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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. [ABSTRACT FROM AUTHOR]

Introduction: There is concern about excessive bleeding when low-molecular-weight heparins (LMWHs) are used for venous thromboembolism (VTE) prophylaxis in renal dysfunction. Our objective was to evaluate whether LMWH VTE prophylaxis was safe and effective in critically ill patients with renal dysfunction by conducting a subgroup analysis of PROTECT, a randomized blinded trial. Methods: We studied intensive care unit (ICU) patients with pre-ICU dialysis-dependent end-stage renal disease (ESRD; pre-specified subgroup; n = 118), or severe renal dysfunction at ICU admission (defined as ESRD or non-dialysis dependent with creatinine clearance [CrCl] <30 ml/min; post hoc subgroup; n = 590). We compared dalteparin, 5000 IU daily, with unfractionated heparin (UFH), 5000 IU twice daily, and considered outcomes of proximal leg deep vein thrombosis (DVT); pulmonary embolism (PE); any VTE; and major bleeding. Adjusted hazard ratios [HR] were calculated using Cox regression. Results: In patients with ESRD, there was no significant difference in DVT (8.3% vs. 5.2%, p = 0.76), any VTE (10.0% vs. 6.9%; p = 0.39) or major bleeding (5.0% vs. 8.6%; p = 0.32) between UFH and dalteparin. In patients with severe renal dysfunction, there was no significant difference in any VTE (10.0% vs. 6.4%; p = 0.07) or major bleeding (8.9% vs. 11.0%; p = 0.66) but an increase in DVT with dalteparin (7.6% vs. 3.7%; p = 0.04). Interaction p-values for comparisons of HRs (ESRD versus not) were non-significant. Conclusions: In critically ill patients with ESRD, or severe renal dysfunction, there was no significant difference in any VTE or major bleeding between UFH and dalteparin. Patients with severe renal dysfunction who received dalteparin had more proximal DVTs than those on UFH; this finding did not hold in patients with ESRD alone. [ABSTRACT FROM AUTHOR]

Purpose: Bleeding frequently complicates critical illness and may have serious consequences. Our objectives are to describe the predictors of major bleeding and the association between bleeding and mortality in medical-surgical critically ill patients receiving heparin thromboprophylaxis. Methods: We prospectively studied patients from 67 intensive care units and six countries enrolled in a thromboprophylaxis trial (NCT00182143) comparing dalteparin with unfractionated heparin. Patients with trauma, orthopedic surgery or neurosurgery were excluded. Trained research coordinators used a validated tool to document bleeding, which underwent duplicate independent blinded adjudication. Major bleeding was defined as hypovolemic shock, bleeding into critical sites, requiring an invasive intervention or transfusion of at least two units of red blood cells, or associated with hypotension or tachycardia in the absence of other causes. Adjusted Cox proportional hazard regression analysis was used to identify major bleeding predictors and the association between bleeding and mortality. Results: Among 3,746 patients, bleeding occurred in 208 [5.6 %, 95 % confidence interval (CI) 4.9-6.3 %]. Time-dependent predictors were prolonged activated partial thromboplastin time [hazard ratio (HR) 1.10, 1.05-1.14 per 10 s increase], lower platelet count (HR 1.16, 1.09-1.24 per 50 × 10/L decrease), therapeutic heparin (HR 3.26, 1.72-6.17), antiplatelet agents (HR 1.38, 1.02-1.88), renal replacement therapy (HR 1.75, 1.20-2.56), and recent surgery (HR 1.64, 1.01-2.65). Type of pharmacologic thromboprophylaxis was not associated with bleeding. Patients with bleeding had a higher risk of in-hospital death (HR 2.09, 1.69-2.57). Conclusions: As major bleeding has modifiable risk factors and is associated with in-hospital mortality, strategies to mitigate these factors should be evaluated in critically ill patients. [ABSTRACT FROM AUTHOR]

Introduction: Research on co-enrollment practices and their impact are limited in the ICU setting. The objectives of this study were: 1) to describe patterns and predictors of co-enrollment of patients in a thromboprophylaxis trial, and 2) to examine the consequences of co-enrollment on clinical and trial outcomes. Methods: In an observational analysis of an international thromboprophylaxis trial in 67 ICUs, we examined the coenrollment of critically ill medical-surgical patients into more than one study, and examined the clinical and trial outcomes among co-enrolled and non-co-enrolled patients. Results: Among 3,746 patients enrolled in PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial), 713 (19.0%) were co-enrolled in at least one other study (53.6% in a randomized trial, 37.0% in an observational study and 9.4% in both). Six factors independently associated with co-enrollment (all P < 0.001) were illness severity (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.19 to 1.53 for each 10-point Acute Physiology and Chronic Health Evaluation (APACHE) II score increase), substitute decision-makers providing consent, rather than patients (OR 3.31, 2.03 to 5.41), experience of persons inviting consent (OR 2.67, 1.74 to 4.11 for persons with > 10 years' experience compared to persons with none), center size (all ORs > 10 for ICUs with > 15 beds), affiliation with trials groups (OR 5.59, 3.49 to 8.95), and main trial rather than pilot phase (all ORs > 8 for recruitment year beyond the pilot). Co-enrollment did not influence clinical or trial outcomes or risk of adverse events. Conclusions: Co-enrollment was strongly associated with features of the patients, research personnel, setting and study. Co-enrollment had no impact on trial results, and appeared safe, acceptable and feasible. Transparent reporting, scholarly discourse, ethical analysis and further research are needed on the complex topic of coenrollment during critical illness. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The aim of this study was to assess the etiology of cardiac troponin elevation among patients admitted to the intensive care unit (ICU) and to examine whether etiology affects mortality and length of stay. Methods: All patients admitted over 2 months underwent screening with troponin measurements and were included if 1 or more measurements were elevated. Two adjudicators retrospectively reviewed patient charts to determine the likely cause of troponin elevation. Results: Of 103 patient admissions, 52 (50.5%) had 1 or more elevated troponin measurements, and 49 (94.2%) had medical charts available for review. Troponin elevation was adjudicated as myocardial infarction (MI) in 53.1% of patients, sepsis in 18.4%, renal failure in 12.2%, and other causes in 16.3%. Overall ICU mortality was 16.0%; 2.0% for patients with no troponin elevation, 23.1% in patients with MI, and 39.1% in patients with troponin elevation not due to MI. Having an elevated troponin level not due to MI was significantly associated with increased hospital mortality compared with having no troponin elevation. Conclusions: The most common cause of troponin elevation among critically ill patients was MI. Patients with elevated troponin had worse outcomes compared with patients without troponin elevation, and troponin elevation not due to MI was predictive of increased hospital mortality. [Copyright &y& Elsevier]

Abstract: Purpose: The aim of the study was to assess agreement among 4 intensivists in diagnosing myocardial infarction (MI) in critically ill patients based on screening electrocardiograms (ECGs) and cardiac troponin (cTn) levels. Methods: Consecutive patients admitted to a medical-surgical intensive care unit (ICU) underwent systematic screening with 12-lead ECGs and cTn measurements throughout their ICU stay. Independently, 4 raters interpreted the ECGs assessing for changes indicative of ischemia and then classified each patient as to whether they met diagnostic criteria for MI based on the screening cTn measurements and ECG results. A priori, 2 raters were designated the primary adjudicators, and their consensus was used as the reference for the agreement statistics. Agreement on MI diagnosis was calculated for the 4 raters and expressed as raw agreement, κ (chance-corrected agreement) and ϕ (chance-independent agreement, calculated using pairs). Results: Among 103 enrolled patients, 37 (35.9%) had MI according to the primary adjudicators. The raw agreement for diagnosing MI was 79% (substantial), κ was 0.24 (fair), and ϕ ranged from 0.12 to 0.73 (slight to substantial). Conclusions: Diagnosing MI in the ICU remains a challenge due to variable agreement in 12-lead ECG interpretation. Such variation in practice may contribute to underrecognition of MI during critical illness. [Copyright &y& Elsevier]

The article examines the frequency of elevated cardiac troponin (cTn) elevation and its association with mortality and length of stay of patients in intensive care units (ICU). Elevated cTn measurements among critically ill patients are associated with increased mortality and ICU length of stay. Further research is needed to clarify the underlying causes of elevated cTn in this population and to examine their clinical significance.

A response from the authors of the article "Thrombocytopenia in critically ill patients receiving thromboprophylaxis: Frequency, risk factors, and outcomes," in the October 2013 issue is presented.

Abstract: Background: This article reports the preparatory studies as well as the design, implementation, and a priori analysis plans of PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) before dissemination of results. PROphylaxis for ThromboEmbolism in Critical Care Trial (NCT00182143) is a randomized, stratified, concealed international trial comparing subcutaneous injection of unfractionated heparin (UFH) 5000 IU or the low–molecular weight heparin (LMWH) dalteparin 5000 IU once daily plus once-daily placebo for the duration of the intensive care unit stay. Methods: The objective of PROTECT is to examine, among medical-surgical critically ill patients, the effect of the LMWH vs heparin on the primary outcome of proximal leg deep vein thrombosis (DVT) and the following secondary outcomes: DVT elsewhere, pulmonary embolism, any venous thromboembolism (DVT or pulmonary embolism), the composite of venous thromboembolism or death, bleeding, and heparin-induced thrombocytopenia. Patients are followed up to death or hospital discharge. Venous thromboembolism events were included after intensive care unit discharge. All patients, families, clinicians, research personnel, and the trial biostatistician are blind to allocation. Results: We describe the pilot work, large trial methodology, implementation methods, and the analytic plan. Patient recruitment is complete, but 2 patients remain in the hospital. The rigorous design of PROTECT suggests that the risk of systematic error will be low. The sample size suggests that the risk of random error will be low. PROTECT will be the largest investigator-initiated peer-review funded thromboprophylaxis trial in critical care in the world. Conclusions: If PROTECT shows that LMWH is more effective than UFH, this trial will change practice in that LMWH may be the anticoagulant thromboprophylaxis of choice for this population. If the results show that UFH is as effective or more effective than LMWH, intensivists in many parts of the world may continue to use UFH, whereas those currently using LMWH may reconsider and change to use UFH. Unfavorable consequences such as major bleeding, ease of use, and the costs of complications will also factor into such decisions. [Copyright &y& Elsevier]

Objectives: To determine the safety and efficacy of probiotics or synbiotics on morbidity and mortality in critically ill adults and children.Data Sources: We searched MEDLINE, EMBASE, CENTRAL, and unpublished sources from inception to May 4, 2021.Study Selection: We performed a systematic search for randomized controlled trials (RCTs) that compared enteral probiotics or synbiotics to placebo or no treatment in critically ill patients. We screened studies independently and in duplicate.Data Extraction: Independent reviewers extracted data in duplicate. A random-effects model was used to pool data. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development, and Evaluation approach.Data Synthesis: Sixty-five RCTs enrolled 8,483 patients. Probiotics may reduce ventilator-associated pneumonia (VAP) (relative risk [RR], 0.72; 95% CI, 0.59 to 0.89 and risk difference [RD], 6.9% reduction; 95% CI, 2.7-10.2% fewer; low certainty), healthcare-associated pneumonia (HAP) (RR, 0.70; 95% CI, 0.55-0.89; RD, 5.5% reduction; 95% CI, 8.2-2.0% fewer; low certainty), ICU length of stay (LOS) (mean difference [MD], 1.38 days fewer; 95% CI, 0.57-2.19 d fewer; low certainty), hospital LOS (MD, 2.21 d fewer; 95% CI, 1.18-3.24 d fewer; low certainty), and duration of invasive mechanical ventilation (MD, 2.53 d fewer; 95% CI, 1.31-3.74 d fewer; low certainty). Probiotics probably have no effect on mortality (RR, 0.95; 95% CI, 0.87-1.04 and RD, 1.1% reduction; 95% CI, 2.8% reduction to 0.8% increase; moderate certainty). Post hoc sensitivity analyses without high risk of bias studies negated the effect of probiotics on VAP, HAP, and hospital LOS.Conclusions: Low certainty RCT evidence suggests that probiotics or synbiotics during critical illness may reduce VAP, HAP, ICU and hospital LOS but probably have no effect on mortality. [ABSTRACT FROM AUTHOR]

Objectives: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. Design: Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. Setting: Sixty-seven medical-surgical ICUs in six countries. Patients: Three thousand seven hundred forty-six medical-surgical critically ill patients. Interventions: All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. Measurements and Main Results: Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). Conclusions: Failure of standard thromboprophylaxis using lowmolecular- weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the incidence, severity, duration and consequences of bleeding during critical illness, and to test the performance characteristics of a new bleeding assessment tool. Methods: Clinical bleeding assessments were performed prospectively on 100 consecutive patients admitted to a medical-surgical intensive care unit (ICU) using a novel bleeding measurement tool called HEmorrhage MEasurement (HEME). Bleeding assessments were done daily in duplicate and independently by blinded, trained assessors. Inter-rater agreement and construct validity of the HEME tool were calculated using Φ. Risk factors for major bleeding were identified using a multivariable Cox proportional hazards model. Results: Overall, 90% of patients experienced a total of 480 bleeds of which 94.8% were minor and 5.2% were major. Inter-rater reliability of the HEME tool was excellent (Φ = 0.98, 95% CI: 0.96 to 0.99). A decrease in platelet count and a prolongation of partial thromboplastin time were independent risk factors for major bleeding but neither were renal failure nor prophylactic anticoagulation. Patients with major bleeding received more blood transfusions and had longer ICU stays compared to patients with minor or no bleeding. Conclusions: Bleeding, although primarily minor, occurred in the majority of ICU patients. One of five patients experienced a major bleed which was associated with abnormal coagulation tests but not with prophylactic anticoagulants. These baseline bleeding rates can inform the design of future clinical trials in critical care that use bleeding as an outcome and HEME is a useful tool to measure bleeding in critically ill patients. [ABSTRACT FROM AUTHOR]