Adverse Gastrointestinal Outcomes Research Articles

Protocol for a systematic review and meta-analysis investigating the impact of continuous versus intermittent enteral feeding in critically ill patients

IntroductionEnteral nutrition (EN) is the recommended nutritional support in most critically ill populations. When given by feeding tube, EN may be administered either continuously or intermittently. It is unclear which approach is superior in reducing gastrointestinal complications—such as diarrhea—and meeting nutritional targets. The main objectives of this systematic review and meta-analysis are to (1) determine whether continuous or intermittent enteral nutrition is associated with higher incidence of adverse gastrointestinal outcomes, including diarrhea, and (2) determine which feeding modality is associated with reaching nutritional goals.Methods and analysisThis systematic review protocol is reported in accordance with guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. We will search MEDLINE, Embase, the Cochrane Library, and the World Health Organization (WHO) International Clinical Trials Registry (ICTRP) search portal for studies comparing continuous EN and intermittent EN in critically ill patients with no date or language restrictions. Studies will be screened, selected, and extracted independently and in duplicate. We will assess the risk-of-bias assessment using the Cochrane Collaboration’s Risk of Bias (RoB) 2 tool. The primary outcome will include the incidence of diarrhea; secondary outcomes include other adverse GI outcomes (nausea, vomiting, abdominal pain, and constipation), as well as reaching nutritional goals, and length of ICU and hospital stay and mortality. We will pool data using a random-effects model and assess the certainty of the evidence for each outcome using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology.Ethics and disseminationEthics approval is not required for this study as no original data will be collected. We will disseminate results through peer-reviewed publication and conference presentations.Systematic review registrationPROSPERO CRD42022330118.

Enteral Feedings Do Not Increase the Risk of NEC in ELBW Infants Undergoing Treatment of Patent Ductus Arteriosus With Acetaminophen.

Acetaminophen (APAP) is an alternative to indomethacin and ibuprofen for treatment of patent ductus arteriosus (PDA). The side effect profile of non-steroidal anti-inflammatory drugs (NSAIDs) presents enteral feeding safety concerns; however, the safety of enteral feeding on APAP is largely unknown. Optimal feeding strategies during pharmacological PDA treatment are unknown, leading to practice variation. This study aims to assess the incidence of adverse gastrointestinal (GI) outcomes in neonates treated with APAP for PDA closure while receiving enteral feedings. Single-center retrospective cohort study of 59 extremely low birth weight (ELBW), premature neonates who received APAP for PDA treatment divided into Low Volume (LV; ≤ 20 mL/kg/day) and High Volume (HV; > 20 mL/kg/day) enteral feeding groups. The primary outcome was the incidence of any suspected or confirmed necrotizing enterocolitis (NEC). Timing of nutrition milestones, parenteral nutrition (PN) days, and adverse outcomes (feeding intolerance, liver dysfunction, death prior to discharge) were evaluated. The incidence of suspected or confirmed NEC was 19.5% in the LV group and 13.3% in the HV group (p = 0.593). The HV group reached full feeds 6 days sooner (18 vs 24 days, p = 0.024) and had fewer PN days (17 vs 23.5 days, p = 0.044) with no difference in adverse outcomes. Provision of > 20 mL/kg/day of enteral feeds during APAP treatment of PDA decreased time to full feeds and PN days compared to trophic feedings (≤ 20 mL/kg/day) with no difference in adverse GI outcomes. Continuing enteral feeding during APAP PDA treatment appears safe while improving achievement of nutritional milestones.

Antenatal Magnesium Sulfate and adverse gastrointestinal outcomes in Preterm infants-a systematic review and meta-analysis.

To evaluate the effect of antenatal magnesium sulfate (MgSO4) on mortality and morbidity outcomes related to the gastrointestinal system (GI) in preterm infants. Data sources: A systematic literature search was conducted in November 2022. PubMed, CINAHL Plus with Full Text (EBSCOhost), Embase (Elsevier), and CENTRAL (Ovid) were searched. There were 6695 references. After deduplication, 4332 remained. Ninety-nine full-text articles were assessed and forty four articles were included in the final analysis. Randomized or quasi-randomized clinical trials and observational studies that evaluated at least one of the pre-specified outcomes were included. Preterm infants whose mothers were given antenatal MgSO4 were included and whose mothers did not receive antenatal MgSO4 were the comparators. The main outcomes and measures were: Necrotizing enterocolitis (NEC) (stage ≥ 2), surgical NEC, spontaneous intestinal perforation (SIP), feeding intolerance, time to reach full feeds, and GI-associated mortality. A random-effects model meta-analysis was performed to yield pooled OR and its 95% CI for each outcome due to expected heterogeneity in the studies. The analysis for each predefined outcome was performed separately for adjusted and unadjusted comparisons. All included studies were assessed for methodological quality. The risk of bias was assessed using elements of the Cochrane Collaboration's tool 2.0 and the Newcastle-Ottawa Scale for randomized controlled trials (RCTs) and non-randomized studies (NRS), respectively. The study findings were reported as per PRISMA guidelines. A total of thirty-eight NRS and six RCTs involving 51,466 preterm infants were included in the final analysis. There were no increased odds of stage ≥2 NEC, (NRS : n = 45,524, OR: 0.95; 95% CI: 0.84-1.08, I2- 5% & RCT's: n = 5205 OR: 1.00; 95% CI: 0.89-1.12, I2- 0%), SIP (n = 34,186, OR: 1.22, 95% CI: 0.94-1.58, I2-30%), feeding intolerance (n = 414, OR: 1.06, 95% CI: 0.64-1.76, I2-12%) in infants exposed to antenatal MgSO4. On the contrary, the incidence of surgical NEC was significantly lower in MgSO4 exposure infants (n = 29,506 OR:0.74; 95% CI: 0.62-0.90, ARR: 0.47%). Studies assessing the effect on GI-related mortality were limited to make any conceivable conclusion. The certainty of evidence (CoE) for all outcomes was adjudged as 'very low' as per GRADE. Antenatal magnesium sulfate did not increase the incidence of gastrointestinal-related morbidities or mortality in preterm infants. With the current evidence concerns, regarding the adverse effects of MgSO4 administration leading to NEC/SIP or GI-related mortality in preterm infants should not be a hurdle in its routine use in antenatal mothers.

To Feed or Not to Feed: A Critical Overview of Enteral Feeding Management and Gastrointestinal Complications in Preterm Neonates with a Patent Ductus Arteriosus.

The management of enteral feeds in preterm infants with a hemodynamically significant patent ductus arteriosus (hs-PDA) is a major challenge for neonatologists due to the fear of gastrointestinal (GI) complications. This review aims to analyze the available evidence on the complex relation between the presence and management of PDA, enteral feeding practices, and GI outcomes in the preterm population. There is limited evidence, based on small and heterogeneous trials, that hs-PDA may affect the splanchnic hemodynamic response to enteral feeds. While the presence of PDA seems a risk factor for adverse GI outcomes, the benefits of feeding withholding during pharmacological PDA treatment are controversial. The lack of robust evidence in support of or against a timely feeding introduction or feeding withholding during pharmacological PDA closure in preterm neonates does not allow to draw any related recommendation. While waiting for further data, the feeding management of this population should be carefully evaluated and possibly individualized on the basis of the infants’ hemodynamic and clinical characteristics. Large, multicentric trials would help to better clarify the physiological mechanisms underlying the development of gut hypoperfusion, and to evaluate the impact of enteral feeds on splanchnic hemodynamics in relation to PDA features and treatment.

Gastrointestinal safety of coxibs: systematic review and meta-analysis of observational studies on selective inhibitors of cyclo-oxygenase 2.

Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

Enteral feeding during indomethacin treatment for patent ductus arteriosus: association with gastrointestinal outcomes.

Enteral feeds are often discontinued or reduced during indomethacin treatment for patent ductus arteriosus (PDA) in preterm neonates, but the clinical impact of this practice is unknown. The objective of this study was to study the associations between enteral feed volume at the time of indomethacin therapy in preterm neonates with PDA and subsequent gastrointestinal outcomes. Retrospective cohort study. Single-center level III Neonatal Intensive Care Unit. All consecutive preterm neonates who had received treatment with indomethacin for PDA over a 5-year period were included and categorized based on enteral feed volume exposure during treatment (Group A: nil per oral (NPO, N=229); Group B: ⩽60 ml kg(-1) day(-1) (N=142); Group C:>60 ml kg(-1) day(-1) (N=44)). Baseline characteristics and clinical outcomes were compared between the three groups. The primary outcome was necrotizing enterocolitis (NEC) ⩾stage IIa, while secondary outcomes included other gastrointestinal complications and common prematurity-related morbidities. Group C had a higher gestational age (mean±s.d.; A: 26.3±1.8; B: 26.1±1.8; C: 27.0±2.0 weeks), birth weight (A: 864±239; B: 847±202; C: 932±234 g) and postnatal age at the time of indomethacin treatment (A: 5.3±2.9; B: 7.2±4.9; C: 15.4±6.6 days). All groups had similar rates of the primary outcome NEC (A: 6.1%, B: 7.8% and C: 4.6%, respectively). They also had similar rates of the secondary outcomes with the exception of days to reach enteral feeds of 120 ml kg(-1) day(-1) (A: 22.8±8.5; B: 20.5±8.6; C: 16.8±7.7; P<0.05 for all inter-group comparisons). Secondary analysis including only those neonates who were not already NPO before indomethacin treatment (N=261) and categorized based on preemptive management (made NPO; enteral feed volume reduced; enteral feed volume unchanged/increased) also showed similar results. This large retrospective study did not identify any association between enteral feed volumes during indomethacin treatment or preemptive reduction in enteral feeds and subsequent incidence of adverse gastrointestinal outcomes in preterm neonates. Preemptive reduction in enteral feed volume was associated with longer time to reach full enteral feeds.

Recent Safety Concerns With Proton Pump Inhibitors

There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI-induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks.

Effects of Proton Pump Inhibitors in Patients Receiving Clopidogrel

With great interest we read the results of a meta-analysis by Kwok et al. about the effects of proton pump inhibitors (PPIs) on adverse gastrointestinal events in patients receiving clopidogrel. The authors analysed the published literature in a field that has received much attention recently, mainly because of a suggested interaction between clopidogrel and PPIs. Of interest, the authors also published some months ago a meta-analysis on the cardiovascular outcomes of the combined use of clopidogrel and PPIs. Based on both their publications, we would like to make two comments on (i) the heterogeneity of included studies; and (ii) the practical advice to physicians regarding the issue of potential interaction in clinical practice. Kwok et al. identified ten relevant studies that can be characterized by much heterogeneity in the results and also in study design, population, and outcomes. For example, only one study was a randomized clinical trial, two were retrospective cross-sectional studies, two were casecontrol studies and five were retrospective cohort studies. In their study, the authors acknowledged that heterogeneity in outcome definitions was present and they therefore performed subgroup analyses on separate outcomes. However, we question whether these studies can be pooled at all because of the variations as mentioned above. Second, the results of both meta-analyses were used to convince both physicians and patients that the combined use of clopidogrel and PPIs is indeed not harmful. They stated that there are no clear differences in cardiovascular outcomes between clopidogrel users with or without a PPI, and that PPIs are associated with a reduction in gastrointestinal bleeding. However, these are all relative risks and mostly based on studies that performed many statistical adjustments. It is important to stress that physicians and patients face absolute risks in clinical practice instead of relative risks. In a recent publication by our group, which was not included by Kwok et al., we concluded that although there seems to be no clinical interaction, patients using the combination of clopidogrel and a PPI have a 2-fold increased unadjusted risk for cardiovascular outcomes, and even a 5-fold increased unadjusted risk for gastrointestinal outcomes. In conclusion, physicians should interpret the results of these meta-analyses with caution because it can be disputed whether these studies can be pooled. Based on our results, we conclude that patients using the combination of clopidogrel and a PPI are at an increased (absolute) risk of cardiovascular and gastrointestinal adverse outcomes. This is probably not due to the combined use of these medications but to the fact these patients have an inferior cardiovascular and gastrointestinal risk profile and the occurrence of channelling bias in the published studies.

Drugs to Prevent Malaria in Travellers: A Systematic Review of Randomized Controlled Trials

Background: Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti-mosquito measures and drug prophylaxis. We did a systematic review to assess the effects of currently used antimalaria drugs, given as prophylaxis to non- immune adult and child travellers to regions with chloroquine-resistant Plasmodium falciparum malaria. Methods: We included randomized and quasi-randomized controlled trials of any antimalaria drug regimen currently used by inter- national travellers, compared against any other currently used regimen. In August 2009 we searched MEDLINE, EMBASE, LILACS, BIOSIS, mRCT, and the Cochrane Register of Controlled Trials (CENTRAL), without time restrictions. We searched reference lists, conference proceedings and one specialist journal, and contacted researchers and drug companies. We summarized the characteristics of the eligible trials, assessed their quality using standard criteria, and extracted relevant outcomes data. Where appropriate, we combined the results of different trials. Results: Eight trials (4240 participants) were included. One-quarter of trial participants were soldiers. Duration of exposure to malaria ranged from 15 days to 13 weeks. All trials reported common adverse events from antimalaria drugs. Atovaquone-proguanil users and doxycycline users had similar frequencies of reported adverse effects. Atovaquone-proguanil users had fewer reports of any adverse effect than mefloquine users (RR 0.72, 95% CI 0.6 to 0.85), also fewer gastrointestinal adverse effects (RR 0.54, 95% CI 0.42 to 0.7), and fewer neuropsychiatric adverse effects (RR 0.49, 95% CI 0.38 to 0.63). Chloroquine-proguanil users had more reports of any adverse effect than users of other drugs (RR 0.84, 95% CI 0.73 to 0.96), also more gastrointestinal adverse effects (RR 0.71, 95% CI 0.6 to 0.85). We found no evidence on primaquine in travellers. Conclusions: There is limited evidence on which currently available drug is most effective in preventing malaria. Atovaquone-proguanil and doxycycline are the best tolerated regimens. Doxycycline monohydrate appears exceptionally useful due to its good safety profile, low cost and protective efficacy against many travel-related infections, besides malaria. Mefloquine is associated with adverse neuropsy- chiatric outcomes. Chloroquine-proguanil is associated with adverse gastrointestinal outcomes. There is no evidence to support the use of primaquine as prophylaxis in travellers.

Risk of Adverse Gastrointestinal Events from Inhaled Corticosteroids

To determine whether patients prescribed inhaled corticosteroids are at risk for adverse gastrointestinal effects. Retrospective cohort study. Urban health center with an academic affiliation. A total of 19,443 adults (mean age 31.8 yrs) with airways disease, defined as a diagnosis of asthma or chronic obstructive pulmonary disease, and who were prescribed both an inhaled corticosteroid and albuterol (7156 patients) or inhaled albuterol alone (12,287 patients) between November 1977 and February 2002. The frequency of adverse gastrointestinal events in the patients who used inhaled corticosteroids and albuterol was compared with that in the patients who used albuterol alone. Adverse gastrointestinal outcomes included events such as gastritis, ulcers, and bleeding. Cox proportional hazards models were used to determine the risk of adverse events, controlling for possible confounders such as alcohol use or nonsteroidal antiinflammatory drug use. Adverse gastrointestinal events were observed in 461 (6.4%) patients using inhaled corticosteroids and albuterol and in 302 (2.5%) patients using only albuterol. After controlling for potential confounders, patients who used inhaled corticosteroids and albuterol had an increased risk for adverse gastrointestinal events compared with patients who used only inhaled albuterol (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02-1.56). A prescription for a spacer device reduced this risk among patients using an inhaled corticosteroid (HR 0.26, 95% CI 0.20-0.34). Patients using inhaled corticosteroids appear to have a slight risk for adverse gastrointestinal events that is mitigated in patients who used a spacer device.

Pre‐endoscopic proton pump inhibitor therapy reduces recurrent adverse gastrointestinal outcomes in patients with acute non‐variceal upper gastrointestinal bleeding

Proton pump inhibitors (PPIs) following endoscopic haemostasis reduce rebleeding rates in patients with high-risk acute non-variceal upper gastrointestinal bleeding. Many advocate the use of PPIs prior to endoscopy, although its incremental benefit is unproven. To determine if providing PPIs before endoscopy reduces adverse gastrointestinal outcomes in acute non-variceal upper gastrointestinal bleeding patients. We performed a retrospective review to identify patients presenting to two tertiary care centres with acute non-variceal upper gastrointestinal bleeding between 1999 and 2004. Subjects receiving PPI therapy before endoscopy were compared with those not receiving pre-endoscopic PPI therapy. The primary outcome measure was the development of any adverse bleeding outcome (rebleeding, surgery for control of bleeding, in-hospital mortality, readmission within 30 days for acute non-variceal upper gastrointestinal bleeding). 385 patients were included in our study [132 (12 intravenous/120 po) pre-endoscopic PPI vs. 253 no pre-endoscopic PPI]. Patients receiving pre-endoscopic PPI therapy were significantly less likely to develop adverse outcomes compared with those not given pre-endoscopic PPIs (25% vs. 13%, P = 0.005). Rebleeding, upper gastrointestinal surgery, mortality and length of hospital stay were also significantly lower in patients receiving pre-endoscopic PPI. The use of PPIs before endoscopy significantly reduces the risk of developing adverse gastrointestinal outcomes in patients with acute non-variceal upper gastrointestinal bleeding. Future studies are required to better characterize this relationship.

Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis

Objective To determine the risk of an adverse upper gastrointestinal event in patients taking different cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-inflammatory drugs.Design Nested case-control study.Setting 367 general practices contributing...

THE RISKS AND COSTS OF UPPER GASTROINTESTINAL DISEASE ATTRIBUTABLE TO NSAIDS

NSAIDs, including both aspirin and nonaspirin NSAIDs, are among the most frequently used drugs, and their use may result in serious adverse gastrointestinal outcomes and significant medical costs. The increased risks for adverse upper GI hemorrhage and peptic ulcer disease associated with NSAID use have been demonstrated in observational studies and clinical trials; an overview of these results is presented in this article. The magnitude of these risks should play an important role in clinical decision making and should influence decisions regarding the use of this class of drugs.