Proton pump inhibitors for gastrointestinal bleeding prophylaxis in critically ill patients: A systematic review protocol.

BACKGROUND: Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for preventing upper gastrointestinal bleeding in critically ill patients. However, concerns have arisen about the possible harms of using PPIs, including potentially increased risk of pneumonia, Clostridioides difficile infection, and more seriously, an increased risk of death in the most severely ill patients. Triggered by the REVISE trial, which is a forthcoming large randomized trial comparing pantoprazole to placebo in invasively mechanically ventilated patients, we will conduct this systematic review to evaluate the efficacy and safety of PPIs versus no prophylaxis for critically ill patients. METHODS: We will systematically search randomized trials that compared gastrointestinal bleeding prophylaxis with PPIs versus placebo or no prophylaxis in adults in the intensive care unit (ICU). Pairs of reviewers will independently screen the literature, and for those eligible trials, extract data and assess risk of bias. We will perform meta-analyses using a random-effects model, and calculate relative risks for dichotomous outcomes and mean differences for continuous outcomes, and the associated 95% confidence intervals. We will conduct subgroup analysis to explore whether the impact of PPIs on mortality differs in more and less severely ill patients. We will assess certainty of evidence using the GRADE approach. DISCUSSION: This systematic review will provide the most up-to-date evidence regarding the merits and limitations of stress ulcer prophylaxis with PPIs in critically ill patients in contemporary practice.

Associations between enteral nutrition and outcomes in the SUP-ICU trial: Protocol for exploratory post hoc analyses.

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding.

Stress ulcer prophylaxis in critically ill adult patients with sepsis at risk of gastrointestinal bleeding: a retrospective cohort study.

BACKGROUND: The Surviving Sepsis Campaign Guidelines recommend stress ulcer prophylaxis (SUP) for patients with sepsis who have gastrointestinal (GI) bleeding risks; however, the effect of SUP has not been specially studied in these patients. AIMS: To determine the effects of SUP versus no prophylaxis on patient-important outcomes in critically ill adult patients with sepsis who have risk factors for GI bleeding. METHODS: This retrospective cohort study utilised data from the Medical Information Mart for Intensive Care III database. We compared those who received SUP with proton-pump inhibitors or histamine-2 receptor antagonists for ≥3 days with those who received no prophylaxis. Propensity score matching (PSM) was conducted to make comparisons between groups with similar distributions of study variables. The primary outcome was inhospital mortality. RESULTS: A total of 7744 patients were included in the analysis, with 1088 (14.0%) in the non-SUP group and 6656 (86.0%) in the SUP group. A 1:1 PSM created 866 patients in each cohort. No significant differences were noted between the two groups with regard to inhospital mortality (22.3% vs 20.4%; P = 0.379), GI bleeding (4.7% vs 6.4%; P = 0.172), pneumonia (38.9% vs 36.6%; P = 0.346), Clostridium difficile infection (CDI) (6.4% vs 8.9%; P = 0.0.057) or intensive care unit (ICU) length of stay (LOS) (4.2 days vs 4.6 days; P = 0.394). CONCLUSIONS: Among critically ill, septic, adult patients at risk for GI bleeding, SUP showed no effect on hospital mortality, the rate of GI bleeding, pneumonia, CDI and ICU LOS.

Assessment of adherence to the national stress ulcer prophylaxis guidelines: A cross-sectional analysis.

Background: Clinical guidelines support the use of stress ulcer prophylaxis (SUP) in patients at risk of gastrointestinal (GI) bleeding such as those with coagulopathy, renal replacement therapy, and mechanical ventilation. Despite the observed benefits of SUP, its overuse has been highly associated with serious adverse effects. Objective: To assess the adherence to the national SUP guidelines in a tertiary hospital in Saudi Arabia. Methods: A cross-sectional study was conducted using electronic health records at King Fahad Specialist Hospital (KFSH), Buraydah, Saudi Arabia. We collected the data from January 1st to December 31st, 2020. Adult patients aged 18 and older who received SUP prescriptions were included. Descriptive analysis was performed to assess the adherence to the guidelines and to explore the factors associated with SUP use in a hospital-based setting. Results: A total of 424 patients were enrolled in this study. The median age of patients was 55.2 years old. Only 54% of patients were candidates for SUP. Internal medicine and surgery wards ranked the highest in prescribing SUP at 34.2% and 30.4%, respectively. The most common major criterion to start SUP was the concomitant use of two or more of these medications (anticoagulants, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antidepressants) followed by using NSAIDs or corticosteroids by older adult patients aged (≥65 years) or have GI bleeding history at 43.2% and 21.5%, respectively. Conclusion: The observed overuse of anti-ulcer drugs (AUD) indicates a need for greater adherence to SUP guidelines. Areas of improvement can be implemented to ensure appropriate adherence to SUP guidelines to control the costs and avoid unnecessary anti-ulcer-related adverse effects.

Are Proton Pump Inhibitors More Effective Than Histamine-2-Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients? A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: Histamine-2-receptor antagonists (H2RAs) have been largely replaced by proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) despite the inconclusive evidence concerning comparative effectiveness. OBJECTIVE: To compare the effectiveness of PPIs and H2RAs on SUP in real-world setting. METHODS: PubMed, Embase, and the Cochrane Library were searched from inception to September 19, 2021. We included cohort studies comparing PPIs with H2RAs in critically ill adult patients and explicitly reporting the outcome of gastrointestinal (GI) bleeding or mortality. Newcastle-Ottawa Scale was used to assess potential risk of bias. We conducted a random-effects meta-analysis and only the studies with adjusted effect estimates were pooled. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of the evidence. RESULTS: Thirteen cohort studies (N = 145 149) were eligible and 11 of them available for full texts were of low to moderate risk of bias. Meta-analysis of adjusted effect estimates indicated that PPIs were associated with a significantly higher risk of GI bleeding, compared with H2RAs (8 studies, odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.30-3.01, low certainty). Post hoc pooling analysis also suggested that PPIs were associated with a slightly higher risk of mortality in comparison with H2RAs (7 studies, OR = 1.27, 95% CI = 1.13-1.42, low certainty). CONCLUSION AND RELEVANCE: The systematic review of cohort studies showed that PPIs were associated with higher risks of GI bleeding and mortality, although the certainty of evidence was low. Overall, we suggest not excluding H2RAs for SUP, while further studies are essential for elucidating the risk stratification, optimal regimen, and specific duration.

Impact of Stress Ulcer Prophylaxis Discontinuation Guidance in Mechanically Ventilated, Critically Ill Patients: A Pre-Post Cohort Study.

Purpose: Recent data highlight unclear efficacy and potential negative sequelae of stress ulcer prophylaxis (SUP) in the intensive care unit (ICU). Minimizing SUP exposure has pertinent clinical and other implications. This study assessed medication use and clinical outcomes before and after implementation of a practice guideline promoting early discontinuation of SUP in mechanically ventilated ICU patients. Methods: Retrospective, single-center, pre-post cohort study within a medical ICU at a large, academic medical center. Adult patients requiring mechanical ventilation and receiving SUP via a histamine-2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) were eligible for inclusion. The clinical practice guideline was implemented on January 1, 2020. The impact of implementation was assessed via percent of patient-days with inappropriate SUP. Incidence of clinically important GI bleed was the primary safety outcome. Results: A total of 137 pre-guideline and 112 post-guideline patients were included. Comorbidity burden was similar between groups. A higher prevalence of baseline vasopressor receipt (39% vs 67%, P < .01) and acute kidney injury (56% vs 69%, P = .04) was observed in post-guideline patients. Post-guideline patients experienced a significantly lower percentage of patient-days of inappropriate SUP (25% vs 50%, P < .01) as well as higher rates of SUP discontinuation before extubation (71% vs 12%, P < .01) and during ICU stay (93% vs 50%, P < .01). Post-guideline patients observed a significantly lower incidence of SUP at hospital discharge (4% vs 35%, P < .01). No differences in bleeding outcomes were observed, though post-guideline patients experienced longer durations of mechanical ventilation, ICU stay, and hospital stay. Conclusions: Implementation of an early SUP discontinuation guideline was associated with significant improvements in SUP prescribing practices. Baseline differences between groups likely explain observed differences in clinical outcomes.

Reassessing the Use of Proton Pump Inhibitors and Histamine-2 Antagonists in Critically Ill Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the associations of stress ulcer prophylaxis with gastrointestinal (GI) bleeding, nosocomial pneumonia (NP), mortality, and length of stay in the pediatric intensive care unit (PICU). STUDY DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies in the English language assessing the effects of proton pump inhibitors and histamine-2 receptor antagonists on patients in the PICU published before October 2018 from the PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials databases. A random-effects Mantel-Haenszel risk difference (MHRD) model was used to pool all the selected studies for meta-analysis. Primary outcomes were the incidences of GI bleeding and NP. Secondary outcomes included mortality and length of PICU stay. RESULTS: Seventeen studies (4 RCTs and 13 observational studies) with a total of 340 763 patients were included. The overall incidence of GI bleeding was 15.2%. There was no difference in the risk of GI bleeding based on stress ulcer prophylaxis status (MHRD, 5.0%; 95% CI, -1.0% to 11.0%; I2 = 62%). There was an increased risk of NP in patients who received stress ulcer prophylaxis compared with those who did not (MHRD, 5.3%; 95% CI, 3.5%-7.0%; I2 = 0%). An increased risk of mortality was seen in patients receiving stress ulcer prophylaxis (MHRD, 2.1%; 95% CI, 2.0%-2.2%; I2 = 0%), although this association was no longer found when 1 large study was removed in a sensitivity analysis. There was no statistically significant difference in length of PICU stay between the groups (standardized mean difference, 0.42 days; 95% CI, -0.16 to 1.01 days; I2 = 89.8%). CONCLUSIONS: Stress ulcer prophylaxis does not show a clear benefit in reducing GI bleeding or length of PICU stay. Observational studies suggest an increased risk of NP and mortality with stress ulcer prophylaxis, which remains to be validated in clinical trials.

Reducing Inappropriate Proton Pump Inhibitors Use for Stress Ulcer Prophylaxis in Hospitalized Patients: Systematic Review of De-Implementation Studies.

BACKGROUND: A large proportion of proton pump inhibitor (PPI) prescriptions, including those for stress ulcer prophylaxis (SUP), are inappropriate. Our study purpose was to systematically review the effectiveness of de-implementation strategies aimed at reducing inappropriate PPI use for SUP in hospitalized, non-intensive care unit (non-ICU) patients. METHODS: We searched MEDLINE and Embase databases (from inception to January 2020). Two authors independently screened references, performed data extraction, and critical appraisal. Randomized trials and comparative observational studies were eligible for inclusion. Criteria developed by the Cochrane Effective Practice and Organisation of Care (EPOC) group were used for critical appraisal. Besides the primary outcome (inappropriate PPI prescription or use), secondary outcomes included (adverse) pharmaceutical effects and healthcare use. RESULTS: We included ten studies in this review. Most de-implementation strategies contained an educational component (meetings and/or materials), combined with either clinical guideline implementation (n = 5), audit feedback (n = 3), organizational culture (n = 4), or reminders (n = 1). One study evaluating the de-implementation strategy effectiveness showed a significant reduction (RR 0.14; 95% CI 0.03-0.55) of new inappropriate PPI prescriptions. Out of five studies evaluating the effectiveness of de-implementing inappropriate PPI use, four found a significant reduction (RR 0.21; 95% CI 0.18-0.26 to RR 0.76; 95% CI 0.68-0.86). No significant differences in the occurrence of pharmaceutical effects (n = 1) and in length of stay (n = 3) were observed. Adverse pharmaceutical effects were reported in two studies and five studies reported on PPI or total drug costs. No pooled effect estimates were calculated because of large statistical heterogeneity between studies. DISCUSSION: All identified studies reported mainly educational interventions in combination with one or multiple other intervention strategies and all interventions were targeted at providers. Most studies found a small to moderate reduction of (inappropriate) PPI prescriptions or use.

Physicians' knowledge, attitude, and prescribing behavior regarding stress ulcer prophylaxis in China: a multi-center study.

BACKGROUND: Perioperative patients are at risk of developing stress ulcers (SU), which can cause clinically important bleeding. Stress ulcer prophylaxis (SUP) is widely applied to the patients in Intensive care unit (ICU) as well as the general ward, so it may lead to overmedication. However, there have been no surveys regarding SUP knowledge or prescribing habits. OBJECTIVE: Our study assessed the knowledge, attitudes, and prescribing behavior of the surgeons toward perioperative patients regarding SUP and determined factors associated with low knowledge and high level of prescribing behaviors. METHODS: We performed a cross-sectional survey using questionnaires, randomly sampling 1266 surgeons on their current SUP practices. RESULTS: Proton pump inhibitors for SUP were used the most (94%); 43% used lansoprazole. Guideline awareness was inconsistent; the most familiar guideline was the National Medical Journal of China, and 46% were unaware of any guidelines. The predictors of low knowledge score regarding SUP in multivariable analysis were the hospital grade (p = 0.000), the type of hospital (p = 0.044), attendance at continuing education programs (p = 0.037), the awareness of clinical practice guidelines (CPGs) for SUP (p = 0.000). Twenty-one percent of physicians were high prescribers. High prescribing behavior was associated with hospital grade(p = 0.000), education level(p = 0.010) and attendance at continuing education programs (p = 0.000). CONCLUSION: We found that most surgeons used SUP, primarily proton pump inhibitors. However, surgeons knew little about the SUP guidelines, which may lead to insufficient SUP knowledge and overmedication. In addition, hospital grade, the type of hospital and attendance at continuing education programs may also affect the low knowledge of SUP. Hospital grade, education level and attendance at continuing education programs may affect high prescribing behavior.

Predictors of gastrointestinal bleeding in adult ICU patients in the SUP-ICU trial.

BACKGROUND: In previous studies of predictors of gastrointestinal (GI) bleeding in the intensive care unit (ICU), most patients received pharmacological stress ulcer prophylaxis (SUP). We aimed to assess associations between potential predictors of clinically important GI bleeding (CIB) and overt GI bleeding in adult ICU patients, while considering the effect and potential interaction with use of SUP. METHODS: We included 3291 acutely admitted adult ICU patients with risk factors for GI bleeding randomized to SUP (pantoprazole) or placebo in the SUP-ICU trial. We used logistic regression models adjusted for allocation to SUP to estimate associations between 23 potential predictors and CIB (primary outcome) and overt GI bleeding (secondary outcome). Furthermore, we assessed associations between potential predictors and both outcomes in each allocation group and assessed potential interaction with allocation to SUP. RESULTS: Increasing SAPS II and SOFA scores, use of circulatory support and renal replacement therapy were associated with increased risk of CIB and overt GI bleeding; chronic lung disease was associated with increased risk of overt GI bleeding. Results for the remaining potential predictors were compatible with both no difference or increased and decreased risks. We found no strong evidence for any interaction between treatment allocation and any potential predictors. CONCLUSION: In adult ICU patients at risk of GI bleeding, severity of illness, use of circulatory support and renal replacement therapy were associated with higher odds of CIB, with no strong evidence of interaction with SUP.

Current practice of stress ulcer prophylaxis in a surgical patient cohort in a German university hospital.

INTRODUCTION: Stress ulcer prophylaxis (SUP) has been a widespread practice both in intensive care units (ICU) and internal wards at the beginning of the twenty-first century. Clinical data suggests an important overuse of acid suppressive therapy (AST) for this indication. Data on current clinical practice of SUP in surgical patients in a non-ICU setting are spares. In the light of a growing number of reports on serious side effects of AST, this study evaluates the use of AST for SUP in a normal surgical ward in a German university hospital. METHODS: Between January 2016 and June 2016, SUP was analysed retrospectively in 1132 consecutive patients of the Department of Surgery of the Universitätsmedizin Greifswald. RESULTS: The patients managed with and without SUP were similar with respect to demographic data and treatment with anticoagulants, SSRI and glucocorticoids. Patients with SUP were treated more frequently by cyclooxygenase inhibiting drugs (NSAID, COX2-inhibitors), were more frequently treated in the intermediated care unit and had a longer hospital stay. Risk factors for the development of stress ulcers were similarly present in patient groups managed with and without SUP. About 85.7-99.6% of patients were given SUP without an adequate risk for stress ulcer development, depending on the method used for risk assessment. DISCUSSION: Still today, SUP is widely overused in non-ICU surgical patients. Information campaigns on risk factors for stress ulcer development and standard operating procedures for SUP are required to limit potential side effects and increased treatment costs.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

A Retrospective Cohort Analysis of the Use of Enteral Nutrition Plus Pharmacologic Prophylaxis or Enteral Nutrition Alone.

Background: Due to the risk of development of stress ulcers in intensive care unit (ICU) patients, pharmacologic prophylaxis is often utilized. However, some literature describes the use of enteral nutrition instead as stress ulcer prophylaxis. Methods: The purpose of this study is to determine if enteral nutrition is similar to pharmacologic stress ulcer prophylaxis (SUP) with enteral nutrition for reduction of gastrointestinal (GI) bleeding, perforation, or ulceration in ICU patients. This was a retrospective, single-center cohort study that took place at an academic medical center. Adult ICU patients receiving enteral nutrition who had a risk factor for stress-related mucosal damage were included. The primary outcome was the incidence of GI bleeding, perforation, or ulcer formation. Results: Overall, 167 patients were included in the study, 147 in the pharmacologic prophylaxis plus EN group (PPEN) and 20 in the enteral therapy only (EN) group. Of 167 patients included, 22 patients (21 in the PPEN group and 1 in the EN group) developed a primary outcome of GI bleeding, perforation, or ulceration (14.3% vs 5%, P = .4781). Patients in the PPEN group had a higher incidence of pneumonia (42.2% vs 15%, P = .0194), but no difference was seen between groups when patients with pneumonia present on admission were excluded (20.6% vs 10.5%, P = .5254). Conclusion: In this small cohort of patients, enteral nutrition alone is as effective as pharmacologic therapy in addition to enteral nutrition for the reduction of stress-related GI bleeding, perforation, and ulceration.

Impact of a multidisciplinary quality improvement initiative to reduce inappropriate usage of stress ulcer prophylaxis in hospitalized patients.

AIMS: To promote effective methods to improve overutilization patterns of acid-suppressive therapy in hospitalized patients and to evaluate the impact of multidisciplinary team efforts to reduce inappropriate use of stress ulcer prophylaxis in low-risk patients. METHODS: A multidisciplinary quality improvement initiative incorporating education, medication use reviews and reconciliation, and pharmaceutical intervention was implemented in June 2018 for surgical patients hospitalized via emergency department. For the pre-post analysis and time series analysis, patients admitted during April and May were classified into the pre-intervention cohort and those admitted during July and August into the post-intervention cohort. RESULTS: Three hundred and seventeen patients were included in this study (153 and 164 in the pre- and post-intervention cohorts, respectively). The multidisciplinary program was effective in reducing overuse of stress ulcer prophylaxis and healthcare expenses associated with it. Biweekly education on risk factors warranting stress ulcer prophylaxis was provided for clinicians, and acid-suppressive therapy was removed from a preset list of admission orders. The incidence of inappropriate prophylaxis use declined substantially following intervention in overall patients (OR = 0.51, P = 0.01) and a significant decrease was primarily observed among non-ICU patients (OR = 0.50, P = 0.01). Interrupted time series analysis confirmed the significant decline in inappropriate use post intervention (coefficient = -0.63, P < 0.001). The total healthcare expenses associated with such overuse decreased by 58.5% from US$ 19.39 to US$ 8.04 per 100 patient-days. CONCLUSIONS: Our multidisciplinary team efforts were associated with improvement in stress ulcer prophylaxis overuse patterns, resulting in a substantial decrease in the incidence of inappropriate use, especially in general wards, and associated healthcare costs.

Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Acutely ill patients are at risk of stress-related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients. METHODS: We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). The primary outcomes were all-cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials. RESULTS: We included 65 comparisons from 62 trials (n = 9713); 43 comparisons were from intensive care units. Only three trials (n = 3596) had overall low risk of bias. We did not find an effect on all-cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA-adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA-adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health-related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses. CONCLUSIONS: We did not observe a difference in all-cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive. STUDY REGISTRATION: PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.

The SUP-ICU Trial: Does It Confirm or Condemn the Practice of Stress Ulcer Prophylaxis?

Purpose: Stress ulcer prophylaxis (SUP) is routinely administered to critically ill patients for the prevention of stress ulcer-induced, clinically important bleeding (CIB). Recently, the value of SUP has been questioned due to the perceived decline in CIB and the potential for infectious complications secondary to acid suppressive therapy. The SUP-ICU trial is a large, randomized controlled trial comparing intravenous pantoprazole with placebo for the indication of SUP. It is hoped that this trial would answer many of the questions pertaining to the overall value of SUP. This article will provide an in-depth assessment of the SUP-ICU trial in the context of the overall body of literature in this area. Furthermore, applications for clinical practice and recommendations on the provision of SUP are provided. Summary: The SUP-ICU trial revealed no difference in the primary outcome of 90-day mortality with pantoprazole but lower rates of CIB were noted (which was a secondary outcome). Overall, these data provide important insight into the value of SUP along with other questions related to the provision of SUP such as the relationship between CIB and mortality, infectious complications, and enteral nutrition. Conclusions: The SUP-ICU trial is a landmark trial describing the value of SUP in a modern-day setting of intensive care unit (ICU) practice. The provision of SUP should be continued in high-risk patients. Future studies are ongoing that will add further insight to this routine practice.

Outcomes of Prophylactic Pantoprazole in Adult Intensive Care Unit Patients Receiving Dialysis: Results of a Randomized Trial.

BACKGROUND: Intensive care unit (ICU) patients with acute kidney injury requiring renal replacement therapy (RRT) are considered at high risk of gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP) is often prescribed. We aimed to assess the incidence of GI bleeding and effects of SUP in these patients. METHODS: We assessed GI bleeding in ICU patients receiving RRT at baseline (and at any time in the ICU) and effects of prophylactic pantoprazole versus placebo in the international SUP in the ICU (SUP-ICU) trial. All analyses were conducted according to a published protocol and statistical analysis plan. RESULTS: Data of 3,291 acutely admitted adult ICU patients with one or more risk factors for GI bleeding randomized to pantoprazole or placebo intravenously once daily during ICU stay (until ICU discharge, death, or a maximum of 90 days) were analyzed. Some 20 out of 258 (7.8%, 95% CI 4.5-11.1%) and 52 out of 568 (9.2%, 95% CI 6.8-11.6%) of the patients receiving RRT at baseline and at any time in ICU, respectively, developed clinically important GI bleeding in the ICU. We did not observe statistically significant differences in the intervention effect (pantoprazole vs. placebo) in the proportion of patients with clinically important GI bleeding, clinically important events, infectious adverse events, use of interventions to stop GI bleeding, or 90-day mortality in patients with versus without RRT at baseline. CONCLUSIONS: In adult ICU patients receiving RRT at baseline, we observed high incidences of clinically important GI bleeding, but did not observe effects of pantoprazole versus placebo in this subgroup.

Acid Suppression to Prevent Gastrointestinal Bleeding in Patients With Ventricular Assist Devices.

BACKGROUND: The high incidence of gastrointestinal bleeding (GIB) in patients with ventricular assist devices (VAD) is well known, but there is limited evidence to support the use of proton pump inhibitors (PPIs) or histamine receptor antagonists (H2RA) for preventing GIB in patients with VAD. MATERIALS AND METHODS: The surgical ICU and VAD databases within a large regional academic cardiac mechanical support and transplant center were queried for patients who underwent VAD implantation between 2010 and 2014. An observational cohort study was conducted to identify which acid suppressing drug regimen was associated with the fewest number of GIB events within 30 d after VAD implantation: PPI, H2RA, or neither. Secondary outcomes included timing, etiology, and location of GIB. Multivariable logistic regression was used to compare treatment cohorts to GIB. Odds ratios, 95% confidence intervals, and P-values were reported from the model. RESULTS: One hundred thirty-eight patients were included for final analysis, 19 of which had a GIB within 30 days of VAD implantation. Both H2RA and PPI use were associated with reduced GIB compared with the cohort with no acid suppressive therapy. In the multivariate analysis, the PPI cohort showed a statistically significant reduction in GIB (Odds ratio 0.18 [95% confidence interval 0.04-0.79] P = 0.026). CONCLUSIONS: Using PPI postoperatively in patients with new VAD was associated with a reduced incidence of GIB. Given that GIB is a known complication after VAD placement, clinicians should consider the use of acid suppressive therapy for primary prevention.

Time to onset of gastrointestinal bleeding in the SUP-ICU trial: A pre-planned substudy.

BACKGROUND: The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). METHODS: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status. RESULTS: Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P = .37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); this significantly increased in the later period (to HR 0.85, 95% CI 0.53-1.37; P = .02). Patients with later compared to earlier CIB received more transfusions and had more diagnostic/therapeutic procedures for CIB. CONCLUSIONS: Clinically important gastrointestinal bleeding mostly occurred more than 2 days after randomization. University hospital admission was associated with significantly decreased risk of CIB in the earlier period only.

Pantoprazole in ICU patients at risk for gastrointestinal bleeding-1-year mortality in the SUP-ICU trial.

BACKGROUND: The long-term effects of stress ulcer prophylaxis with pantoprazole are unknown in ICU patients. We report 1-year mortality outcome in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. METHODS: In the SUP-ICU trial, acutely admitted adult ICU patients at risk of gastrointestinal bleeding were randomised to intravenous pantoprazole 40 mg vs placebo (saline) once daily during their ICU stay. We assessed mortality at 1 year and did sensitivity analyses according to the trial protocol and statistical analysis plan. RESULTS: A total of 3261 of the 3291 patients with available data (99.1%) were followed up at 1 year after randomisation; 1635 were allocated to pantoprazole and 1626 to placebo. At 1 year after randomisation, 610 of 1635 patients (37.3%) had died in the pantoprazole group as compared with 601 of 1626 (37.0%) in the placebo group (relative risk, 1.01; 95% confidence interval 0.92-1.10). The results were consistent in the sensitivity analysis adjusted for baseline risk factors and in those of the per-protocol population. We did not observe heterogeneity in the effect of pantoprazole vs placebo on 1-year mortality in the predefined subgroups, that is, patients with and without shock, mechanical ventilation, liver disease, coagulopathy, high disease severity (SAPS II > 53) or in medical vs surgical ICU patients. CONCLUSION: We did not observe a difference in 1-year mortality among acutely admitted adult ICU patients with risk factors for gastrointestinal bleeding allocated to stress ulcer prophylaxis with pantoprazole or placebo during the ICU stay. (The SUP-ICU trial was funded by Innovation Fund Denmark and others; ClinicalTrials.gov number, NCT02467621).