Perioperative Nonsteroidal Anti-inflammatory Drugs (NSAID) Administration and Acute Kidney Injury (AKI) in Major Gastrointestinal Surgery: A Prospective, Multicenter, Propensity Matched Cohort Study.

OBJECTIVE: This study aimed to determine the relationship between early postoperative nonsteroidal anti-inflammatory drug (NSAID) administration and postoperative acute kidney injury (AKI) and anastomotic leak. SUMMARY BACKGROUND DATA: NSAIDs have analgesic, opioid-sparing, and anti-inflammatory effects. However, their postoperative use is limited by concerns around increased risk of AKI and anastomotic leak. METHODS: A secondary analysis of a multicenter, prospective cohort study including patients undergoing elective or emergency major gastrointestinal surgery from September to December 2015 across 173 hospitals in the United Kingdom and ireland. Exposure to early postoperative NSAIDs was defined as NSAID administration on postoperative days 0 to 3. The primary outcome was the 7-day postoperative AKI rate. Propensity score matching was used to balance treatment groups and estimate treatment effects that are presented as odds ratios, alongside the corresponding 95% confidence interval (CI). RESULTS: Overall 19.8% (1039/5240) of patients received early NSAIDs. AKI rates were 10.6% in the early NSAID group and 14.9% in the no NSAID group. The anastomotic leak rate in patients who received an anastomosis was 4.8% in the NSAIDs group and 6.0% in the no NSAIDs group. Following propensity score matching, early use of NSAIDs was not significantly associated with AKI (adjusted odds ratio 0.80, 95% CI 0.63-1.00, P = 0.057). This finding was consistent in subgroup analyses by NSAID dosage and timing. In patients who had a gastrointestinal anastomosis, NSAIDs were not associated with anastomotic leak (adjusted odds ratio 0.85, 95% CI 0.58-1.21, P = 0.382). CONCLUSIONS: Administration of NSAIDs in the early postoperative period is safe in selected patients following major gastrointestinal surgery.

Effect of postoperative non-steroidal anti-inflammatory drugs on anastomotic leakage after pancreaticoduodenectomy.

BACKGROUND: Although the association between an increase in anastomotic leakage (AL) and non-steroidal anti-inflammatory drugs (NSAIDs) has been reported in gastrointestinal surgeries, this issue has rarely been addressed for pancreaticoduodenectomy (PD). We aimed to investigate the association between postoperative NSAIDs administration and clinically relevant AL (CR-AL) following PD. METHODS: We retrospectively evaluated 2,163 consecutive patients who underwent PD between 2007 and 2019. The patients were divided into two groups; patients who received and did not receive NSAIDs by postoperative day (POD) 5. We conducted a propensity score analysis using inverse probability of treatment weighting (IPTW) to adjust the baseline differences between both groups. We compared the occurrence of CR-AL and other postoperative outcomes before and after IPTW. Further, we used the multivariable binary logistic regression method for a sensitivity analysis for CR-AL. RESULTS: A total of 2,136 patients were included in the analysis. Of these, 222 (10.4%) received NSAIDs by POD 5. The overall occurrence rate of CR-AL was 14.9%. After IPTW, postoperative NSAIDs were significantly associated with CR-AL (odds ratio [OR]: 1.24, 95% CI [1.05, 1.47], P = 0.012), prolonged postoperative hospitalization (OR: 1.31, 95% CI [1.14, 1.50], P < 0.001), and unplanned readmission within 30 days postoperatively (OR 1.48: 95% CI [1.15, 1.91], P = 0.002). However, this association was not consistent in the sensitivity analysis. CONCLUSIONS: Postoperative NSAIDs use was significantly associated with an increase in CR-AL incidence following PD. However, sensitivity analysis failed to show its association, which precludes a firm conclusion of its detrimental effect.

Postoperative Complications After Colorectal Surgery: Where Are We in the Era of Enhanced Recovery?

PURPOSE OF REVIEW: Individual elements in enhanced recovery pathways may be associated with specific complication risks. In this review, we highlight three areas of controversy surrounding complications in enhanced recovery: (1) whether enhanced recovery is associated with increased rates of acute kidney injury, (2) whether NSAID use is associated with anastomotic leaks, and (3) whether early urinary catheter removal is justified following colorectal surgery. RECENT FINDINGS: Acute kidney injury has been reported at several institutions following implementation of enhanced recovery pathways highlighting the importance of institutional data tracking. NSAID use has been implicated in anastomotic leak rates for non-elective colorectal procedures, and criteria for its use should be implemented. Early urinary catheter removal has been supported despite increased urinary retention rates in order to decrease urinary tract infections. Enhanced recovery protocols will continue to evolve, and risk profiles associated with individual elements should continue to be evaluated.

Gastropharyngeal Anastomotic Leak in Medullary Thyroid Carcinoma Following Initiation of a Tyrosine Kinase Inhibitor: A Case Report of an Unusual Side Effect of Cabozantinib.

BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for 1% to 2% of thyroid cancers in the United States. When identified early, total thyroidectomy is most often curative. However, in advanced disease, more aggressive treatment such as laryngectomy and esophagectomy may be indicated. Postsurgical fistula formation and leak is a potential complication in such cases. These fistulas are most likely to occur at the anastomotic site in cases of laryngectomy or esophagectomy. Concomitant chemotherapy and radiation increase this risk. Tyrosine kinase inhibitors (TKI) such as Cabozantinib are used as therapy for metastatic MTC. These drugs have previously been associated with dehiscence of anastomotic sites in the gastrointestinal tract. While previously identified in the bowel, this report represents the first documented case of gastropharyngeal anastomosis leak described in the context of TKI use for head and neck cancer. CASE PRESENTATION: We present the case of a 72-year-old male previously diagnosed with MTC. His gastropharyngeal anastomosis status-post laryngopharyngectomy and gastric pull up had been stable for 23 years. Over the past year, he developed back pain and was found to have spinal metastases of MTC. He was subsequently started on Cabozantinib to slow the progression of the disease. Within months of starting this TKI, a bleeding pharyngocutaneous fistula developed at the anastomosis site of the gastric pull up and pharynx. Upon discontinuation of Cabozantinib, the fistula healed with no further complications. CONCLUSIONS: To our knowledge, this is the first documented case of gastropharyngeal anastomotic leak related to TKI use. A causal relationship is highly plausible given the previously stable anastomosis and the suspicious advent of complications within months of initiation of this new drug. While previously limited to cases of intraabdominal bowel dehiscence, this report now suggests that wound dehiscence must be considered a known side effect of TKIs throughout the gastrointestinal tract, including the gastropharynx. As such, the risk of anastomotic dehiscence should be discussed with the patient prior to starting a TKI.

NSAID administration post colorectal surgery increases anastomotic leak rate: systematic review/meta-analysis.

BACKGROUND: Current enhanced recovery guidelines suggest that opioid sparing medications should be used for analgesia whenever possible following colorectal surgery. The present study aims to assess whether post-operative NSAID use is associated with an increased anastomotic leak rate after a colonic or rectal anastomosis. METHODS: A systematic review was performed for studies investigating anastomotic leak rate following NSAID use vs control after colonic or rectal anastomosis. Meta-analysis was performed to assess for overall risk of anastomotic leak with NSAID use, as well as sub-group analysis to compare selective vs non-selective NSAIDs and drug-specific NSAID safety profiles. RESULTS: Seven studies were included in the final review. Use of an NSAID post-operatively was associated with an overall increased risk of anastomotic leakage [OR 1.58 (1.23, 2.03), P = 0.0003]. Non-selective NSAIDs were associated with an increased risk [OR 1.79 (1.47, 2.18), P < 0.00001], but selective NSAIDs were not. The non-selective NSAID diclofenac was associated with an increased leak rate [OR 2.79 (1.96, 3.96), P < 0.00001], but ketorolac was not [OR 1.36 (0.89, 2.06), P = 0.16]. CONCLUSIONS: Great caution must be taken when prescribing NSAIDs following colonic or rectal anastomotic creation. The safety profile varies within the NSAID class and further research is needed to clarify which NSAIDs are safe for use and which are not.

Parecoxib's effects on anastomotic and abdominal wound healing: a randomized Controlled trial.

BACKGROUND: Current evidence regarding the effects of selective cyclooxygenase inhibitors on gastrointestinal anastomoses is controversial. An experimental randomized control study was conducted in our institution to histopathologically evaluate the consequences of parecoxib, on intestinal and abdominal wound healing. METHODS: Twenty-four adult Wistar rats underwent laparotomy, ascending colon transection, and hand-sewn anastomosis. They were randomized to receive either parecoxib (0.5 mg/kg twice daily) or 0.9% normal saline by intraperitoneal injection postoperatively. Animals were euthanatized either on the third or the seventh postoperative day. Semiquantitative methods were used to evaluate both intestinal and abdominal wounds for inflammatory cell composition, angiogenesis, fibroblasts, granular tissue, collagen deposition, epithelization, and presence of necrosis, exudate, and abscess formation. Results are presented as (parecoxib: median [IQR] versus control: median [IQR], P-value). RESULTS: No macroscopic anastomotic leakage or wound dehiscence was observed. Intestinal anastomoses in the parecoxib group, showed significantly decreased epithelization (2 [1] versus 3 [1], [P = 0.004]) and collagen deposition (2 [0] versus 3 [1], [P = 0.041]). No difference was observed in angiogenesis (3 [1] versus 2.5 [1], [P = 0.158]). Abdominal wall specimens appeared to demonstrate decreased epithelization (2 [2] versus 4 [0.5], [P = 0.0004]) in the treatment group. No difference between the two groups was identified regarding collagen deposition (2.5 [1] versus 2 [0.5], [P = 0.280]) and angiogenesis (2.5 [1] versus 2 [1], [P = 0.633]). Necrosis was significantly more present in the parecoxib group in both specimen types, (3.5 [1] versus 2.5 [1], [P = 0.017]) and (3 [1] versus 1 [0.5], [P < 0.0001]). CONCLUSIONS: The present study shows that despite the absence of clinical adverse effects, parecoxib can impair anastomotic and abdominal wound healing on a histopathological level.

Role of diclofenac sodium and paracetamol on colonic anastomosis: An experimental rodent model.

BACKGROUND: Despite many advances in surgery and technology, colonic anastomosis remains a challenge after colonic resection. The purpose of this study is to compare the safety of using diclofenac sodium and paracetamol for analgesia in colonic anastomosis on rats. METHODS: Wistar-Hannover rats were randomly allocated to four groups: Group 1, sham-operated group; Group 2, control group; Group 3, diclofenac sodium group; Group 4, paracetamol group. After laparotomy, the left colon was transected and a single-layer anastomosis was made with 5/0 vicryl in Groups 2, 3, and 4. Only laparotomy was performed in Group 1. After anastomosis, we administered saline to Group 2, diclofenac sodium to Group 3, and paracetamol to Group 4 for 7 days. Then, all animals were decapitated. The anastomotic region was resected, and bursting pressure was measured. Then, the specimen was sent to the laboratory for histological examination and hydroxyproline analysis. RESULTS: Bursting pressure and hydroxyproline level were significantly higher in the paracetamol group (p<0.05). When we looked at the fibrosis levels of these groups, it was also higher in paracetamol group. CONCLUSION: Bursting pressure, hydroxyproline levels, and fibrosis levels indicate that the perioperative use of paracetamol for analgesia when undergoing colonic anastomosis is safer than diclofenac sodium.

Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence after colorectal surgery: a meta-analysis.

BACKGROUND: Enhanced recovery after surgery protocols supports the post-operative use of nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize the use of opioids. However, there is an increasing concern on the impaired wound healing of anastomosis associated with NSAID use, potentially causing a higher risk of anastomotic leakage. The aim was to conduct a meta-analysis to evaluate the association of NSAIDs with anastomotic leakage after colorectal surgery. METHODS: A literature search was conducted using the MEDLINE, PubMed, Cochrane Library and Clinicaltrial.gov. Studies identified were appraised with standard selection criteria. Data points were extracted and meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Seventeen studies comprising of 26 098 patients were examined. The analysis of all studies showed a significantly lower rate of anastomotic dehiscence in the no-NSAID group (pooled odds ratio (OR) = 2.00, 95% confidence interval (CI) = 1.48-2.71, P < 0.00001). The analysis of randomized controlled trials (RCTs) demonstrates similar dehiscence rates between both groups (P = 0.17). In subgroup analysis, non-selective NSAIDs was associated with a higher risk of anastomotic dehiscence (pooled OR = 2.02, 95% CI = 1.62-2.50, P < 0.00001). However, there was no difference in the incidence of anastomotic leakage between no-NSAID group and selective NSAID group (P = 0.05). CONCLUSION: Use of NSAIDs after colorectal surgery may be associated with a higher risk of anastomotic leakage. It is important to balance between the benefits of faster post-operative recovery and potential adverse effects of NSAIDs. Selective NSAIDs may be safer than non-selective ones. More RCTs are warranted to further evaluate the relationship between anastomotic leakage and use of NSAIDs, especially selective ones.

Ketorolac and Other NSAIDs Increase the Risk of Anastomotic Leakage After Surgery for GEJ Cancers: a Cohort Study of 557 Patients.

OBJECTIVE: The objective of this study is to investigate the impact of ketorolac and other nonsteroidal anti-inflammatory drugs on anastomotic leakage after surgery for gastro-esophageal-junction cancer. Within the last two decades, the incidence of gastro-esophageal-junction cancer has increased in the western world and surgery is the curative treatment modality of choice. Anastomotic leakage is a feared complication of gastro-esophageal surgery, as it increases recurrence, morbidity, and mortality. Nonsteroidal anti-inflammatory drugs are widely used for postoperative pain relief. Nonsteroidal anti-inflammatory drugs have, however, in colorectal surgery, been shown to increase the risk of anastomotic leakage. METHOD: In a historical cohort study, we investigated the impact of nonsteroidal anti-inflammatory drugs on anastomotic leakage in 557 patients undergoing surgery for gastro-esophageal-junction cancer. Data were collected from a prospective maintained database, the Danish National Patient Registry, and patient medical records. Data were analyzed using univariate and multivariate statistical models and were stratified for theoretical confounders. RESULTS: In univariate analysis, we did not observe any difference in age, gender, tobacco exposure, or comorbidity status between patients experiencing anastomotic leakage and those without. In multivariate analysis, gender, histology, and type of anastomosis proved to affect odds ratios for anastomotic leakage. After adjustment for possible confounders, we found an odds ratio of 6.05 (95% confidence interval 2.71; 13.5) for ketorolac use and of 5.24 (95% confidence interval 1.85; 14.8) for use of other nonsteroidal anti-inflammatory drugs for anastomotic leakage during the first seven postoperative days. CONCLUSION: In the present study, we found a strong association between the postoperative use of ketorolac and other nonsteroidal anti-inflammatory drugs and the risk for anastomotic leakage after surgery for gastro-esophageal-junction cancers.

Nonsteroidal anti-inflammatory drugs and the risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in colorectal surgery due to their opioid-sparing effect. However, several studies have indicated an increased risk of anastomotic leakage following NSAID treatment, although conflicting results exist. The primary goal of this study was to further examine whether postoperative NSAIDs are independently associated with anastomotic leakage after anterior resection for rectal cancer. METHODS: Patients who underwent anterior resection for rectal cancer during 2007-2013 in 15 different hospitals in three healthcare regions in Sweden were included in the study. Registry data and information from patient records were retrieved. The association between NSAID treatment (for at least two days in the first postoperative week) and symptomatic anastomotic leakage (within 90 days) was evaluated with multiple logistic regression, with adjustment for pertinent confounding factors. RESULTS: Some 1495 patients were included in the study. Of these, 27% received postoperative NSAIDs for at least two days in the first postoperative week. Symptomatic anastomotic leakage occurred in 11% and 14% in the NSAID and non-NSAID group, respectively. With adjustment for confounders, the odds ratio for leakage among patients who received NSAIDs compared with those who did not was 0.88 (95% CI 0.65-1.20). No differences were seen between non-selective and COX-2-selective NSAIDs. CONCLUSION: Postoperative NSAID treatment does not seem to increase the risk of symptomatic anastomotic leakage after anterior resection for rectal cancer. NSAID use appears to be safe, but a well-powered randomized clinical trial is warranted.

Colonic anastomoses and non-steroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAID) play an important role in the treatment of post-operative pain, particularly in the context of enhanced recovery after colorectal surgery. Several recent articles have suggested that NSAID may have a deleterious effect on colo-colic or colo-rectal anastomoses. The aim of this review is to analyze the evidence based on meta-analyses and cohort studies in the literature. A systematic review of clinical studies identified twelve studies including two meta-analyses and ten comparative cohort studies that included a large number of patients. The data in these studies are heterogeneous, often biased, and do not permit a formal recommendation based on a high level of evidence. The main conclusion of this review is that the balance of benefit vs. risk (analgesic effect/risk of anastomotic disruption) is acceptable; it appears (with a low level of evidence) that a prescription of NSAID for 48h after surgery may be recommended for elective colon surgery. Nevertheless, it is important to respect the specific contra-indications of NSAID and avoid post-operative NSAID use if there are risk factors for anastomotic leakage: advanced age, malnutrition, severe co-morbidities, intra-operative difficulties.

Non-Steroidal Anti-Inflammatory Drug Use and Risk of Anastomotic Leakage after Anterior Resection: A Protocol-Based Study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been introduced as opioid-sparing analgesics in colorectal surgery. However, recent research has implicated these drugs as risk factors for anastomotic dehiscence. METHODS: The Swedish Colorectal Cancer Registry was used to identify all patients operated with anterior resection for rectal cancer at centres that performed more than 25 abdominal operations per year, from 2007 to 2012, inclusive. The registry provided individual patient data on demographic variables and symptomatic anastomotic leakage. The patient exposure to NSAIDs was defined according to the protocol of the hospital at which the patient was operated. Logistic regression was employed to estimate ORs and 95% CIs, adjusting for confounders. RESULTS: The study cohort comprised 2,605 patients operated at 21 centres. In the NSAID group, 102/1,458 (7.0%) suffered an anastomotic leak, as compared to 124/1,023 (10.8%) in the non-NSAID group. With adjustment for confounding, patients treated at NSAID hospitals had a reduced risk of developing anastomotic leakage (OR 0.68; 95% CI 0.48-0.96). CONCLUSIONS: In this retrospective protocol-based study, NSAIDs did not increase the risk of anastomotic leakage after anterior resection for rectal cancer. The postoperative use of NSAIDs may not be detrimental, but more research is warranted.

Risk of anastomotic leakage with nonsteroidal anti-inflammatory drugs within an enhanced recovery program.

INTRODUCTION: Anastomotic leakage is a serious complication after colorectal resection. Recent studies suggest that nonsteroidal anti-inflammatory drugs may increase the risk of anastomotic leakage. We investigated this association in our enhanced recovery population. MATERIAL AND METHODS: Patients undergoing an elective colon or rectal resection with primary anastomosis because of malignancy and treated within our enhanced recovery program were included. Univariable and multivariable logistic regression analyses were used to study risk factors for anastomotic leakage. RESULTS: Between 2006 and 2013, 856 patients were included. The anastomotic leakage rate was significantly higher in the group that received nonsteroidal anti-inflammatory drugs compared to patients who did not: 9.2 vs. 5.3%, p = 0.038. This higher rate was only seen in patients receiving diclofenac: for colonic resections, 11.8 vs. 6.0%, p = 0.016; for rectal resections, 13.1 vs. 0%, p = 0.017. Only male sex (odds ratio 2.20, p = 0.005) was also independently associated with anastomotic leakage. CONCLUSION: The results of this study are in line with other comparable studies in the literature, showing an increased risk for anastomotic leakage with diclofenac. The use of diclofenac in colorectal surgery can no longer be recommended. Alternatives for postoperative analgesia need to be explored within an enhanced recovery program.

Effect of non-steroidal anti-inflammatory drugs on the increasing the incidence of colonic anastomosis in rats.

BACKGROUND: Anastomotic leakage is one of serious complications of colorectal surgery. Research is inconsistent about whether non-steroidal anti-inflammatory drugs influence the healing of colorectal anastomoses and increase the incidence of anastomotic leakage. OBJECTIVE: To study the influence of NSAIDs on the healing of rat colonic anastomoses. DESIGN: This was an animal randomized-control trial. This study was approved by the ethical committee of Yangpu Hospital, Tongji University. INTERVENTION: 90 healthy Sprague-Dawley rats were randomly divided into 6 groups of 15 rats/group. Trail was performed in C (cotrol group) with no drugs, group M with morphine for analgesia, group F with flurbiprofen axeil, group L with lornoxicam, and group P with parecoxib sodium. MAIN OUTCOME MEASURES: The main outcomes measures were serological indexes including vascular endothelial growth factor, prostaglandin E2, hydroxyproline, and C reactive protein; histological specimens from the anastomotic stoma tissue including the collagen proportion, and hydroxyproline, cycloxygenase-2, and vascular endothelial growth factor content; physical indicators, including stoma fracture pressure, fracture strength and anastomotic leakage. RESULTS: No significant difference was observed among the indices of each group (P > 0.05). A significant difference occurred after operation (P < 0.05), with the data for groups K and M being dramatically higher than those for group F. LIMITATION: The study was nonblinded. CONCLUSION: The postoperative usages of non-steroidal anti-inflammatory drugs can decrease the strength of anastomotic tissue, and increase the incidence of anastomotic leakage.