Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer : a randomized , double-blind clinical trial

Objective: to evaluate the effect of perioperative administration of symbiotics on the incidence of surgical wound infection in patients undergoing surgery for colorectal cancer. Methods: We conducted a randomized clinical trial with colorectal cancer patients undergoing elective surgery, randomly assigned to receive symbiotics or placebo for five days prior to the surgical procedure and for 14 days after surgery. We studied 91 patients, 49 in the symbiotics group (Lactobacillus acidophilus 108 to 109 CFU, Lactobacillus rhamnosus 108 to 109 CFU, Lactobacillus casei 108 to 109 CFU, Bifi dobacterium 108 to 109 CFU and fructo-oligosaccharide (FOS) 6g) and 42 in the placebo group. Results: surgical site infection occurred in one (2%) patient in the symbiotics group and in nine (21.4%) patients in the control group (p=0.002). There were three cases of intraabdominal abscess and four cases of pneumonia in the control group, whereas we observed no infections in patients receiving symbiotics (p=0.001). Conclusion: the perioperative administration of symbiotics significantly reduced postoperative infection rates in patients with colorectal cancer. Additional studies are needed to confirm the role of symbiotics in the surgical treatment of colorectal cancer.

Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: a randomized, double-blind clinical trial 568 Rev Col Bras Cir 2017; 44 (6): 567-573 study, neoadjuvant treatment (chemotherapy and radiotherapy), previous use of products with prebiotic, probiotic and/or symbiotic function or fiber modulus, and refusal to participate.We also excluded from the analysis patients with tumors that were considered non-resectable during surgery and those who had other organs resected concomitantly (uterus, bladder, liver, spleen).
The present study was performed after approval by the Ethics in Research Committee of the Porto Alegre Clinics Hospital, protocol number 12.0284.We obtained an informed consent term from all patients before inclusion.This work was entered in the ClinicalTrials.govregistry (identifier NCT01468779) and followed the recommendations of the Consolidated Standards of Reporting Trials (CONSORT 2010).

Groups of study
Preoperative assessment of the patients included a complete clinical history and physical examination, carcinoembryonic antigen dosage, colonoscopic examination, computed tomography of the abdomen and pelvis and chest X-ray and/or computed tomography of the chest.In addition, all patients underwent subjective global assessment (SGA) and anthropometric assessments 13 .
The sachets for both groups had the same appearance and the substances had the same color and flavor.The pharmacist, exclusively involved in the manufacturing of the symbiotics and placebo, randomized patients using a computer-generated sequence of numbers.
Both the investigators and the patients were blinded as to to group allocation until the end of the test.
However, blinding could be disrupted if patients had severe adverse events that might be related to the product being investigated.
On the day before surgery, all patients underwent routine bowel preparation.They also received intravenous gentamicin and metronidazole one hour before surgery.

Clinical variables
Postoperative infection was defined as infection occurring within 30 days of surgery.Infections were classified as incisional (surgical wound), organ/space (where surgery was performed) or at a distant site (urinary tract infection, pneumonia).The length of hospital stay was defined as the number of days elapsed from surgery to discharge.Deaths occurring within 30 days of surgery were considered surgical.

Statistical analysis
The sample size was based on a previous study that found a reduction in infection rates from 40% to 12.5% after administration of symbiotics 14 .
For a statistical power of 80% and an expected sampling loss rate of 10%, the sample size would be 90 patients.The sample size calculations were done with the COMPARE2 1.72 software.
We analyzed the data with the Statistical Program for Social Sciences program version 20.0 (SPSS Inc., Chicago, IL, USA, 2008) for Windows.We studies continuous variables using the Kolmogorov-Smirnov test.For the bivariate analysis of categorical variables, we used the Pearson Chi-square test or the Fisher's Exact Test.For continuous variables, when comparing two independent groups, were applied the Student's t or the Mann Whitney U test .We set the level of significance at p<0.05.

RESULTS
We initially included one hundred patients in the study.Of these, were excluded nine: four with unresectable tumors and five patients who required concomitant resection of other organs.After exclusions, the  Only one patient in the symbiotics group presented surgical wound infection, while nine cases were diagnosed in the control group (p=0.002).There was also a significant difference between the groups in relation to other infectious complications.While we observed three cases of intraabdominal abscess and four cases of pneumonia in the control group, we diagnosed no cases in the symbiotics group (p=0.001).
The incidence of noninfectious postoperative complications such as nausea, vomiting, abdominal distension, ileus, diarrhea or constipation was not different between the study groups (p=0.161).The mean hospitalization time was 11.2 days for the patients in the symbiotics group and 12.69 days for the patients in the control group was, with no statistical significance.There were no significant differences between the groups regarding mortality rates and re-hospitalization.

DISCUSSION
Recent clinical studies have evaluated the effect of immunomodulatory diets with probiotics and symbiotics on the incidence of infections related to different gastrointestinal surgeries.Promising results were demonstrated in resections of the pancreas, liver and esophagus [5][6][7]15 . Regrding colorectal resections, however, the results so far have been conflicting due to differences in the populations studied, type of surgery, type of probiotics and symbiotics used, and analysis methodology 11,12,16,17 .
Our study is the first to evaluate the effect of symbiotics not only on cancer patients undergoing minimally invasive colorectal surgery, including robotic and laparoscopic resections, but also in patients undergoing conventional open colorectal surgery.
In this sense, we prospectively evaluated a homogeneous population of patients with histologically confirmed colorectal adenocarcinoma submitted to elective and potentially curative oncological resection.We decided not to include patients undergoing surgery for benign colorectal diseases, considering the particular nutritional and immunological aspects of patients with colorectal cancer.Patients submitted to resection of multiple adjacent organs were excluded, as these surgeries are generally more extensive and related to increased morbidity.In addition, patients whose tumors were considered non-resectable were excluded.As shown in table 1, after patients randomization, we ended the study groups with similar clinical and demographic characteristics.
Because of the nature of colorectal surgery, infectious complications, especially wound infections, are extremely common, with a negative impact on quality of life, length of hospitalization, and costs.In this study, the perioperative use of symbiotics significantly reduced the incidence of wound infection.
Among the functions of the symbiotic compounds, the best characterized is the increase of the resistance of the strains against pathogens.Probiotic cultures compete with pathogenic microorganisms, whose growth is inhibited by the production of organic acids (lactate, propionate, butyrate and acetate), reinforcing the natural defense mechanisms of the body [18][19][20] .Modulation of the intestinal microbiota by probiotic microorganisms occurs through a mechanism called "competitive exclusion" and the strains that beneficially act in such cases are Bifidobacterium bifidum, Lactobacillus rhamnosus, Saccharomyces boulardii and Lactobacillus plantarum 21 .
The effect of probiotics on the immune response has also been demonstrated.Evidence in in vitro systems and animal models suggest that probiotics stimulate nonspecific and specific immune response.These effects are mediated by the activation of macrophages through an increase in cytokine levels and natural killer cell (NK) activity.The intestinal mucosa is the body's first line of defense against pathogenic invasions and action of toxic elements.After ingestion, the antigens encounter the GALT (gut-associated lymphoid tissue), which represents a mechanism of protection against pathogens.It also prevents the proteic hyperstimulation of the immune response through a mechanism known as tolerance to ingested content.
The main protective mechanism of GALT is the humoral immune response mediated by IgA secretion, which prevents the entry of potentially harmful antigens, while at the same time interacting with pathogens of the mucosa without increasing the damage.
Numerous studies have shown that some probiotic strains can increase S-IgA and modulate the production of cytokines involved in the regulation, activation, growth and differentiation of immune cells.It should be emphasized that the beneficial effects of probiotics on the immune system occur without triggering a harmful inflammatory response.However, not all lactic acid bacterial strains are equally effective.The immune response may be increased when one or more probiotics are consumed simultaneously and act synergistically, as appears to be the case with Lactobacillus given in conjunction with Bifidobacterium (SAAD), which we used in this study [22][23][24] .
In our study, the use of symbiotics also reduced the incidence of remote infections such as pneumonia, which only occurred in the control group.This finding is in line with the results of a meta-analysis conducted by Yang et al. 25  We observed, therefore, that the perioperative administration of symbiotics in patients submitted to elective surgery for colorectal cancer significantly reduced the rates of postoperative infection.Our results suggest that preoperative and postoperative oral ingestion of symbiotics may represent a promising strategy to prevent surgical infections in patients with colorectal cancer.Additional studies are needed to confirm the role of these microorganisms in colorectal surgery.
that analyzed 28 randomized trials involving 2511 patients undergoing different abdominal surgeries, including esophagectomies, pancreatectomies, hepatectomies, liver transplants and colectomies.The incidence of infections was lower among patients receiving symbiotics than in controls, particularly for respiratory, urinary, and wound infections.Hospitalization time was also shorter in patients receiving symbiotics.In our study, however, there was no difference between groups in relation to the length of hospital stay.He et al. 11 carried out a specific meta-analysis to estimate the probiotic/symbiotic treatment efficacy in patients undergoing colorectal resection.Only six randomized clinical trials involving 361 patients were included.Two studies aimed at preoperative use of probiotics or symbiotics, a study on postoperative treatment, and three evaluated pre and postoperative treatment.In addition to the differences in the products used, there was also heterogeneity between studies in the inclusion criteria and the types of sur-gery performed.The pre or perioperative administration of symbiotics had a positive effect on the incidence of total surgical infections and pneumonia.More recently, Komatsu et al. 9 performed a randomized, controlled, unicentric study, including patients undergoing elective laparoscopic colorectal surgery.A total of 379 patients were randomly assigned to two groups: 173 in the symbiotics group and 206 in the control group.After applying selection criteria, 362 patients (168 of the symbiotic group and 194 for the control group) were considered eligible for the study.Infection occurred in 29 (17.3%)patients of the symbiotics group and in 44 (22.7%) of the control group.According to the authors, symbiotics were not an effective treatment to reduce the incidence of infectious complications after colorectal resection.In our study, we included not only patients submitted to minimally invasive surgeries, but also conventional open surgeries, which represented the majority of our cases.One of the potential advantages of minimally invasive surgery is less surgical trauma, with less acute inflammatory response and immune disorders.All infection cases occurred among patients undergoing open surgery, which suggests that the symbiotics effect is more important in this type of surgery.
Flesch Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: a randomized, double-blind clinical trial 569 Rev Col Bras Cir 2017; 44(6): 567-573 intervention group (symbiotics) consisted of 49 patients and the control group (placebo), of 42.Both groups were similar, showing no statistical differences in demographic and clinical characteristics (Table 1