CAT Draft                                                                                                        Shadman Noshin

Clinical & PICO Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible.

63 y/o male with a PMHx of HTN, DM, GERD, prostate cancer s/p brachytherapy (2011) and colorectal cancer has decided to undergo resection of colorectal cancer. During a visit before the surgery, the patient mentions that he read on a magazine that perioperative treatment with probiotics reduces the chance of postoperative infection and wants to know if this is true.

PICO Question: Does the perioperative treatment with probiotics in colorectal surgery reduce the chance of postoperative infection rate?

PICO Search Elements:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Patients with colorectal cancer undergoing colorectal surgery	Probiotics	No probiotics	Reduced infection rate
Patients with colorectal cancer undergoing colorectal resection	Bifidobacterium		Reduced rate of wound infection
	Lactobacillus		Reduced rate of surgical site infection
	Saccharomyces boulardii		Reduced postoperative complications
	Combination of different types of probiotics		Reduced postoperative infectious complications

 

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done in a previous PICO search.
A minimum of 3 databases should be used.

PubMed

Perioperative probiotics colorectal surgery (No filter) → 18 results

Perioperative probiotics colorectal surgery infection (No filter) → 10 results

Perioperative probiotics colorectal cancer surgery (No filter) → 12 results

perioperative probiotics colorectal surgery reduced infection (No filter) → 2 results

Perioperative probiotics colorectal resection infection (No filter) → 5 results

NEJM

Perioperative probiotics colorectal surgery (No filter) → 1 result

Perioperative probiotics colorectal surgery infection (No filter) → 1 result

Perioperative probiotics colorectal cancer surgery (No filter) → 1 result

Cochrane Library

Perioperative probiotics colorectal surgery (No filter) → 11 result

Perioperative probiotics colorectal surgery infection (No filter) → 0 result

Perioperative probiotics colorectal cancer surgery (No filter) → 10 result

Trip Database

Perioperative probiotics colorectal surgery infection (No filter) → 38 results

Perioperative probiotics colorectal surgery infection (Filter: Systematic review) → 1 result

Perioperative probiotics colorectal surgery infection (Filter: clinical trials) → 2 results

Perioperative probiotics colorectal surgery (No filter) → 43 results

Perioperative probiotics colorectal surgery (Filter: controlled trial) → 11 results

Perioperative probiotics colorectal surgery (Filter: systematic reviews) → 2 results

Perioperative probiotics colorectal cancer surgery (No filter) → 32 results

Perioperative probiotics colorectal cancer surgery (Filter: systematic review) → 0 result

Perioperative probiotics colorectal cancer surgery (Filter: clinical trials) → 3 results

Google Scholar

Perioperative probiotics colorectal cancer surgery (No filter) → 5,000 results

Perioperative probiotics colorectal cancer surgery (Filter: since 2014) → 1,860 results

Perioperative probiotics colorectal cancer surgery (Filter: since 2018) → 327 results

Perioperative probiotics colorectal surgery infection (Filter: since 2014) → 1,190 results

Perioperative probiotics colorectal surgery infection (Filter: since 2018) → 232 results

Perioperative probiotics colorectal surgery (Filter: since 2014) 26 725 results

Perioperative probiotics colorectal surgery (Filter: since 2018) → 138 results

 

Articles Chosen (5-8) for Inclusion (please copy and paste the abstract with link):

1. A Four-Probiotics Regimen Reduces Postoperative Complications After Colorectal Surgery: A Randomized, Double-Blind, Placebo-Controlled Study.

Citation: Kotzampassi, K., Stavrou, G., Damoraki, G., Georgitsi, M., Basdanis, G., Tsaousi, G., Giamarellos-Bourboulis, E.J. (2015). A Four-Probiotics Regimen Reduces Postoperative Complications After Colorectal Surgery: A Randomized, Double-Blind, Placebo-Controlled Study. World Journal of Surgery 39(11), 2776-83. https://www.ncbi.nlm.nih.gov/pubmed/25894405

Abstract:

BACKGROUND:

Heterogeneous results of published studies led to conduct a randomized clinical trial to assess the efficacy of a new formulation of four probiotics as prophylaxis for complications after colorectal surgery.

METHODS:

A double-blind, placebo-controlled randomized study was conducted enrolling patients undergoing colorectal surgery for cancer. Capsules of placebo or of a formulation containing Lactobacillus acidophilus, L. p lantarum, Bifidobacterium lactis and Saccharomyces boulardii were administered starting one day before operation and continuing for another 15 days postoperatively. Patients were followed up for 30 days with the development of postoperative complications as the primary outcome. Gene expression and serum levels of cytokines were measured on postoperative day 4 ( www.clinicaltrials.gov NCT02313519).

RESULTS:

The study was prematurely stopped after enrolment due to efficacy in the primary outcome. Administration of probiotics significantly decreased the rate of all postoperative major complication (28.6 vs. 48.8 % of the placebo arm, p 0.010, odds ratio 0.42). Major benefit was found in the reduction of the rate of postoperative pneumonia (2.4 vs. 11.3 %, p 0.029), of surgical site infections (7.1 vs. 20.0 %, p 0.020) and of anastomotic leakage (1.2 vs. 8.8 %, p 0.031). The time until hospital discharge was shortened as well. Gene expression of SOCS3 was positively related with gene expression of TNF and of circulating IL-6 in the probiotic group but not in the placebo group.

CONCLUSIONS:

The studied probiotic formulation significantly decreased the risk of postoperative complications, namely mechanical ventilation, infections and anastomotic leakage. Modulation of the gene expression of SOCS3 is one suggested mechanism.

 

2. The Effects of Perioperative Probiotic Treatment on Serum Zonulin Concentration and Subsequent Postoperative Infectious Complications After Colorectal Cancer Surgery: A Double-Center and Double-Blind Randomized Clinical Trial.

Citation: Liu, Z.H., Huang, M.J., Zhang, X.W., Wang, L., Huang, N.Q., Peng, H., Lan, P., Peng, J.S., Yang, Z., Xia, Y., Liu, W.J., Yang, J., Qin, H.L., & Wang, J.P. (2013). The Effects of Perioperative Probiotic Treatment on Serum Zonulin Concentration and Subsequent Postoperative Infectious Complications After Colorectal Cancer Surgery: A Double-Center and Double-Blind Randomized Clinical Trial. The American Journal of Clinical Nutrition 9(1), 117-26. https://www.ncbi.nlm.nih.gov/pubmed/23235200/

Abstract:

BACKGROUND:

Zonulin is a newly discovered protein that has an important role in the regulation of intestinal permeability. Our previous study showed that probiotics can decrease the rate of infectious complications in patients undergoing colectomy for colorectal cancer.

OBJECTIVE:

The objective was to determine the effects of the perioperative administration of probiotics on serum zonulin concentrations and the subsequent effect on postoperative infectious complications in patients undergoing colorectal surgery.

DESIGN:

A total of 150 patients with colorectal carcinoma were randomly assigned to the control group (n = 75), which received placebo, or the probiotics group (n = 75). Both the probiotics and placebo were given orally for 6 d preoperatively and 10 d postoperatively. Outcomes were measured by assessing bacterial translocation, postoperative intestinal permeability, serum zonulin concentrations, duration of postoperative pyrexia, and cumulative duration of antibiotic therapy. The postoperative infection rate, the positive rate of blood microbial DNA, and the incidence of postoperative infectious complications-including septicemia, central line infection, pneumonia, urinary tract infection, and diarrhea-were also assessed.

RESULTS:

The infection rate was lower in the probiotics group than in the control group (P < 0.05). Probiotics decreased the serum zonulin concentration (P < 0.001), duration of postoperative pyrexia, duration of antibiotic therapy, and rate of postoperative infectious complications (all P < 0.05). The p38 mitogen-activated protein kinase signaling pathway was inhibited by probiotics.

CONCLUSIONS:

Perioperative probiotic treatment can reduce the rate of postoperative septicemia and is associated with reduced serum zonulin concentrations in patients undergoing colectomy. We propose a clinical regulatory model that might explain this association.

 

3. Impact of Perioperative Probiotic Treatment for Surgical Site Infections in Patients with Colorectal Cancer.

Citation: Aisu, N., Tanimura, S., Yamashita, Y., Yamashita, K., Maki, K., Yoshida, Y., Sasaki, T., Takeno, S., & Hoshino, S. (2015). Impact of Perioperative Probiotic Treatment for Surgical Site Infections in Patients with Colorectal Cancer. Experimental and Therapeutic Medicine 10(3), 966-972. https://www.ncbi.nlm.nih.gov/pubmed/26622423

Abstract:

The aim of the present study was to estimate the effect of the perioperative administration of probiotics in patients undergoing colorectal cancer (CRC) surgery. The study focused on a total of 156 consecutive surgeries carried out from among all the elective CRC surgeries performed between April 2009 and March 2013. The patients involved in surgeries undertaken between April 2009 and October 2011 were placed in the non-probiotic group (group A, 81 patients) and those involved in surgeries between November 2011 and March 2013 were placed in the probiotic group (group B, 75 patients). Postoperative infectious complications were recorded, and the immune responses and fecal microbiota were determined. A breakdown of infectious complications showed that 21 (13.5%) patients experienced superficial incisional surgical site infections (SSIs), of which 16 patients were from group A (19.8%), and five patients from group B (6.7%) (P=0.016). The ImmuKnow® adenosine triphosphate values peaked on the first postoperative day (POD) in both groups. In group A, the ImmuKnow value of the first POD was increased significantly compared with the preoperative value (P=0.022). In group B, the value of the first POD did not increase compared with the preoperative value (P=0.28). In conclusion, probiotic treatment can reduce superficial incisional SSIs in patients undergoing CRC surgery. Perioperative probiotic treatment can enhance immune responses and improve the intestinal microbial environment.

 

4. Probiotics as a Preventive Strategy for Surgical Infection in Colorectal Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Trials.

Citation: de Andrade Calaça, P.R., Bezerra, R.P., Albuquerque, W.W.C., Porto, A.L.F., & Cavalcanti, M.T.H. (2017). Probiotics as a Preventive Strategy for Surgical Infection in Colorectal Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Trials. Translational Gastroenterology and Hepatology 2(67). https://www.ncbi.nlm.nih.gov/pubmed/28905008

Abstract:

BACKGROUND:

Infection following abdominal surgery remains a major factor in morbidity among colorectal cancer (CRC) patients. Probiotic therapy has been suggested to improve the clinical and laboratory outcome of patients undergoing gastrointestinal surgery. The aim of this study was to investigate the efficacy of probiotic lactic acid bacteria in patients with CRC in the pre- and postoperative phases.

METHODS:

Systematic database searches identified 1,080 related articles. However, only seven articles were selected according to the eligibility criteria for qualitative and quantitative evaluation.

RESULTS:

Most of the reviewed articles presented satisfactory results related to the prevention of surgical inflammation in patients undergoing resection of CRC when using strains of Lactobacillus genus, predominantly.

CONCLUSIONS:

Probiotics are suggested to prevent surgical inflammation of CRC, at the same time that the combination of particular microorganisms administered is beneficial to the treatment and surgical recovery.

 

5. Probiotics Reduce Postoperative Infections in Patients Undergoing Colorectal Surgery: A Systematic Review and Meta-Analysis.

Citation: Liu, P.C., Yan, Y.K., Ma, Y.J., Wang, X.W. Geng, J., Wang, M.C., Wei, F.X., Zhang, Y.W, Xu, X.D., & Zhang, Y.C. (2017). Probiotics Reduce Postoperative Infections in Patients Undergoing Colorectal Surgery: A Systematic Review and Meta-Analysis. Gastroenterology Research and Practice. https://www.ncbi.nlm.nih.gov/pubmed/28484489

Abstract:

Background: We performed this meta-analysis to investigate the efficacy of probiotics on prevention of infection-related complications following colorectal resection.

Method: PubMed, EMBASE, Cochrane Library, and the Web of Science were searched up to January 2016. According to the results, only randomized controlled trials that compared the efficacy of probiotics on patients with colorectal resection were included for meta-analysis.

Results: Nine studies including a total of 1146 patients met the criteria (556 received multistrain probiotic bacteria, 590 with non-multistrain probiotic bacteria). The combination of multistrain probiotics was beneficial in the reduction of total infections (OR = 0.30, 95%CI: 0.15-0.61, p = 0.0009), including surgical site infections (SSI) (OR = 0.48, 95%CI: 0.25-0.89, p = 0.02) and nonsurgical site infections (NSSI) (OR = 0.36, 95%CI: 0.23-0.56, p < 0.00001). However, there was no significant reduction in total infections (OR = 0.74, 95%CI: 0.50-1.09, p = 0.13) or SSI (OR = 0.77, 95%CI: 0.52-1.12, p = 0.17) with the application of non-multistrains of probiotics.

Conclusion: Combinations of multistrain probiotic bacteria showed promise in preventing the incidence of infections following colorectal surgery. However, the efficacy of one or two strains of probiotics remains undetermined.

 

6. A Randomized Double-Blind Trial on Perioperative Administration of Probiotics in Colorectal Cancer Patients.

 

Citation: Gianotti, L., Morelli, L., Galbiati, F., Rocchetti, S., Coppola, S., Beneduce, A., Gilardini, C., Zonenschain, D., Nespoli, A., & Braga, M. (2010). A Randomized Double-Blind Trial on Perioperative Administration of Probiotics in Colorectal Cancer Patients. World Journal of Gastroenterology 16(2), 167-75. https://www.ncbi.nlm.nih.gov/pubmed/20066735

Abstract:

AIM: To investigate whether probiotic bacteria, given perioperatively, might adhere to the colonic mucosa, reduce concentration of pathogens in stools, and modulate the local immune function.

METHODS: A randomized, double-blind clinical trial was carried out in 31 subjects undergoing elective colorectal resection for cancer. Patients were allocated to receive either a placebo (group A, n = 10), or a dose of 10(7) of a mixture of Bifidobacterium longum (BB536) and Lactobacillus johnsonii (La1) (group B, n = 11), or the same mixture at a concentration of 10(9) (group C, n = 10). Probiotics, or a placebo, were given orally 2 doses/d for 3 d before operation. The same treatment continued postoperatively from day two to day four. Stools were collected before treatment, during surgery (day 0) and 5 d after operation. During the operation, colonic mucosa samples were harvested to evaluate bacterial adherence and to assess the phenotype of dendritic cells (DCs) and lymphocyte subsets by surface antigen expression (flow cytometry). The presence of BB536 and La1 was evaluated by the random amplified polymorphism DNA method with specific polymerase chain reaction probes.

RESULTS: The three groups were balanced for baseline and surgical parameters. BB536 was never found at any time-points studied. At day 0, La1 was present in 6/10 (60%) patients in either stools or by biopsy in group C, in 3/11 (27.2%) in group B, and none in the placebo group (P = 0.02, C vs A). There was a linear correlation between dose given and number of adherent La1 (P = 0.01). The rate of mucosal colonization by enterobacteriacae was 30% (3/10) in C, 81.8% (9/11) in B and 70% (7/10) in A (P = 0.03, C vs B). The Enterobacteriacae count in stools was 2.4 (log10 scale) in C, 4.6 in B, and 4.5 in A (P = 0.07, C vs A and B). The same trend was observed for colonizing enterococci. La1 was not found at day +5. We observed greater expression of CD3, CD4, CD8, and naive and memory lymphocyte subsets in group C than in group A with a dose response trend (C > B > A). Treatment did not affect DC phenotype or activation, but after ex vivo stimulation with lipopolysaccharides, groups C and B had a lower proliferation rate compared to group A (P = 0.04). Moreover, dendritic phenotypes CD83-123,  CD83-HLADR, and CD83-11c (markers of activation) were significantly less expressed in patients colonized with La1 (P = 0.03 vs not colonized).

CONCLUSION: La1, but not BB536, adheres to the colonic mucosa, and affects intestinal microbiota by reducing the concentration of pathogens and modulates local immunity.

 

7. The Effect of Perioperative Probiotics Treatment for Colorectal Cancer: Short-Term Outcomes of a Randomized Controlled Trial.

Citation: Yang, Y., Xia, Y., Chen, H., Hong, L., Feng, J., Yang, J., Yang, Z., Shi, C., Wu, W., Gao, R., Wei, Q., Qin, H., & Ma, Y. (2016). The Effect of Perioperative Probiotics Treatment for Colorectal Cancer: Short-Term Outcomes of a Randomized Controlled Trial. Oncotarget 7(7), 8432-40. https://www.ncbi.nlm.nih.gov/pubmed/26824990

Abstract:

This study was designed to mainly evaluate the anti-infective effects of perioperative probiotic treatment in patients receiving confined colorectal cancer (CRC) respective surgery. From November 2011 to September 2012, a total of 60 patients diagnosed with CRC were randomly assigned to receive probiotic (n = 30) or placebo (n = 30) treatment. The operative and post-operative clinical results including intestinal cleanliness, days to first – flatus, defecation, fluid diet, solid diet, duration of pyrexia, average heart rate, length of intraperitoneal drainage, length of antibiotic therapy, blood index changes, rate of infectious and non-infectious complications, postoperative hospital stay, and mortality were investigated. The patient demographics were not significantly different (p > 0.05) between the probiotic treated and the placebo groups. The days to first flatus (3.63 versus 3.27, p = 0.0274) and the days to first defecation (4.53 versus 3.87, p = 0.0268) were significantly improved in the probiotic treated patients. The incidence of diarrhea was significantly lower (p = 0.0352) in probiotics group (26.67%, 8/30) compared to the placebo group (53.33%, 16/30). There were no statistical differences (p > 0.05) in other infectious and non-infectious complication rates including wound infection, pneumonia, urinary tract infection, anastomotic leakage, and abdominal distension. In conclusion, for those patients undergoing confined CRC resection, perioperative probiotic administration significantly influenced the recovery of bowel function, and such improvement may be of important clinical significance in reducing the short-term infectious complications such as bacteremia.

Explanation: I tried choosing the more recent articles, even if they have small sample size, as they would provide me with up-to-date information. Also, I tried narrowing down to articles that had higher level of evidence, such systemic reviews/meta-analysis and RCTs. For instance, although my last two articles have a small sample size, I chose them as they are published within last 10 years, and because they are RCTs, they would provide me with higher level of evidence.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
1. Kotzampassi, et al. (2015)	Randomized, double-blind, placebo-controlled study	-164 participants undergoing colorectal surgery for colorectal cancer  -The afternoon prior to surgery and following bowel cleansing, the patients were randomized to either receive 4 capsules of placebo or probiotics. They also received one capsule (either placebo or probiotics) twice a day 100 mL with water on the day of surgery and for the next 14 consecutive days   -82 in placebo group   -84 in the treatment group who received a combination of Lactobacillus acidophilus LA-5, Lactobacillus plantarum, Bifidobacterium lactis BB-12 and Saccharomyces boulardii capsule	-The aim of the study was to see the efficacy of combination of four probiotics prophylaxis for patients undergoing colorectal surgery.  -Primary outcome that was measured was the occurrence of major postoperative complications, such as, anastomotic leakage, wound infection and dehiscence and any other infection (pneumonia, UTI) accompanied by severe sepsis, within the 30 days of surgery.   -The secondary measures that were studied were the occurrence of minor postoperative complications, such as, peripheral venous thrombosis, pulmonary embolism, acute heart failure and acute renal failure, within 30 days; the time until development of complications within 30 days; days on mechanical ventilation, duration of postoperative ileus and total hospital days; and gene expression and serum cytokines.	-The overall complication rate was 48.8% in the placebo and 28.6% in the treatment group.  -Reduction of complications in the treatment group included significant reduction in the incidence of postoperative infections, mostly lower respiratory tract infections and surgical site infections, reduction in anastomotic leakage and the need for postoperative intubation and mechanical ventilation.   – The time until development of first major complication was shorter in the placebo group than the probiotics group   -One patient from the placebo group developed a massive pulmonary embolism but none from the treatment group.   -The time until first bowel movement was shorter for the probiotics group   -Both gene expression of TNF and circulating concentrations of IL-6 were under the control of SOCS3 in the probiotics group, whereas they were not under control of SOCS3 in the placebo group   – The length of hospital stay was shorter in the probiotics group   -The time until alive discharge was shorter in the probiotics group compared to the placebo	-Small study size  -Premature closure of the study due to achievement of the primary endpoint   -The probiotics were made in Greece, which could have impacted the result
2. Liu, et al. (2013)	Randomized clinical trial	-150 participants  -Inclusion criteria include, 1. age between 25 and 75 years of age, 2. a diagnosis confirmed by biopsy and histologic testing, 3. radical resection previously performed, and 4. no distant metastasis.   -Exclusion criteria include, 1. age of >75 years old, 2. Being pregnant, 3. known lactose intolerance, 4. clinically significant immunodeficiency, 5. Additional gastrointestinal disorders, such as, Crohn disease or ulcerative colitis, 6. use of antibiotics during the 10 days before surgery, 7. evidence of infection, 8. use of other probiotics preoperatively or excessive fiber intake within the 2 weeks of surgery, 9. history of an emergency surgery, 10. bowel preparation for colonoscopy within 6 days before surgery, 11. history of a proctectomy with low rectal anastomosis or surgery for a polypoid lesion, 12. previous laparoscopic surgery, 13. receipt of preoperative neoadjuvant chemotherapy or radiotherapy, and 14. distant metastasis.   -75 in the control group received encapsulated maltodextrin   -75 in the probiotics group received a combination of 3 probiotics, Lactobacillus plantarum, Lactobacillus acidophilus-11 and Bifidobacterium longum-88, 2 grams/day   -Both groups received capsules for a total of 16 days, 6 days preoperatively and 10 days postoperatively.   -The smell and taste of the 2 types of capsules were the same	-The effect of perioperative probiotics use on serum zonulin concentrations in participants undergoing colorectal surgery due to colorectal carcinoma.  -The study looked at postoperative infection rate, positive rate of blood microbial DNA, in the incidence of postoperative infections, such as, septicemia, central line infection, pneumonia, UTI and diarrhea, assessing bacterial translocation, serum zonulin concentrations which is a protein that has an important role in the regulation of intestinal permeability, duration of postoperative fever and cumulative duration of antibiotic therapy	-Infection rate was lower in the treatment group (P<0.05) than the placebo group  – Probiotics decreased the serum zonulin concentration (P<0.001)   -The blood microbial DNA positive rate also decreased in the treatment group   -The duration of postoperative fever, duration of antibiotic therapy, and the rate of postoperative infectious complications (all P<0.05) were all decreased in the probiotics group	-Small sample size  -The colon mucosal short circuit current for TER and HRP flux could not be determined before treatment
3. Aisu, et al. (2014)	Cohort study of patients with colorectal cancer undergoing colorectal surgery	-156 patients  -81 surgeries done between April 2009 to October 2011 were placed into the non-probiotic group   -75 surgeries done between November 2011 to March 2013 were placed in probiotics group and received 6 tablets of combination of Enterococcus faecalis T110, Clostridium butyricum TO-A and Bacillus mesentericus TO-A per day. The probiotics were started 3 to 15 days prior to surgery and restarted the day the patient started drinking water.   -Exclusion criteria: inoperable patients   -All the surgeries were done by the same team, which included 3 surgeons	-The study wanted to assess the effect of perioperative probiotics administration in patients with colorectal cancer undergoing colorectal surgery  -Assessed postoperative infectious complications, immune responses and fecal microbiota	-16 patients from the non-probiotic group and 5 patients from the probiotic groups had surgical site infections, 1 patient from the probiotic group had pneumonia and none from the non-probiotic group, 1 patient from the probiotic group had UTI and none from the non-probiotic group, and 5 patients from the probiotic group had enteritis and 3 from the non-probiotic group.  -Probiotics improved host immune responses which led to prevention of infectious complications and also enhanced the intestinal microbial environment   -The study suggested that probiotic treatment can reduce superficial incisional surgical site infections in patients undergoing colorectal surgery	-Small study size  -The surgeries were done in Japan and their techniques might be slightly different from the US, which could have an impact on the study result   -Not everyone received probiotics for same number of days, which could have affected the result, especially the infection rate   -Not everyone started the probiotics on the same day after surgery
4. de Andrade Calaça, et al. (2017)	Systematic review and meta-analysis of randomized trials	-7 randomized trials included with 826 patients altogether with colorectal cancer who underwent colorectal surgeries  -Inclusion criteria: studies done on humans, published in English, Spanish or Portuguese from 2005 to 2016 and the period when the patients received probiotics.   -Exclusion criteria: non-original articles, such as, letters, editorials, comments and book chapter, not presenting dosage information and studies done on cell or animal models.	-They wanted to assess the postoperative infectious complications, detection of pathogenic bacteria in blood and surgical site infection post probiotic use.	-A significant difference between the two groups in the rate of surgical site infection was noted in only one of the studies  -Only 2 studies showed a positive impact of probiotics when it came of controlling postoperative infectious complications   -4 articles showed a positive response of the probiotics use when the researchers were assessing the amount of bacteria detection in blood.	-Not all the studies were blinded  -Different studies used different probiotics   -The duration of probiotic use was different for different studies   -2 of the studies did not provide the information about the age of their patients
5. Liu, et al. (2017)	Systematic review and meta-analysis of randomized trials	-9 studies with 1,146 patients with colorectal cancer who underwent colorectal surgeries  -562 patients received probiotics and 584 were in the control group   -Inclusion criteria: all randomized trials that looked at the efficacy of probiotics for colorectal surgery infection and complications   -Exclusion criteria included: 1. patients who received preoperative chemoradiotherapy, 2. only prebiotics were administered during the peri-operation period; 3. lack of key data, and 4. duplicate studies published by the same intuitions, in which case, the researchers selected the highest quality and the latest publications, unless endpoints were mutually exclusive	-The study assessed for surgical site infections  -The study also aimed to find out nonsurgical site infections, such as, UTI, pneumonia and bacteremia   -Assessed if any improvement in anastomotic leakage and bacterial translocation	-Probiotics were overall beneficial in the reduction of surgical site infections  -Probiotics also reduced nonsurgical site infections   -No significant reduction in total infection rate in non-multistrain probiotic group compared to the multistrain probiotic group   -No statistically significant difference seen between the control and treatment group when it came to bacterial translocation and anastomotic leakage	-Different studies used different probiotics  -Some studies used single strain of probiotic while others used multi-strains of probiotics   -The duration of probiotic use was different for different studies   -Some of the trials were not double blinded   -There is some risk of bias in treatment allocation concealment in some of the studies.
6. Gianotti, et al. (2010)	Randomized controlled double-blind trial	-31 patients with colorectal cancer undergoing colorectal resection  -10 patients received placebo, 11 received a dose of of a mixture of Bifidobacterium longum (BB536) and Lactobacillus johnsonii (La1) and rest of the 10 received the same mixture at a concentration of  2 doses per day for 3 days before the surgery and postoperatively from day 2 to day 4.	-To assess whether perioperative probiotic administration can adhere to the colonic mucosa and if this treatment could change the gut microflora by reducing the pathogenic bacteria and if they could modulate the local immune response in the patients with colorectal cancer undergoing colorectal resection	-Lactobacillus johnsonii (Lal) adheres to colonic mucosa and colonizes feces but not Bifidobacterium longum (BB536)  -Lactobacillus johnsonii (Lal), but not Bifidobacterium longum (BB536), reduces pathogenic bacteria in the colon, since it adheres to colonic mucosa   -Only Lactobacillus johnsonii (Lal) can modulate the intestinal immune response   -The amount of dose and time of administration with respect to surgery are key factors in obtaining these results	-Very small sample size  -Cannot be generalized to all patients with colorectal carcinoma undergoing colorectal resection, as this study does not look at the rate of postoperative infections
7. Yang, et al. (2016)	Randomized controlled double-blinded trial	-60 patients with colorectal cancer  -30 patients received placebo containing maltodextrin and sucrose and the other 30 received a combination of Bifidobacterium longum, Lactobacillus acidophilus and Enterococcus faecalis 5 days before and 7 days after colorectal resection   -Both placebo and probiotics had the same package   -The baseline of the patients of the two groups were quite homogenous	-The study was designed to assess the anti-infective effects of perioperative probiotic administration in patients with colorectal cancer undergoing colorectal surgery  -Also assess if there was any statistical difference in gender, age, BMI, tumor location, TNM stage and tumor differentiation between the two groups	-No statistically significant difference in the incidence of bacteremia in both of the groups (P=0.0528)  -No statistically significant difference (P>0.05) in other infectious complications rate   -The incidence of diarrhea was significantly lower (p = 0.0352) in the probiotics group (8/30 patients) compared to the placebo group (16/30 patients)   -No significant differences noted with regard to gender (p = 0.604), age (p = 0.567), BMI (p = 0.895), tumor location (p = 0.855), TNM stage (p = 0.771), and tumor differentiation (p = 0.707) between the placebo and the treatment groups.   -1 patient from each group had anastomotic leakage; thus, no statistically significant difference in anastomotic leakage between both of the groups	-Small sample size

Conclusion(s):

– Briefly summarize the conclusions of each article, then provide an overarching conclusion.

Article #1 by Kotzampassi, et al. concluded that there was a significant reduction in the incidence of postoperative infections, such as, surgical site infection and lower respiratory tract infections. There was also a decrease in the rate of anastomotic leakage and need for intubation and mechanical ventilation in the next 30 days after colorectal surgeries.

Article #2 by Liu, et al. claimed that there was a decrease in the rate of infection in the treatment group compared to the placebo group. The probiotics group also had a decrease in postoperative fever, the rate of postoperative infectious complications and the duration of antibiotic therapy.

Article #3 by Aisu, et al. reported that there was an improvement of host immune response post probiotic administration, and that there was a significant decrease in surgical site infections in the probiotics group.

Article #4 by de Andrade Calaca, et al. mentioned that a significant difference was noted in the surgical site infections among the two groups and that probiotics group had a lower infection rate.

Article #5  by Liu, et al. stated that probiotics were overall beneficial in reducing surgical site infections, but there was no significant decrease noted in total infection rate in non-multistrain probiotic group. In addition, there was no statistically significant difference in bacterial translocation and anastomotic leakage between different groups.

Article #6 by Gianotti, et al. asserted that Lactobacillus johnsonii (Lal) adheres to colonic mucosa, colonizes feces and can modulate the intestinal immune response, but not Bifidobacterium longum (BB536). Moreover, the amount of dose and the time of administrations with respect to surgery were key factors.

Article #7 by Yang, et al. affirmed that there is no statistically significant difference between both groups when comparing the rates of infectious complications, bacteremia and anastomotic leakage. However, the study also reported that they found a statistically significant difference in the incidence of diarrhea, which was lower in the treatment group.

All the articles, except the last one, show that, up to certain extent, there is some benefit of probiotic administration perioperatively, as they mostly help to reduce postoperative infectious complications and surgical site infections. There are some other benefits mentioned in some articles, such as, lower rate of intubation, mechanical ventilation, bacterial translocation and anastomotic leakage; however, these benefits are not evaluated by all of the articles.

 

Clinical Bottom Line:

As mentioned above in the conclusion section, based on the research, it seems like there is some beneficial effects of perioperative probiotics administration, such as, lower risk of surgical site infections and lower risk of other infectious complications. However, before we conclude anything, we have to take into consideration many other factors, particularly, the limitations of the studies.

Weight of the evidence: The studies were of various sizes, some had large population, whereas, most of them had very small population. In this case, we would put more weight on the articles that had a larger population, specifically, on the 4^th and 5^th articles. Moreover, both of these articles are systematic reviews and meta-analysis of randomized controlled trials, which means they are able to provide us with higher level of evidence. However, before concluding anything, there are more factors to look at, such as, the number of days and the types of antibiotics used for each study. Patients from different studies received different types of antibiotics and for different length of days, which could definitely affect the rate of infection. Also, different studies used different types of probiotics; some used single strain but most used multistrain probiotics, which could also have an impact on the overall result. Nonetheless, based on the types of study and the population size, I would say that we should put more emphasis on the 4^th and 5^th studies; however, we have a slight contradiction in the result of both of the studies. The 4^th article by de Andrade Calaca, et al. mentioned that there was a significant decrease in the infection rate among the patients in the treatment group; whereas, the 5^th article by Liu, et al. mentioned that although there was overall beneficial effect of probiotic administration in reducing the surgical site infection, there was no significant decrease noted in total infection rate in non-multistrain probiotic group.

Magnitude of effects: The magnitude of effect can be significant as postoperative infection in a patient who has/had colorectal cancer can increase the rate of morbidity, mortality, the length of hospital stays and overall healthcare cost.

Clinical significance: The first study showed that perioperative probiotics administration had a clinically significant decrease in the rate of postoperative major complications (28.6% complication rate in probiotics versus 48.8% complication rate in the placebo group). Moreover, postoperative pneumonia rate was 2.4% in the probiotics group and 11.3% in the placebo group, surgical site infection rate was 7.1% in the probiotics group and 20.0% in the placebo group, and anastomotic leakage rate was 1.2% in the probiotic and 8.8% in the placebo group. In the third article, by Aisu, et al., it was revealed that 16 patients from the placebo group and 5 patients from the probiotics group had surgical site infection. So, there was a clinically significant difference in both of the groups’ surgical site infection rate, although both of studies had relatively small sample size.

The studies that were included in my research, most of them had small size of population, except the 2 systematic reviews and meta-analysis, and even if we consider their population size, they do not have a large sample size; they are just larger compared to the other 5 studies. I tried finding larger studies with high level of evidence, but these are the most recent studies I was able to find. Most of the articles concluded that perioperative probiotic administration had some benefits, and none of the studies specifically mentioned about any adverse effect associated with probiotic use. Although these studies do not provide us with sufficient amount of evidence to come to a conclusion, most of the articles show some benefit of probiotics, due to which I would feel more comfortable giving my patient probiotic perioperatively. Also, when I looked up, there is usually no side effects, but some patients might develop bloating and temporary increase in gas formation, which are pretty benign side effects. However, the main issue is that different studies used different probiotics, due to which we cannot pinpoint a type of probiotics that would be beneficial for our patients. Most of the studies used lactobacillus and Bifidobacterium genus probiotics. So, for my patient, I would use a combination of different types of lactobacillus and Bifidobacterium strains perioperatively to see if there is any improvement in his bowel function and if he develops any postoperative infections. I would start him on probiotics about 3-5 days before the surgery to see if he develops any side effects.

My clinical bottom line would be that there is some benefit of perioperative probiotics used in colorectal surgeries, but because of the limitations of my studies (mostly small sample size), it is difficult to strongly conclude anything. However, since probiotics usually do not have any severe side effects, I would suggest using them for colorectal surgeries, specially lactobacillus and Bifidobacterium genus. However, patients should be monitored for any possible side effects. In order to come to a definite conclusion on this topic, I would say that a larger systematic review/meta-analysis of large RCTs should be performed.