Nonsteroidal Anti-inflammatory Drugs Exposure Research Articles

The Effect of Nonsteroidal Anti-inflammatory Drugs on Union Rates Following Joint Arthrodesis: A Meta-Analysis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used and prescribed medications because of their important role in reducing inflammation and pain, in addition to their non-addictive properties and safety profiles. However, some studies have documented an association between NSAIDs and delayed union or nonunion of joint arthrodesis procedures due to a potential inhibition of the bone's inflammatory healing response. As a result, some orthopedic surgeons hesitate to prescribe NSAIDs after an arthrodesis procedure. The purpose of this meta-analysis is to review all relevant literature regarding the effect of NSAIDs on union rates after arthrodesis and determine if NSAID therapy increases the risk of non-union in the setting of arthrodesis procedures. The study hypothesis was that NSAIDs would not have a significant effect on therisk of nonunion after arthrodesis. A thorough systematic review of Medline, Embase, the Cochrane Database of Systematic Reviews, and the Web of Science identified 3,050 articles to be screened. The variables of interest encompassed demographic factors, procedural details, type and administration of NSAIDs, the number of patients exposed to NSAIDs with and without successful union (case group), as well as the number of patients who did not receive NSAIDs with and without successful union (control group). All the data were analyzed using a maximum likelihood random-effects model. The number of non-union events versus routine healing from each study was used to calculate the odds ratio (OR) of successful healing after arthrodesis procedures with versus without NSAID therapy. Thirteen articles met the inclusion criteria for the meta-analysis. NSAID exposure showed an increased risk of nonunion, delayed union, or both following arthrodesis procedures; however, this did not meet statistical significance (OR, 1.48; confidence interval [CI], 0.96 to 2.30). A sub-analysis of pediatric and adult studies showed a significant increase in non-union risk in adults (OR, 1.717; CI, 1.012 to 2.914) when removing the pediatric cohort (p = 0.045). This meta-analysis provides evidence that NSAIDs can increase the risk of nonunion, delayed union, or both following arthrodesis procedures in adults. However, the study did not identify a risk of nonunion, delayed union, or both following arthrodesis procedures in the pediatric population.

Antibiotic Use in the 12 Months Prior to Ileal Pouch-Anal Anastomosis Increases the Risk for Pouchitis

Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC); however, clinical and environmental risk factors for pouchitis remain poorly understood. We explored the relationship between specific clinical factors and the incidence of pouchitis. We established a population-based cohort of all adult persons in Denmark undergoing proctocolectomy with IPAA for UC from 1996-2020. We used Cox proportional hazard modeling to assess the impact of antibiotic, nonsteroidal anti-inflammatory drug (NSAID) exposure, and appendectomy on diagnosis of acute pouchitis in the first 2 years after IPAA surgery. Among 1616 eligible patients, 46% developed pouchitis in the first 2 years after IPAA. Antibiotic exposure in the 12 months before IPAA was associated with an increased risk of pouchitis (adjusted hazard ratio [aHR], 1.41; 95% confidence interval [CI], 1.22-1.64) after adjusting for anti-tumor necrosis factor alpha use and sex. Compared with persons without any antibiotic prescriptions in the 12 months before IPAA, the risk of pouchitis was increased in those with 1 or 2 courses of antibiotics in that period (aHR, 1.30; 95% CI, 1.11-1.52) and 3 or more courses (aHR, 1.77; 95% CI, 1.41-2.21). NSAID exposure in the 12 months before IPAA and appendectomy were not associated with risk of acute pouchitis (P= .201 and P= .865, respectively). In this population-based cohort study, we demonstrated that antibiotic exposure in the 12 months before IPAA is associated with an increased risk of acute pouchitis. Future prospective studies may isolate specific microbial changes in at-risk patients to drive earlier interventions.

Prolonged Non-Steroidal Anti-Inflammatory Drug Exposure After Pleurodesis Increases Pneumothorax Recurrence: A Retrospective Cohort Study

The use of non-steroidal anti-inflammatory drugs (NSAID) in patients undergoing pleurodesis remains controversial. Although many surgeons are comfortable prescribing NSAIDs post-operatively, some oppose this practice due to concerns of suppressing the inflammatory response and quality of pleurodesis. Only a small body of inconsistent publications exists with respect to guiding therapy in this common clinical scenario. A retrospective cohort study was undertaken assessing effect of NSAID exposure on pleurodesis outcomes. An institutional thoracic surgery database was reviewed yielding 147 patients who underwent pleurodesis for pneumothorax between 2010 and 2018. Medical records and imaging were reviewed for patient characteristics, NSAID exposure, recurrent pneumothorax and other adverse events. There was no overall difference between rates of recurrence and procedural failure of pleurodesis (Relative Risk [RR] 1.67 [95% CI 0.74-3.77]). However, NSAID exposure of >48 hours was associated with increased risk of recurrent pneumothorax (RR 2.16 [95% CI 1.05-4.45]). There was no increased rate of other adverse events related to NSAID usage. NSAID exposure does not increase failure rates or other adverse events following pleurodesis for pneumothorax. However, prolonged NSAID exposure post-pleurodesis may increase procedural failure rates. Further large volume randomised control trials are required.

Identifying Risk Factors for Cardiovascular Events Among Active-Duty Service Members and Veterans Prescribed Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

Oral NSAIDs are widely used analgesic medications for the treatment of musculoskeletal and inflammatory conditions. NSAIDs are associated with adverse effects that arise from COX enzyme inhibition including cardiovascular events. The combined role of patient and prescription factors associated with NSAID use on cardiovascular risk is not well characterized. The purpose of this study is to identify the risk factors with cardiovascular events among NSAID users. This study is a retrospective, nested case-control study, within the DAVINCI database, among active-duty service members and veterans with at least one NSAID pharmacy claim between fiscal year (FY) 2015-FY2020. Inclusion criteria individuals ≥18 years of age received a prescription NSAID for ≥7-day supply and a duration ≥1 month overall. Cases experienced nonfatal myocardial infarction, nonfatal stroke, or new onset heart failure. Ten controls were selected per case. Risk factors were identified through logistic regression modeling. The risk factors with strongest association to the primary outcome included age starting at 45 up to 75 and older, the first 90 days of NSAID exposure, cerebrovascular disease, cardiomyopathy, and history of myocardial infarction. Cox-selectivity and dose did not appear to be clinically significant in their association with cardiovascular events. The results of this study indicate that age, initial NSAID exposure, and comorbidities are more predictive than NSAID-specific factors such as COX-selectivity and dose. The results provide the framework for development of a risk score to improve prediction of NSAID-associated cardiovascular events.

P1142 Antibiotic use in the twelve months prior to ileal pouch-anal anastomosis increases the risk for pouchitis: A population-based Danish cohort study

Abstract Background Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), however clinical and environmental risk factors for pouchitis remain poorly understood. We explored the relationship between specific clinical factors and the incidence of pouchitis. Methods We established a population-based cohort of all adult persons in Denmark undergoing proctocolectomy with IPAA for UC between January 1, 1996 and May 31, 2020. We used Cox Proportional Hazard modeling and logistic regression to assess the impact of antibiotic and non-steroidal anti-inflammatory drug (NSAID) exposure and appendectomy on the primary outcome of diagnosis of acute pouchitis in the first 2 years after IPAA surgery. A 2-year time window was utilized given the clinical relevance of early pouchitis and to mirror prior studies in both administrative claims and the Danish health registers. Results Among 1,616 eligible patients, 738 (46%) developed pouchitis in the first 2 years after IPAA. Among all patients undergoing IPAA surgery for UC, 51% were prescribed antibiotics in the 12 months prior to the index date and 17% were prescribed NSAIDs in the 12 months prior to the index date. In Kaplan-Meier analyses, those persons who were prescribed antibiotics in the 12 months prior to the final stage of IPAA surgery were significantly more likely to develop pouchitis in the 2 years after the index date when compared to patients who were not prescribed antibiotics (p<0.001, Figure 1B). Additionally, male patients demonstrated a decreased risk for pouchitis in the first 2 years after the index date when compared to female patients (p=0.014, Figure 1A). Antibiotic exposure in the 12 months prior to IPAA was associated with an increased risk of pouchitis (adjusted Hazard Ratio [aHR] 1.40, 95% CI 1.21-1.62) after adjusting for year of surgery and sex (Table 1). In a secondary analysis, compared to persons without any antibiotic prescriptions in the 12 months prior to IPAA, the risk of pouchitis was increased in those with 1 or 2 courses of antibiotics in that period (aHR 1.29, 95% CI 1.10-1.51) and 3 or more courses (aHR 1.79, 95% CI 1.43-2.23, Figure 1C). NSAID exposure in the 12 months prior to IPAA and appendectomy were not associated with risk of acute pouchitis (p=0.201 and p=0.865 respectively). Conclusion In this population-based cohort study, we demonstrated that antibiotic exposure in the 12 months prior to IPAA is associated with an increased risk of acute pouchitis. Future prospective studies may isolate specific microbial changes in at-risk patients to drive earlier interventions.

Trends in harmful drug exposure during pregnancy in France between 2013 and 2019: A nationwide cohort study.

Describe the trends of exposure to harmful drugs during pregnancy over recent years in France. Nationwide cohort study. The French National administrative health Data System (SNDS). Pregnancies starting between 2013 and 2019 and outcomes corresponding to live births, medical terminations of pregnancy, and stillbirths. Each pregnancy was divided into a preconceptional period of 90 days before conception and three trimesters from conception to birth. Harmful drugs were defined according to their risks to the fetus: teratogenicity or fetotoxicity. Exposure was defined using the critical period during pregnancy for each type of harmful drug: preconceptional period or first trimester for teratogenic drugs and second or third trimesters for fetotoxic drugs. Prevalence of pregnancies exposed to at least one harmful drug. Among 5,253,284 pregnancies, 204,402 (389 per 10,000) pregnancies were exposed to at least one harmful drug during the critical periods: 48,326 (92 per 10,000) pregnancies were exposed to teratogenic drugs during the preconceptional period or the first trimester, and 155,514 (299 per 10,000) pregnancies were exposed to fetotoxic drugs during the second or third trimesters. Teratogenic drugs were mainly retinoids for topical use (44 per 10,000 pregnancies), antiepileptics (13 per 10,000 pregnancies) and statins (13 per 10,000 pregnancies). Fetotoxic drugs were mainly non-steroidal anti-inflammatory drugs (NSAIDs), for systemic (128 per 10,000 pregnancies) and topical use (122 per 10,000 pregnancies). Exposure to teratogenic drugs decreased from the preconceptional period to the first trimester. Exposure to fetotoxic drugs decreased from the second to the third trimester. Between 2013 and 2019, we found a decrease in harmful drug exposure overall, mainly for topical and systemic NSAIDs and for topical retinoids. In this nationwide study, about one in 25 pregnancies was exposed to at least one harmful drug, mainly NSAIDs and topical retinoids. Although the prevalence of harmful drug exposure decreased over the study period, NSAID exposure in the second and third trimester remains of concern.

NSAID prescribing and adverse outcomes in common infections: a population-based cohort study

ObjectivesInfections in primary care are often treated with non-steroidal anti-inflammatory drugs (NSAIDs). This study evaluates whether NSAID prescribing is associated with adverse outcomes for respiratory (RTIs) or urinary track (UTI)...

All-cause and immune checkpoint inhibitor-associated acute kidney injury in immune checkpoint inhibitor users: a meta-analysis of occurrence rate, risk factors and mortality.

Immune checkpoint inhibitors (ICIs) have been associated with acute kidney injury (AKI). However, the occurrence rate of ICI-related AKI has not been systematically examined. Additionally, exposure to proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs) were considered as risk factors for AKI, but with inconclusive results in ICI-related AKI. Our aim was to analyse the occurrence rate of all-cause AKI and ICI-related AKI and the occurrence rates of severe AKI and dialysis-requiring AKI, and to determine whether exposure to PPIs and NSAIDs poses a risk for all-cause and ICI-related AKI. This study population was adult ICI recipients. A systematic review was conducted by searching MEDLINE, Embase and PubMed through October 2023. We included prospective trials and observational studies that reported any of the following outcomes: the occurrence rate of all-cause or ICI-related AKI, the relationship between PPI or NSAID exposure and AKI development or the mortality rate in the AKI or non-AKI group. Proportional meta-analysis and pairwise meta-analysis were performed. The evidence certainty was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. A total of 120 studies comprising 46417 patients were included. The occurrence rates of all-cause AKI were 7.4% (14.6% from retrospective studies and 1.2% from prospective clinical trials). The occurrence rate of ICI-related AKI was 3.2%. The use of PPIs was associated with an odds ratio (OR) of 1.77 [95% confidence interval (CI) 1.43-2.18] for all-cause AKI and an OR of 2.42 (95% CI 1.96-2.97) for ICI-related AKI. The use of NSAIDs was associated with an OR of 1.77 (95% CI 1.10-2.83) for all-cause AKI and an OR of 2.57 (95% CI 1.68-3.93) for ICI-related AKI. Our analysis revealed that approximately 1 in 13 adult ICI recipients may experience all-cause AKI, while 1 in 33 adult ICI recipients may experience ICI-related AKI. Exposure to PPIs and NSAIDs was associated with an increased OR risk for AKI in the current meta-analysis.

A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy

Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2−/−) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2−/− mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2−/− mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.

Non-steroidal anti-inflammatory drug use and markers of Parkinson's disease progression: A retrospective cohort study

BackgroundPrevious studies demonstrated reduced incidence of Parkinson's disease (PD) with regular non-steroidal anti-inflammatory drug (NSAID) exposure, particularly ibuprofen. No studies have investigated the impact of NSAID exposure on markers of disease progression for established PD. MethodsThis is a retrospective observational study using two cohorts. The Deprenyl and Tocopheral Anti-Oxidative Therapy of Parkinsonism (DATATOP) study enrolled 800 drug naïve people with PD with a median follow-up duration of 6.5 years. The DATATOP primary outcome measures were mortality at last study visit. The Parkinson's Progression Markers Initiative (PPMI) cohort was limited to drug naïve PD participants (423 at time of analysis). The PPMI primary outcome measure was annual rate of change in ipsilateral putamen 123I-ioflupane binding ratio at four years study duration. Regular NSAID exposure was defined as any scheduled NSAID use (as needed use was excluded). Analysis was performed separately for recent exposure and cumulative exposure time (CET). ResultsTotal CET median and interquartile range (years) for ibuprofen, non-aspirin NSAID, and aspirin were respectively 0.9 (0.3–2.9), 1.1 (0.3–2.6), and 1.5 (0.4–2.8) for DATATOP and 0.4 (0.01–2.2), 1.4 (0.3–4.4), and 5.5 (2.6–7.1) for PPMI. Exposure was usually discontinuous. Exposure to ibuprofen was low in both cohorts. There was no significant association between NSAID recent exposure or CET and primary outcome measures in either cohort. ConclusionsNSAID exposure in established PD does not appear to provide protective effect although exposure may not have occurred continuously enough in these two cohorts to provide benefit. Statistical power for ibuprofen exposure analyses was limited.

Evaluation and Updated Classification of Acute Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAID-Exacerbated or -Induced Food Allergy (NEFA/NIFA).

There are hypersensitivity reactions (HRs) to foods in which nonsteroidal anti-inflammatory drugs (NSAIDs) act as aggravating factors (NSAID-exacerbated food allergy, NEFA) or cofactors (NSAID-induced food allergy, NIFA), often misdiagnosed as HRs to NSAIDs. Urticarial/angioedematous and/or anaphylactic reactions to ≥ 2 chemically unrelated NSAIDs do not meet the current classification criteria. However, they may be considered as part of a cross-reactive type of acute HR, which is NSAID-induced urticaria/angioedema with/without respiratory and/or systemic symptoms of anaphylaxis (NIUAA). To evaluate patients reporting acute HRs to NSAIDs and classify them according to updated criteria. 414 patients with suspected HRs to NSAIDs were studied prospectively. NEFA/NIFA was diagnosed in those who met all the following criteria: 1) mild reactions to (NEFA) or tolerance of (NIFA) the suspected foods without taking NSAIDs; 2) cutaneous and/or anaphylactic reactions to the combination foods + NSAIDs; 3) positive allergy tests to the suspected foods; 4) negative drug challenges (DCs) with the NSAIDs involved. 252 patients (60.9%) were diagnosed with NSAID hypersensitivity, 108 of whom had NIUAA. NSAID hypersensitivity was excluded in 162 patients (39.1%) who tolerated DCs with the suspected NSAIDs, 9 of whom were diagnosed with NEFA and 66 with NIFA. Pru p 3 was implicated in 67 of these 75 cases. NEFA/NIFA accounts for about 18% of patients reporting HRs to NSAIDs, with Pru p 3 as the main responsible food allergen. Therefore, patients with cutaneous and/or anaphylactic reactions to NSAIDs should be carefully questioned about all foods ingested within 4 hours before or after NSAID exposure, and targeted food allergy tests should be considered in the diagnostic workup of these patients. If testing is positive, DCs with the suspected NSAIDs should also be considered.

Acute kidney injury among preterm infants receiving nonsteroidal anti-inflammatory drugs: A pilot study.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequently prescribed class of medications in the neonatal intensive care unit (NICU). We aimed to reveal acute kidney injury (AKI) epidemiology in NSAID-exposed premature infants admitted to the NICU using a standardized definition and determine the percentage of NSAID-exposed patients with adequate serum creatinine (SCr) monitoring. This retrospective study compared infants born at ≤34 weeks gestational age who received NSAID for intraventricular hemorrhage prophylaxis (prophylaxis group) or symptomatic treatment for patent ductus arteriosus (PDA; treatment group) between January and December 2014at a tertiary NICU. All available SCr and 12-h urine output (UO) values were recorded from admission until day seven post-NSAID exposure. AKI incidence was determined using the neonatal modified Kidney Disease Improving Global Outcomes classification, defined as an increase in SCr (i.e., 1.5 fold rise from previous SCr measurement within seven days or 26.5mmol/L increase within 48h) or UO<1mL/kg/hour, excluding the first 24h of life. We identified 70 eligible subjects; 32 received prophylactic NSAIDs, and 38 received indomethacin or ibuprofen for treating symptomatic PDA. AKI incidence for the entire cohort was 23% (16/70). The prophylaxis group had a significantly lower AKI rate than the treatment group (9% vs. 34%; p=0.014). The treatment group had a higher proportion of infants with adequate SCr monitoring during NSAID treatment than the prophylaxis group (87% vs. 13%, p<0.001). NSAID-associated AKI occurred in approximately one-quarter of premature infants overall, and the AKI incidence was higher in infants treated with NSAIDs for the symptomatic treatment of PDA than in those receiving prophylactic treatment during the first day of life. Standardized protocols for monitoring daily SCr and UO after exposure should be implemented for all neonates with NSAID exposure to improve early AKI recognition and management.

Is the use of nonsteroidal anti-inflammatories after bowel anastomosis in trauma safe?

With an increasing interest in multimodal and opioid-reducing pain strategies, nonsteroidal anti-inflammatory drugs (NSAIDs) have become common place in the care of injured patients. Long-standing concerns of increased anastomotic leak (AL) rate with the use of NSAIDs, however, have persisted. We hypothesized that there would be no significant risk associated with NSAID use after bowel anastomosis in trauma patients. All patients presenting to a level 1 trauma center who required intestinal resection and anastomosis from 2011 to 2017 were reviewed. Patients receiving NSAIDs were compared with those managed without NSAIDs. Primary outcome of interest was anastomosis-related complications (AL, intra-abdominal abscess, anastomotic bleed, fascial dehiscence, fascial dehiscence, and enterocutaneous fistula). Multivariable logistic regression analyses were performed with propensity adjustment for inverse probability of NSAID treatment weights. A total of 295 patients met the inclusion criteria with 192 receiving NSAIDs. Patients receiving NSAIDs had lower abdominal Abbreviated Injury Scale and Injury Severity Score ( p < 0.046). Arrival systolic blood pressure, diastolic blood pressure, and Glasgow Coma Scale were higher in the NSAID group ( p < 0.013). After propensity weighting, NSAID use was not a major predictor of anastomotic complication ( p = 0.39). There was an increased risk of AL with perioperative vasopressor exposure (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.17-9.05; p < 0.001). Increasing red blood cell transfusions in the first 24 hours were associated with intra-abdominal complications (OR, 1.02; 95% CI, 1.00-1.04; p = 0.05). Nonsteroidal anti-inflammatory drug exposure demonstrated a weak association with AL (OR, 1.92; 95% CI, 0.97-3.90; p = 0.06). Consistent with previous studies, perioperative vasopressor exposure and increased number of red blood cell transfusions are risk factors for ALs and intra-abdominal complications, respectively. Nonsteroidal anti-inflammatory drug use in trauma patients with multiple risk factors may be associated with an increased risk of AL and should be used with caution in the setting of other established risk factors. Therapeutic/Care Management; Level III.

Short-term effects of various non-steroidal anti-inflammatory drugs (NSAIDs) on Danio rerio embryos

Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) without a medical prescription and their frequent prevalence in aquatic habitats, there are major health and environmental issues. NSAIDs have been found in surface water and wastewater in concentrations ranging from ng/L to μg/L all over the world. The purpose of this study was to determine the relationship between NSAIDs (diclofenac, ketoprofen, paracetamol and ibuprofen) exposure and associated adverse effects in the assessment of indirect human health risks posed by Danio rerio (zebrafish) and Environmental Risk Assessment (ERA) of these NSAIDs in aquatic environments. Therefore, the objectives of this study were to (i) reveal abnormality endpoints of early developmental stages, after exposure of zebrafish and (ii) perform an ecological risk assessment of aquatic organisms upon exposure to NSAIDs detected in surface waters based on the risk quotients (RQs) method. According to the toxicity data collected, all of the malformations appeared after diclofenac exposure at all concentrations. The most notable malformations were the lack of pigmentation and an increase in yolk sac volume, with EC50 values of 0.6 and 1.03 mg/L, respectively. The results obtained for the ERA revealed RQs higher than 1 for all the four NSAIDs chosen, posing ecotoxicological pressure in aquatic environments. Overall, our findings provide a critical contribution to the formulation of high-priority actions, sustainable strategies and strict regulations that minimize the negative effects of NSAIDs on the aquatic ecosystem.•To determine the LC50, lethal conditions such as coagulation, absence of heartbeat and blood flow, absence of tail separation and development of somites were taken into account.•The EC50 was calculated using sublethal parameters such as blood coagulation, pericardial edema, yolk sac edema or hypertrophy.•The 4 compounds present a high risk individually and in mixture with a RQ >> 1.

Acute Kidney Injury in a Cohort of Critical Illness Patients Exposed to Non-Steroidal Anti-Inflammatory Drugs.

To determine whether non-steroidal anti-inflammatory drug (NSAIDs) exposure prior to intensive care unit (ICU) admission affects the development of acute kidney injury (AKI) with renal replacement therapy (RRT). An administrative database is used to establish a cohort of patients who were admitted to the ICU. The exposure to NSAIDs that the patients had before admission to the ICU is determined. Demographic variables, comorbidities, AKI diagnoses requiring RRT, and pneumonia during the ICU stay are also measured. Multivariate logistic regression and inverse probability weighting (IPW) are used to calculate risks of exposure to NSAIDs for patients with AKI requiring RRT. In total, 96,235 patients were admitted to the ICU, of which 16,068 (16.7%) were exposed to NSAIDs. The incidence of AKI with RRT was 2.71% for being exposed to NSAIDs versus 2.24% for those not exposed (p &lt; 0.001). For the outcome of AKI, the odds ratio weighted with IPW was 1.28 (95% CI: 1.15-1.43), and for the outcome of pneumonia as a negative control, the odds ratio was 1.07 (95% CI: 0.98-1.17). The impact of prior exposure to NSAIDs over critically ill patients in the development of AKI is calculated as 8 patients per 1000 exposures. The negative control with the same sources of bias did not show an association with NSAID exposure.

Comparative Risks of Nonsteroidal Anti-inflammatory Drugs on Cardiovascular Diseases: A Population-Based Cohort Study.

Through examining the incidence of cardiovascular diseases (CVDs) among nonsteroidal anti-inflammatory drug (NSAID) users and nonusers, this study aims to compare the risks contributed by different NSAIDs in a Chinese population. The retrospective cohort including 4 298 368 adults without CVD from electronic health records between 2008 and 2017 in Hong Kong was adopted. A total of 4.5% of individuals received NSAIDs including celecoxib, etoricoxib, diclofenac, ibuprofen, indomethacin, mefenamic acid, or naproxen for ≥4 consecutive weeks at baseline. Cox regression, including NSAID use as a time-dependent covariate and adjusted with patient's characteristics, was conducted to examine the association between NSAID exposure and incident CVD. After a median follow-up of 6.9years (30million person-years), a total of 258 601 cases of incident CVD was recorded. NSAID use was shown to be associated with a significantly higher risk of CVD (hazard ratio [HR], 1.32 [95%CI, 1.28-1.37]) compared to non-NSAID use. Similar results in coronary heart disease (HR, 1.37 [95%CI, 1.31-1.43]), stroke (HR, 1.27 [95%CI, 1.21-1.33]), and heart failure (HR, 1.25 [95%CI, 1.16-1.34]) were obtained. Overall, similar CVD risk was observed across users of NSAIDs except for etoricoxib, which showed a higher risk (HR, 2.01 [95%CI, 1.63-2.48]). Considering that a higher CVD risk was consistently displayed among NSAID users, NSAIDs should be used cautiously, and the usage of etoricoxib in the Chinese population should be reviewed.

The Association Between Nonsteroidal Anti-Inflammatory Drug Use and Inflammatory Bowel Disease Exacerbations: A True Association or Residual Bias?

Studies suggest that nonsteroidal anti-inflammatory drugs (NSAID) may contribute to inflammatory bowel disease (IBD) exacerbations. We examined whether variation in the likelihood of IBD exacerbations is attributable to NSAID. In a cohort of patients with IBD (2004-2015), we used 3 analytic methods to examine the likelihood of an exacerbation after an NSAID exposure. First, we matched patients by propensity for NSAID use and examined the association between NSAID exposure and IBD exacerbation using an adjusted Cox proportional hazards model. To assess for residual confounding, we estimated a previous event rate ratio and used a self-controlled case series analysis to further explore the relationship between NSAID and IBD exacerbations. We identified 15,705 (44.8%) and 19,326 (55.2%) IBD patients with and without an NSAID exposure, respectively. Findings from the Cox proportional hazards model suggested an association between NSAID and IBD exacerbation (hazard ratio 1.24; 95% confidence interval 1.16-1.33). However, the likelihood of an IBD exacerbation in the NSAID-exposed arm preceding NSAID exposure was similar (hazard ratio 1.30; 95% confidence interval 1.21-1.39). A self-controlled case series analysis of 3,968 patients who had both an NSAID exposure and IBD exacerbation demonstrated similar exacerbation rates in the 1 year preceding exposure, 2-6 weeks postexposure, and 6 weeks to 6 months postexposure, but a higher incidence in 0-2 weeks postexposure, suggesting potential confounding by reverse causality. While we see an association between NSAID and IBD exacerbations using traditional methods, further analysis suggests this may be secondary to residual bias. These findings may reassure patients and clinicians considering NSAID as a nonopioid pain management option.

Nonsteroidal anti-inflammatory drug exposure and the risk of microscopic colitis

BackgroundMedication consumption has been suggested as a risk factor for microscopic colitis (MC), but studies of varying design have yielded inconsistent results. Our aim was to evaluate the association between medications and MC.MethodsA hybrid cohort of prospectively identified patients undergoing colonoscopy with biopsies for suspicion of MC (N = 144) and patients with MC enrolled within three months of diagnosis into an MC registry (N = 59) were surveyed on medication use. Medication use was compared between patients with and without diagnosis of MC by chi-squared test and binomial logistic regression adjusted for known risk factors of MC: age and gender.ResultsIn total, 80 patients with MC (21 new, 59 registry) were enrolled. Patients with MC were more likely to be older (p = 0.03) and female (p = 0.01) compared to those without MC. Aspirin and other non-steroidal anti-inflammatory drugs were more commonly used among patients who developed MC (p < 0.01). After controlling for age and gender, these medications remained independent predictors of MC with odds ratio for any non-steroidal anti-inflammatory drug use of 3.04 (95% CI: 1.65–5.69). No association between MC and other previously implicated medications including proton pump inhibitors and selective serotonin reuptake inhibitors was found.ConclusionsIn this cohort of patients with chronic diarrhea, we found use of aspirin and non-steroidal anti-inflammatory drugs, but not other implicated medications to be associated with the development of MC. Whether these drugs trigger colonic inflammation in predisposed hosts or worsen diarrhea in undiagnosed patients is unclear. However, we feel that these findings are sufficient to discuss potential non-steroidal anti-inflammatory drug cessation in patients newly diagnosed with MC.

Effect of non-steroidal anti-inflammatory drugs on fracture healing in children: A systematic review.

BACKGROUNDNon-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications in the United States. Although they are safe and effective means of analgesia for children with broken bones, there is considerable variation in their clinical use due to persistent concerns about their potentially adverse effect on fracture healing.AIMTo assess whether NSAID exposure is a risk factor for fracture nonunion in children.METHODSWe systematically reviewed the literature reporting the effect of NSAIDs on bone healing. We included all clinical studies that reported on adverse bone healing complications in children with respect to NSAID exposure. The outcomes of interest were delayed union or nonunion. Study quality was assessed using the Newcastle-Ottawa scale for non-randomized studies. A final table was constructed summarizing the available evidence.RESULTSA total of 120 articles were identified and screened, of which 6 articles were included for final review. Nonunion in children is extremely rare; among the studies included, there were 2011 nonunions among 238822 fractures (0.84%). None of the included studies documented an increased risk of nonunion or delayed bone healing in those children who are treated with NSAIDs in the immediate post-injury or peri-operative time period. Additionally, children are likely to take these medications for only a few days after injury or surgery, further decreasing their risk of adverse side-effects.CONCLUSIONThis systematic review suggests that NSAIDS can be safely prescribed to pediatric orthopaedic patients absent other contraindications without concern for increased risk of fracture non-union or delayed bone healing. Additional prospective studies are needed focusing on higher risk fractures and elective orthopaedic procedures such as osteotomies and spinal fusion.

Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer.

AimThe aim of this work was to investigate whether nonsteroidal anti‐inflammatory drugs (NSAIDs) could be beneficial or harmful when used perioperatively for colorectal cancer patients, as inflammation may affect occult disease and anastomotic healing.MethodThis is a protocol‐based retrospective cohort study on colorectal cancer patients operated on between 2007 and 2012 at 21 hospitals in Sweden. NSAID exposure was retrieved from postoperative analgesia protocols, while outcomes and patient data were retrieved from the Swedish Colorectal Cancer Registry. Older or severely comorbid patients, as well as those with disseminated or nonradically operated tumours were excluded. Multivariable regression with adjustment for confounders was performed, estimating hazard ratios (HRs) for long‐term outcomes and odds ratios (ORs) for short‐term outcomes, including 95% confidence intervals (CIs).ResultsSome 6945 patients remained after exclusion, of whom 3996 were treated at hospitals where a NSAID protocol was in place. No association was seen between NSAIDs and recurrence‐free survival (HR 0.97, 95% CI 0.87–1.09). However, a reduction in cancer recurrence was detected (HR 0.83, 95% CI 0.72–0.95), which remained significant when stratifying into locoregional (HR 0.68, 95% CI 0.48–0.97) and distant recurrences (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent (HR 0.69%, 95% CI 0.51–0.94) in the NSAID‐exposed, mainly due to a risk reduction in colo‐rectal and ileo‐rectal anastomoses (HR 0.47, 95% CI 0.33–0.68).ConclusionThere was no association between NSAID exposure and recurrence‐free survival, but an association with reduced cancer recurrence and the rate of anastomotic leakage was detected, which may depend on tumour site and anastomotic location.