Comparative study of systemic early postoperative inflammatory response among elderly and non-elderly patients undergoing laparoscopic cholecystectomy

Fialho Estudo comparativo da resposta inflamatória sistêmica no pós-operatório precoce entre pacientes idosos e não idosos submetidos à colecistectomia vídeo-laparoscópica 6 Rev Col Bras Cir. 2018; 45(1):e1586 the best approach? Am Surg. 2001;67(7):637-40. 4. Lujan JA, Sanchez-Bueno F, Parrilla P, Robles R, Torralba JA, Gonzalez-Costea R. Laparoscopic vs. open cholecystectomy in patients aged 65 and older. Surg Laparosc Endosc. 1998;8(3):208-10. 5. Coelho JC, Bonilha R, Pitaki SA, Cordeiro RM, Salvalaggio PR, Bonin EA, et al. Prevalence of gallstones in a Brazilian population. Int Surg.1999;84:25-8. 6. González González JJ, Sanz Alvarez L, Graña López JL, Bermejo Abajo G, Navarrete Guijosa F, Martínez Rodríguez E. Litiasis biliar en pacientes mayores de 80 años. ¿cirugía o tratamiento conservador? Rev Esp Enferm Dig. 1997;89(3):196-205. 7. Maxwell JG, Tyler BA, Maxwell BG, Brinker CC, Covington DL. Laparoscopic cholecystectomy in octagenarians. Am Surg. 1998;64(9):826-31; discussion 831-2. 8. Maxwell JG, Tyler BA, Rutledge R, Brinker CC, Maxwell BG, Covington DL, et al. Cholecystectomy in patients aged 80 and older. Ann Surg. 1998;176(6):627-31. 9. Kuy S, Sosa JA, Roman SA, Desai R, Rosenthal RA. Age matters: a study of clinical and economic outcomes following cholecystectomy in elderly Americans. Am J Surg. 2011;201(6):789-96. 10. Festi D, Dormi A, Capodicasa S, Staniscia T, Attili AF, Loria P, et al. Incidence of gallstone disease in Italy: results from a multicenter population-based Italian study (the MICOL Project). World J Gastroenterol. 2008;14(34):5282-9. 11. Glaser F, Sannwald GA, Buhr HJ, Kuntz C, Mayer H, Klee F, et al. General stress response to convencional and laparsocopic cholecystectomy. Ann Surg. 1995;221(4):372-80. 12. Biffi WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? Ann Surg. 1996;224(5):647-64. 13. Kahng KU, Roslyn JJ. Surgical issues for the elderly patients with hepatobiliary disease. Surg Clin North Am. 1994;74(2):345-73. 14. Magnuson TH, Ratner LE, Zenilman ME, Bender JS. Laparoscopic cholecystectomy: applicability in the geriatric population. Am Surg. 1997;63(1):91-5. 15. Casaroli AA, Bevilacqua RG, Rasslan S. Análise multivariada dos fatores de risco no tratamento cirúrgico da colecistite aguda no idoso. Rev Col Bras Cir. 1996;23(1):1-7. 16. Yetkin G, Uludag M, Oba S, Citgez B, Paksoy I. Laparoscopic cholecystectomy in elderly patients. JSLS. 2009;13(4):587-91. 17. Kirshtein B, Bayme M, Bolotin A, Mizrahi S, Lantsberg L. Laparoscopy cholecystectomy for acute cholecystitis in the elderly: is it safe? Surg Laparosc Endosc Percutan Tech. 2008;18(4):334-9. 18. Hazzan D, Geron N, Golijanin D, Reissman P, Shiloni E. Laparoscopic cholecystectomy in octagenarians. Surg Endosc. 2003;17(5):713-76. 19. Pawelec G, Adibzadeh M, Pohla H, Schauadt K. Immunosenescence: ageing of the imune system. Immunol Today. 1995;16(9):420-2. 20. O’Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K. Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol. 1998;113(2):213-9. 21. Marks J, Tacchino R, Roberts K, Onders R, Denoto G, Paraskeva P, et al. Prospective randomized controlled trial of traditional laparoscopic cholecystectomy versus single-incision laparoscopic cholecystectomy: report of preliminary data. Am J Surg. 2011;201(3):369-72; discussion 372-3. 22. Vittimberga FJ Jr, Foley DP, Meyers WC, Callery MP. Laparoscopy surgery and the systemic immune response. Ann Surg. 1998;227(3):326-34. 23. Bruce DM, Smith M, Walker CB, Heys SD, Binnie NR, Gough DB, et al. Minimal access surgery for cholelithiasis induces an attenuated acute phase response. Am J Surg. 1999;178(3):232-4. 24. Decker D, Tolba R, Springer W, Lauschke H, Hirner A, von Ruecker A. Abdominal surgical interventions: local and systemic consequences for the immune system--a prospective study on elective gastrointestinal surgery. J Surg Res. 2005;126(1):128. 25. Riese J, Schoolmann S, Beyer A, Denzel C, Hohenberger W, Haupt W. Production of IL-6 and MCP1 by the human peritoneum in vivo during major abdominal surgery. Shock. 2000;14(2):91-4. 26. Luna RA, Nogueira DB, Varela PS, Rodrigues Neto Ede O, Norton MJ, Ribeiro Ldo C, et al. A prospective, Fialho Estudo comparativo da resposta inflamatória sistêmica no pós-operatório precoce entre pacientes idosos e não idosos submetidos à colecistectomia vídeo-laparoscópica 7 Rev Col Bras Cir. 2018; 45(1):e1586 randomized comparison of pain, inflammatory response, and short-term outcomes between single-port and laparoscopic cholecystectomy. Surg Endosc. 2013;27(4):1254-9. 27. Madureira FA, Manso JE, Madureira Filho D, Iglesias AC. Inflammation in laparoscopic single-site surgery versus laparoscopic cholecystectomy. Surg Innov. 2013;21(3):263-6. Recebido em: 03/11/2017 Aceito para publicação em: 14/12/2017 Conflito de interesse: nenhum. Fonte de financiamento: nenhum. Endereço para correspondência: Antonio Carlos Iglesias E-mail: aciglesias.lf@gmail.com / joseantoniocunha@yahoo.com.br


INTRODUCTION
B razil has been presenting a process of rapid and intense population aging.In the USA, the population aged 65 or over was 8.1% in 2000 and reached 12.4% in 2015.The estimate for 2020 is that about 88.5 million (20.2%) of Americans are 65 or older 1 .In Brazil, it is estimated that the elderly population reaches the order of 30 million in 2020 2 .Consequently, the number of elderly patients who undergo surgical procedures has increased considerably 3,4 .Cholelithiasis is the most common abdominal surgical disease in these individuals 5 and several studies describe the increase of cholecystectomies in octagenarians [6][7][8] .The high prevalence of cholelithiasis makes cholecystectomy one of the most performed surgical procedures in the world 9,10 .
With the advent of minimally invasive surgery, laparoscopic cholecystectomy has become the gold standard treatment for biliary lithiasis, and the laparoscopic procedure has been proven to be associated with a faster recovery and lower systemic inflammatory response 11,12 .
Several population studies have shown that the incidence of cholelithiasis and acute cholecystitis increases with age.The prevalence of cholelithiasis is 9.3% for the general population, 21.4% for individuals between 60 and 69 years of age, and 27.5% for individuals aged 70 years or older 5 .Some studies have shown that biliary lithiasis behaves particularly in the elderly population, since there is an approximation of incidence between the genders, a higher incidence of choledocholithiasis and other complicated forms of the disease (cholecystitis, pancreatitis, biliary fistulas), a higher incidence of gallbladder cancer and higher mortality associated with emergency surgery 6,[13][14][15] .
Other studies demonstrate a higher morbidity in the postoperative evolution of laparoscopic 1 -Federal University of the State of Rio de Janeiro, Digestive System Surgery -Rio de Janeiro -RJ -Brazil

Original Article A B S T R A C T
Objective: to evaluate and compare the early postoperative period systemic inflammatory response between elderly and non-elderly patients submitted to laparoscopic cholecystectomy, mainly performing a quantitative analysis of interleukin-6 (IL-6), a marker of inflammatory activity systemic.Methods: we compared a series of cases over a period of six months at the Gaffrée and Guinle University Hospital of the Federal University of the State of Rio de Janeiro, involving 60 patients submitted to elective laparoscopic cholecystectomy.We used nonprobabilistic sampling for convenience, selecting, from the inclusion criteria, the first 30 patients aged 18-60 years, who comprised group I, and 30 patients with age equal to or greater than 60 years, who formed group II.Results: the 60 patients involved were followed for at least 30 days after surgery and there were no complications.There was no conversion to open surgery.The values of the medians found in the IL-6 dosages for the preoperative period, three hours after the procedure and 24 hours after surgery were, respectively, 3.1 vs. 4.7 pg/ ml, 7.3 vs. 14.1 pg/ml and 4.4 vs 13.3 pg/ml.Conclusion: Elderly patients were more responsive to surgical trauma and had elevated IL-6 levels for a longer period than the non-elderly group.Keywords: Cholecystectomy, Laparoscopic.Systemic Inflammatory Response Syndrome.Interleukin-6.cholecystectomy in the elderly population (especially above 80 years).These individuals present higher complication rates, higher rates of conversion to open surgery and longer hospital stays 7,16,17 .There is no single reason to explain the greater surgical morbidity found in the elderly population.Probably this cause is multifactorial.Some series have shown that the large number of comorbidities present in this population, associated with low cardiopulmonary reserve, negatively influence postoperative recovery 7,18 .Moreover, other authors have already demonstrated differences in the systemic inflammatory response between young and old individuals in certain situations 19,20 .
The objective of this study was to evaluate and compare the systemic inflammatory response between elderly and non-elderly patients submitted to elective laparoscopic cholecystectomy.

METHODS
This is a case series study, conducted over a six-month period, at the Gaffrée and Guinle University

RESULTS
We followed all 60 patients for at least 30 days after the end of surgery.The mean values of C-reactive protein (CRP) measured 24 hours after the surgical procedure were 6.3 for group I and 1.4 for group II, but the standard deviation showed a high variability between observations (Table 3).
Regarding preoperative and postoperative leukometry, the mean had similar results.Group I had 6,581.9/mm³versus 6,678.1/mm³ in group II; and in the postoperative period, 11,246.1/mm³versus 10,864.3/mm³for groups I and II, respectively.The mean platelet analysis present the same similarity.In the preoperative period, the values were 266.9 thousand/mm³ in group I versus 260.5 thousand/ mm³ in group II, and in the postoperative period they were 255.9 thousand/mm³ versus 241.3 thousand / mm³ for groups I and II, respectively (Table 3).As for Interleukin 6 (IL-6), the comparison within each group showed that, in the three moments analyzed (preoperative, three hours after surgery and 24 hours after surgery), its median values in group I were, 3.1, 7.3 and 4.4 pg/ml, respectively, and in group II, 4.7, 14.1 and 13.3 pg/ml, respectively, both with statistically significant differences (Table 4 ).Regarding comparison between groups, the median values of IL-6 were 3.1 x 4.7 pg/ml in the preoperative period, 7.3 x 14.1 pg/ml three hours after the procedure, and 4.4 x 13.3 pg/ml at the 24th postoperative hour.Only the medians of three and 24 hours showed statistically significant differences (Table 5).

DISCUSSION
Tissue injury triggers a systemic inflammatory response 21 , which is influenced by several factors, such as tissue injury volume and trauma intensity.This has already been described when comparing open cholecystectomy with laparoscopic one, the latter with an attenuated inflammatory response, probably due to less associated tissue damage 11,22,23 .Tissue injury from surgical trauma activates different cellular elements responsible for the immune response, like macrophages, neutrophils and natural killer (NK).Once activated, these cells initiate the production of cytokines, such as interleukin-6, which directly participates in the systemic inflammatory response 24 .Riese et al. demonstrated that during abdominal surgeries the peritoneum reacts rapidly, increasing the production of interleukin-6 25 .It has been clearly demonstrated in several studies 12,24,25 that IL-6 can be used as an inflammatory marker, since its levels are elevated early in the face of tissue damage.Therefore, the dosages of interleukin-6 and C-reactive protein have been used by several authors as a method of choice for the evaluation and comparison of the systemic inflammatory response in different groups 26,27 .Like IL-6, C-reactive protein can also be used as a marker of inflammation 2 .
Of the group of patients studied, we observed a predominance of the female gender, remembering that gallstones are more prevalent in females 5,9 .Regarding surgical risk, we found a predominance of individuals with comorbidities in group II.However, we included only patients with controlled comorbidities in this study, to minimize their effects on the behavior of inflammatory markers.We also analyzed the two groups regarding body mass index (BMI) and operative time, since the higher BMI could represent greater technical difficulty and longer surgical time.Therefore, we verified that the means of BMI and operative times were very close between the two groups, emphasizing the homogeneity of the sample.Several studies 26,27 used IL-6 as the main marker of inflammatory response after surgical trauma.
In the results shown in tables 4 and 5, it is possible to note that both groups responded to surgical trauma with elevation of IL-6.In the younger population this initial variation was lower than in the elderly.When comparing the median values of IL-6 dosages of the young and elderly groups in three and 24 hours after surgery, we observed statistically significant differences (p<0.01 and p<0.001, respectively).By analyzing the results, we can suggest that there is an initial major inflammatory response in the elderly group, since there was a more exacerbated IL-6 release in this group, with a statistically significant difference between the medians.
And we also observed that the inflammatory response is more sustained in this same group II.
In summary, it is possible to suggest that the elderly patients have a more exacerbated response to surgical trauma and had this inflammation maintained for a longer period, unlike the younger ones, who responded to the surgical trauma with a lower release of IL-6 and a faster normalization of its levels.
Although CRP was widely used to track inflammatory response in clinical practice, this marker was not sensitive to detect differences in the inflammatory response between the groups (young and old) undergoing a minimally invasive procedure, unlike IL-6, which is a more sensitive marker.Leukometry also behaved similarly between groups I and II.Its initial dosage did not present a significant statistical difference, neither a significant variation between the groups in the postoperative period.
In view of our results, the elderly patient has a more exacerbated response to the surgical trauma of laparoscopic cholecystectomy, an inflammatory response that is maintained for a longer period.
Hospital (HUGG), involving 60 patients submitted to elective laparoscopic cholecystectomy.The criteria used for surgical indication were the clinical history (biliary lithiasis or symptomatic polyp) and ultrasonographic findings, such as microcalculi, a calculus greater than or equal to 3cm, a polyp associated with biliary calculus and a polyp greater than or equal to 1cm in asymptomatic patients.Inclusion criteria were: age equal to or greater than 18 years, any gender, uncomplicated cholelithiasis, patients without comorbidities (ASA-I) or with clinically compensated comorbidities (ASA-II).Exclusion criteria were: need for conversion to open surgery, intraoperative finding of complicated biliary lithiasis (acute cholecystitis, choledocholithiasis and acute pancreatitis), use of immunosuppressive drugs (corticosteroids and immunomodulators), acquired immunodeficiency syndrome, malignant disease in activity, and those who did not sign the informed consent form.We used non-probabilistic sampling for convenience, selecting, according to the inclusion criteria, the first 30 patients aged 18-60 years, who comprised group I, and the first 30 patients with age 60 years or greater, who formed group II.In all the patients studied, we collected blood samples for the quantitative analysis of interleukin-6 (IL-6), a marker of systemic inflammatory activity.This collection occurred in three different moments: in the anesthetic induction, three hours and 24 hours after the end of the procedure.Other parameters studied were plasma leukometry (measured before and after surgery), surgical time (started at the time of the first incision and finished after the last cutaneous suture), presence of comorbidities, body mass index (BMI), variation in pre and post-operative platelet counts and C-reactive protein (CRP) measured 24 hours after the surgical procedure.All patients underwent general anesthesia, without epidural block and without the use of corticoids or opioids.We constructed tables to describe the measures of central tendency (mean and median) and dispersion (minimum and maximum values, amplitude, percentiles and standard deviation) of the continuous quantitative variables.We evaluated the difference between means with the Student's t-test for independent samples, the One-way ANOVA test for comparison of variances for paired samples, the Wilcoxon test for comparison between medians of paired samples, and the Mann-Whitney test to compare medians of unpaired samples.We used the Excel 2016 software and the statistical package SPSS 21.0 (Statistical Package for Social Science -Chicago, IL, 2008) for the analysis.Statistical significance was considered at p<0.05.This work was approved by the HUGG Ethics Committee, protocol number 03297312800005258, and all the patients involved in the present study signed the informed consent form.

Table 1 .
Patients undergoing cholecystectomy by gender and age group.

Table 2 .
Patients undergoing cholecystectomy by ASA and age group.

Table 3 .
Patients' epidemiological and laboratory profile.
SD: Standard Deviation; * Student t Test comparison of means (independent samples).

Table 4 .
IL-6 levels at the preoperative time and at three and 24 hours after the procedure.

Table 5 .
Comparison between the IL6 dosage times, preoperative, three hours and 24 hours.