patients with T2DM and 37.9% in those without T2DM (P<0.001).

 

Patients who had undergone open cholecystectomies (Table 1) were progressively older (P<0.001). Patients with T2DM were older than those without T2DM (mean, 70.7±10.9 vs 64.3±15.9 years). Obesity was more prevalent in patients with T2DM (11.7% vs 6.4%). The rate of emergency open cholecystectomies was decreased over time (P<0.001). LOS significantly decreased over time in patients with or without T2DM (P<0.001). Overall, the IHM was higher for open than for laparoscopic cholecystectomies (Tables 1 and 2). Trends for overall mortality rates after open cholecystectomies differed between patients with or without T2DM, but the decrease of mortality in patients without T2DM was not statistically significant (P=0.197).

 

Patients who had undergone laparoscopic cholecystectomies (Table 2) were progressively older (P<0.001). Patients with T2DM were older than those without T2DM (mean, 67.6±11.1 vs 54.9±16.7 years). Obesity was more prevalent in patients with T2DM (12.6% vs 6.0%); obesity coding almost doubled for laparoscopic cholecystectomies (P<0.001). The rate of emergency laparoscopic cholecystectomies was increased (P<0.001). LOS significantly decreased in patients with or without T2DM (P<0.001). The overall mortality rate remained relatively constant after laparoscopic cholecystectomies, with a higher rate in patients with T2DM.

 

For both procedures, more significantly for laparoscopic cholecystectomy, an older age, a higher comorbidity and an emergency cholecystectomy were associated with a higher IHM (Table 3). Obesity was significantly associated with a significantly lower IHM only in the patients without T2DM who had undergone open cholecystectomies [OR=0.86 (0.77-0.96)]. Patients with T2DM who had undergone open cholecystectomy had a lower IHM [OR=0.82 (0.78-0.87)] but those with laparoscopic cholecystectomy had a higher IHM [OR=1.18 (1.03-1.35)]. The longitudinal trend of IHM showed a significant reduction in patients with or without T2DM, and both for open and laparoscopic cholecystectomies. The results from the sensitivity analysis included conversion to open cholecystectomy with data from 2006 onward (Table 4).

 

 

Our study revealed that patients who underwent cholecystectomy were progressively older, especially for those with T2DM. The annual rate of laparoscopic cholecystectomy was increased but that of open cholecystectomy was decreased. The annual rate of emergency laparoscopic cholecystectomy was increased, whereas the overall annual rate of cholecystectomy (both open and laparoscopic) was higher in patients with T2DM than in those without T2DM.

 

Old age, high comorbidity and emergency cholecystectomy were independent risk factors of IHM. Patients with T2DM had a lower IHM of 18% after an open cholecystectomy and a higher IHM of 18% after a laparoscopic cholecystectomy. IHM decreased in both patients with or without T2DM, and after open and laparoscopic cholecystectomies.

 

Other studies^{[2, 5, 6]} also found the increased annual rate of laparoscopic cholecystectomy and the decreased annual rate of open cholecystectomy. A study^[5] highlighted that laparoscopic emergency surgery was more likely to be performed at high volume centers and multivariate analysis showed that patient-associated factors influenced the outcome more strongly than hospital-related factors. The annual rates of both procedures were higher in patients with T2DM. These figures are referred to census the overall population. Thus, the increased rates may be partially related to the higher prevalence of T2DM in the population. However, we believe that the prevalence rates of T2DM from the Spanish Di@bet.es Study and the National Health Surveys conducted in April 2003, July 2006, October 2009 and December 2011 support our results.^{[11, 17]} Besides, gallstones are more prevalent in patients with T2DM.^[7] Increased rates are also seen in the diabetic patients in other countries.^[18]

 

The IHM is higher in patients after open procedure as reported elsewhere.^[4] Even though the procedure itself could be associated with worse outcomes due to technical reasons, this finding might also reflect different characteristics of the population who have undergone open laparoscopic procedure: an older age, higher comorbidities, more frequent coding for pancreas or gallbladder cancer, and more often emergency operations. Previous studies showed that the elderly are more likely to undergo open cholecystectomy^[19] and that an older age, complications and open or emergency surgery could predict increased mortality.^[20] Dua et al^[21] stated that elderly patients continue to lag behind their younger counterparts in laparoscopic cholecystectomy despite it is associated with a lower mortality in all age groups.

 

In our study, T2DM was associated with a higher IHM of 18% after laparoscopic cholecystectomy. This finding should be interpreted with the finding of a lower risk of open cholecystectomies in T2DM patients. To our knowledge, this is the first study to report such a finding. Nevertheless, we have to be cautious about this finding as the data were collected retrospectively from a registry database. To avoid biased results, we tested the hypotheses in inclusive regression models to account for potential confounding factors, although residual confounding due to allocation bias could play some role. A suboptimal selection process of the patients undergoing laparoscopic procedure cannot be ruled out either and would help explain the relative better outcomes for T2DM patients undergoing open cholecystectomies. Although it remains speculative, an interaction effect between obesity and T2DM cannot be discarded; however, obesity is associated with a better prognosis in every subgroup but in the T2DM patients undergoing open cholecystectomies. The better outcomes associated with obesity were described as the “obesity paradox” by others.^[22] The onset of complications after surgery in patients with diabetes is possible too, and it was formerly underscored by other investigators.^[23] We could not know the exact time of surgery for emergency patients. If surgery was delayed or moved ahead for laparoscopy patients with T2DM, this might influence the results. Lastly, the behavior of patients with T2DM could be different when late infectious complications occurred including tolerance to oxidant stress,^[24] acute lung injury,^[25] antibody responses, and other immunologic functions.^[26]

 

This study is limited by some variables based exclusively on the information from the discharge report. Under or over-report of different conditions is possible for some subgroups of patients. However, in contrast to diagnosis, infra-coding for operative procedures like cholecystectomy is unlikely because in two thirds of patients cholecystectomy can be performed at a non-emergency admission, specifically selected operation.

 

Unfortunately, there is no study assessing the rate of unreported diagnosis of diabetes in administrative databases in Spain. Leong et al,^[27] however, concluded that a commonly-used administrative database definition for diabetes had a pooled sensitivity of 82.3% (95% CI: 75.8%-87.4%) and a specificity of 97.9% (95% CI: 96.5%-98.8%), based on the findings of 6 studies with complete data available. This definition appears to miss approximately one fifth of cases of diabetes and wrongly classifies 2.1% of non cases in the population as diabetes cases. It is likely sensitive to monitor the prevalence trend in the general population if its accuracy remains stable over time. We have no data on the duration of the disease or the specific antidiabetic treatment for the patients. Nevertheless, the quality and validity of our dataset were shown to be useful for health research,^[28] even though some concerns have been raised about the accuracy of collected datasets.

 

In conclusion, laparoscopic cholecystectomy prevails as the preferred approach to treat gallbladder diseases in Spain. Patients with T2DM undergo cholecystectomy after hospitalization more frequently than those without T2DM. Additional studies are needed to confirm whether laparoscopic cholecystectomy is associated with a higher IHM in patients with T2DM and provide insight into this finding despite the reduction of IHM for cholecystectomy after hospitalization.

 

 

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