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.

The effects of pantoprazole vs. placebo on 1-year outcomes, resource use and employment status in ICU patients at risk for gastrointestinal bleeding: a secondary analysis of the SUP-ICU trial.

PURPOSE: Patients in intensive care units (ICUs) are at risk of stress-related gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP), including proton pump inhibitors, is widely used in the attempt to prevent this. In this secondary analysis of Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, we assessed 1-year outcomes in the pantoprazole vs. placebo groups. METHODS: In the SUP-ICU trial, 3298 acutely admitted ICU patients at risk of GI bleeding were randomly allocated, stratified for site, to pantoprazole or placebo. In this secondary analysis, we assessed clinically important GI bleedings in ICU and 1-year mortality, health care resource use (e.g. readmission with GI bleeding, use of home care and general practitioner), health care costs, and employment status for the Danish participants using registry data. RESULTS: Among the 2099 Danish participants, 2092 had data in the registries; 1045 allocated to pantoprazole and 1047 to placebo. The number of clinically important GI bleedings in ICU was 1.9 percentage points [95% CI 0.3-3.5] lower in the pantoprazole group vs. the placebo group, but none of the 1-year outcomes differed statistically significantly between groups, including total health care costs (€1954 [- 2992 to 6899]), readmission with GI bleeding (- 0.005 admissions [- 0.016 to 0.005]), 1-year mortality (- 0.013 percentage points [- 0.051 to 0.026]), and employment (- 0.178 weeks [- 0.390 to 0.034]). CONCLUSION: Among ICU patients at risk of GI bleeding, pantoprazole reduced clinically important GI bleeding in ICU, but this did not translate into a reduction in 1-year mortality, health care resource use or improvements in employment status.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

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.

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

OBJECTIVE: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. STUDY DESIGN AND SETTING: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. RESULTS: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. CONCLUSION: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.

Prophylactic acid suppressants in children in the intensive care unit: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Critically ill children are at risk of stress-induced gastrointestinal ulceration. Acid suppressants are frequently used in intensive care units even though there is uncertainty about the benefits and harms. With this systematic review, we aimed to assess patient-important benefits and harms of stress ulcer prophylaxis (SUP) in children in intensive care. METHODS: We conducted the review according to the PRISMA statement, the Cochrane Handbook, and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). We included randomised clinical trials comparing SUP with histamine-2-receptor antagonists or proton pump inhibitors vs placebo/no prophylaxis in children admitted for intensive care. Primary outcomes were all-cause mortality and overt gastrointestinal bleeding. Secondary outcomes were serious adverse events, hospital-acquired pneumonia, Clostridium difficile enteritis, myocardial ischemia, acute kidney injury and quality of life. RESULTS: We included a total of seven trials (n = 504) with eight trial comparisons. We found no statistically significant difference in all-cause mortality (relative risk (RR) 1.43, 95% confidence interval (CI) 0.86-2.37), overt gastrointestinal bleeding (RR 0.75, 95% CI 0.42-1.35) or hospital-acquired pneumonia (RR 1.18, 95% CI 0.77-1.82) between SUP vs placebo/no prophylaxis. No trials reported on remaining secondary outcomes. TSA was unable to draw firm conclusions for all outcomes and certainty of evidence for all outcomes was "very low." CONCLUSIONS: We found no difference in all-cause mortality, overt gastrointestinal bleeding or hospital-acquired pneumonia in children in intensive care receiving acid suppressants compared with placebo/no prophylaxis. However, the quantity and quality of evidence was very low with no firm evidence for benefit or harm.

Effects of simulated sample sizes on the mortality effect estimates in three randomized intensive care unit trials.

BACKGROUND: Randomized clinical trials (RCTs) are occasionally stopped prematurely before reaching their planned sample sizes. It has been suggested that early stopped RCTs are associated with under- and overestimation of the effect estimates. We simulated the effect of hypothetical premature stopping of three large RCTs done in the intensive care unit (ICU) setting. METHODS: In this post hoc study, we simulated the impact of stopping trials early by calculating mortality effect estimates continuously after the inclusion of each individual patient in three large RCTs, that is the 6S trial on hydroxyethyl starch vs Ringer's acetate in sepsis in ICU, the TRISS trial on lower vs higher haemoglobin threshold for transfusion in septic shock in ICU and the SUP-ICU trial on pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. RESULTS: The three trials included a total of 5087 patients; 798 from the 6S trial, 998 from the TRISS trial and 3291 patients from the SUP-ICU trial. The premature mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included. The premature estimates became stable after inclusion of 205 patients (26% of the final sample size) in the 6S trial, 133 patients(13%) in the TRISS trial and 1926 patients(59%) in the SUP-ICU trial. CONCLUSIONS: In this post hoc study of three international RCTs within intensive care, we found that the simulated interim mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included, but remained instable until the final sample sizes had been included. Thus, this study illustrates the necessity for cautious interpretations of prematurely stopped trials.

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.

Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial.

PURPOSE: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present. METHODS: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots. RESULTS: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63). CONCLUSIONS: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS. GOV IDENTIFIER: NCT02467621.

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.

Predictors of gastrointestinal bleeding in adult ICU patients: a systematic review and meta-analysis.

PURPOSE: To systematically identify predictors of gastrointestinal (GI) bleeding in adult intensive care unit (ICU) patients. METHODS: We conducted a systematic review and meta-analysis of cohort studies including trial cohorts. We searched MEDLINE, EMBASE, and trial registries up to March 2019. Eligible studies assessed potential predictors of clinically important GI bleeding (CIB; primary outcome) or overt GI bleeding (secondary outcome), had > 20 events, and presented adjusted effect estimates. Two reviewers assessed study eligibility, extracted data, and assessed risk of bias and certainty of evidence using GRADE. We meta-analysed adjusted effect estimates if data from ≥ 2 studies were available. RESULTS: We included 8 studies (116,497 patients). 4 studies (including 74,456 patients) assessed potential predictors of CIB, and we meta-analysed 12 potential predictors from these. Acute kidney injury (relative effect [RE] 2.38, 95% confidence interval [CI] 1.07-5.28, moderate certainty) and male gender (RE 1.24, 95% CI 1.03-1.50, low certainty) were associated with increased incidence of CIB. After excluding high risk of bias studies, coagulopathy (RE 4.76, 95% CI 2.62-8.63, moderate certainty), shock (RE 2.60, 95% CI 1.25-5.42, low certainty), and chronic liver disease (RE 7.64, 95% CI 3.32-17.58, moderate certainty) were associated with increased incidence of CIB. The effect of mechanical ventilation on CIB was unclear (RE 1.93, 0.57-6.50, very low certainty). CONCLUSIONS: We identified predictors of CIB and overt GI bleeding in adult ICU patients. These findings may be used to identify ICU patients at higher risk of GI bleeding who are most likely to benefit from stress ulcer prophylaxis.

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.

Heterogeneity of treatment effect of stress ulcer prophylaxis in ICU patients: A secondary analysis protocol.

BACKGROUND: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary outcomes, except for clinically important gastrointestinal bleeding. However, heterogeneity of treatment effect (HTE) not detected by conventional subgroup analyses could be present. METHODS: This is a protocol and statistical analysis plan for a secondary, post hoc, exploratory analysis of the SUP-ICU trial. We will explore HTE in one set of subgroups based on severity of illness (using the Simplified Acute Physiology Score [SAPS] II) and another set of subgroups based on the total number of risk factors for GI bleeding in each patient using Bayesian hierarchical models. We will summarise posterior probability distributions using medians and 95% credible intervals and present probabilities for different levels of benefit and harm of the intervention in each subgroup. Finally, we will assess if the treatment effect interacts with SAPS II and the number of risk factors separately on the continuous scale using marginal effects plots. CONCLUSIONS: The outlined post hoc analysis will explore whether HTE was present in the SUP-ICU trial and may help answer some of the remaining questions regarding the balance between benefits and harms of pantoprazole in ICU patients at risk of GI bleeding. CLINICALTRIALS. GOV REGISTRATION: NCT02467621.

External validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU).

BACKGROUND: The Simplified Mortality Score for the Intensive Care Unit (SMS-ICU) is a clinical prediction model, which estimates the risk of 90-day mortality in acutely ill adult ICU patients using 7 readily available variables. We aimed to externally validate the SMS-ICU and compare its discrimination with existing prediction models used with 90-day mortality as the outcome. METHODS: We externally validated the SMS-ICU using data from 3282 patients included in the Stress Ulcer Prophylaxis in the Intensive Care Unit trial, which randomised acutely ill adult ICU patients with risk factors for gastrointestinal bleeding to prophylactic pantoprazole or placebo in 33 ICUs in Europe. We assessed discrimination, calibration and overall performance of the SMS-ICU and compared discrimination with the commonly used and more complex SAPS II and SOFA scores. RESULTS: Mortality at day 90 was 30.7%. The discrimination (area under the receiver operating characteristic curve) for the SMS-ICU was 0.67 (95% CI: 0.65-0.69), as compared with 0.68 (95% CI: 0.66-0.70, P = 0.35) for SAPS II and 0.63 (95% CI: 0.61-0.65, P < 0.001) for the SOFA score. Calibration (intercept and slope) was 0.001 and 0.786, respectively, and Nagelkerke's R2 (overall performance) was 0.06. The proportions of missing data for the SMS-ICU, SAPS II and SOFA scores were 0.2%, 8.5% and 6.8%, respectively. CONCLUSIONS: Discrimination for 90-day mortality of the SMS-ICU in this cohort was poor, but similar to SAPS II and better than that of the SOFA score with markedly less missing data.

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).

Stress ulcer prophylaxis in critically ill children: Protocol for a systematic review.

BACKGROUND: Stress ulcer prophylaxis is the considered standard of care in many critically ill patients in the intensive care unit (ICU). Whether there is overall benefit or harm of stress ulcer prophylaxis in critically ill children is unknown. Accordingly, we aim to assess patient-important benefits and harms of stress ulcer prophylaxis versus placebo or no treatment in critically ill children in the ICU. METHODS/DESIGN: We will conduct a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis and assess the use of proton pump inhibitors (PPIs) or histamine-2-receptor antagonists (H2RAs) versus placebo or no prophylaxis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: There is a need for an updated systematic review to summarize the benefits and harms of stress ulcer prophylaxis in critically ill children to inform practice and future research.

Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial.

PURPOSE: In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was interaction (P = 0.049) suggesting increased mortality in patients allocated to pantoprazole as compared with placebo. We aimed to explore this further. METHODS: The SUP-ICU trial allocated acutely admitted adults at risk of gastrointestinal bleeding to pantoprazole vs placebo. In this post hoc study, we repeated all the preplanned analyses of SUP-ICU in patients with baseline SAPS II > 53. RESULTS: A total of 1140 patients had a complete SAPS II > 53 and were included. At 90 days, 272/579 patients (47%) assigned to pantoprazole had died, as compared with 229/558 patients (41%) assigned to placebo [relative risk 1.13; 95% confidence interval (CI) 1.00-1.29]. This was supported by sensitivity analyses adjusted for risk factors and those in the per-protocol population. When accounting for patients with incomplete SAPS II in two additional analyses, the relative risk was 1.08; 95% CI 0.96-1.22 and 1.10; 95% CI 0.97-1.25. This was also observed for the secondary outcome days alive without life support. There were no differences between the intervention groups in the other secondary outcomes. CONCLUSIONS: In this post hoc analysis of patients with high disease severity included in the SUP-ICU trial, we observed higher 90-day mortality and fewer days alive without life support with pantoprazole vs placebo. Some of this may have been explained by missing SAPS II data, but further research is needed to draw firm conclusions. CLINICALTRIALS.GOV: ClinicalTrials.gov No. NCT02467621.

Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis.

PURPOSE: Most intensive care unit (ICU) patients receive stress ulcer prophylaxis. We present updated evidence on the effects of prophylactic proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) versus placebo/no prophylaxis on patient-important outcomes in adult ICU patients. METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials assessing the effects of PPI/H2RA versus placebo/no prophylaxis on mortality, gastrointestinal (GI) bleeding, serious adverse events (SAEs), health-related quality of life (HRQoL), myocardial ischemia, pneumonia, and Clostridium (Cl.) difficile enteritis in ICU patients. RESULTS: We identified 42 trials randomising 6899 ICU patients; 3 had overall low risk of bias. We did not find an effect of stress ulcer prophylaxis on mortality [relative risk 1.03, 95% confidence interval (CI) 0.94-1.14; TSA-adjusted CI 0.94-1.14], but the occurrence of any GI bleeding was reduced as compared with placebo/no prophylaxis (0.60, 95% CI 0.47-0.77; TSA-adjusted CI 0.36-1.00). The conventional meta-analysis indicated that clinically important GI bleeding was reduced (RR 0.63, 95% CI 0.48-0.81), but the TSA-adjusted CI 0.35-1.13 indicated lack of firm evidence. The effects of stress ulcer prophylaxis on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis are uncertain. CONCLUSIONS: In this updated systematic review, we were able to refute a relative change of 20% of mortality. The occurrence of GI bleeding was reduced, but we lack firm evidence for a reduction in clinically important GI bleeding. The effects on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis remain inconclusive.

Simulation-based training of junior doctors in handling critically ill patients facilitates the transition to clinical practice: an interview study.

BACKGROUND: Junior doctors lack confidence and competence in handling the critically ill patient including diagnostic skills, decision-making and team working with other health care professionals. Simulation-based training on managing emergency situations can have substantial effects on satisfaction and learning. However, there are indications of problems when applying learned skills to practice. Our aim was to identify first-year doctors' perceptions, reflections and experiences on transfer of skills to a clinical setting after simulation-based training in handling critically ill patients. METHODS: We used a qualitative approach and conducted semi-structured telephone interviews with a sample of twenty first-year doctors six months after a 4-day simulation-based training course in handling critically ill patients. Interviews were transcribed verbatim. A content-analysis approach was used to analyse the data. RESULTS: The following main themes were identified from the interviews: preparedness for clinical practice, organisational readiness, use of algorithms, communication, teamwork, situational awareness and decision making. The doctors gave several examples of simulation-based training increasing their preparedness for clinical practice and handling the critically ill patient. The usefulness of algorithms and the appreciation of non-technical skills were highlighted and found to be helpful in managing clinical difficulties. Concern was expressed related to staff willingness and preparedness in using these tools. CONCLUSIONS: Overall, the simulation-based training seemed to facilitate the transition from being a medical student to become a junior doctor. The doctors experienced an ability to transfer the use of algorithms and non-technical skills trained in the simulated environment to the clinical environment. However, the application of these skills was more difficult if these skills were unfamiliar to the surrounding clinical staff. TRIAL REGISTRATION: Not applicable.