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Purpose Thrombocytopenia (platelet count < 150 x 10.sup.9/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4-46.1) had thrombocytopenia; 23.4% (20-26) had thrombocytopenia at ICU admission, and 19.8% (17.6-22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19-2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic., Author(s): Carl Thomas Anthon [sup.1], Frédéric Pène [sup.2], Anders Perner [sup.1] [sup.3] [sup.4], Elie Azoulay [sup.4], Kathryn Puxty [sup.5], Andry Van De Louw [sup.6], Andreas Barratt-Due [sup.7], Sanjay Chawla [sup.8] [...]

Purpose The AID-ICU trial was a randomised, blinded, placebo-controlled trial investigating effects of haloperidol versus placebo in acutely admitted, adult patients admitted in intensive care unit (ICU) with delirium. This pre-planned Bayesian analysis facilitates probabilistic interpretation of the AID-ICU trial results. Methods We used adjusted Bayesian linear and logistic regression models with weakly informative priors to analyse all primary and secondary outcomes reported up to day 90, and with sensitivity analyses using other priors. The probabilities for any benefit/harm, clinically important benefit/harm, and no clinically important differences with haloperidol treatment according to pre-defined thresholds are presented for all outcomes. Results The mean difference for days alive and out of hospital to day 90 (primary outcome) was 2.9 days (95% credible interval (CrI) - 1.1 to 6.9) with probabilities of 92% for any benefit and 82% for clinically important benefit. The risk difference for mortality was - 6.8 percentage points (95% CrI - 12.8 to - 0.8) with probabilities of 99% for any benefit and 94% for clinically important benefit. The adjusted risk difference for serious adverse reactions was 0.3 percentage points (95% CrI - 1.3 to 1.9) with 98% probability of no clinically important difference. Results were consistent across sensitivity analyses using different priors, with more than 83% probability of benefit and less than 17% probability of harm with haloperidol treatment. Conclusions We found high probabilities of benefits and low probabilities of harm with haloperidol treatment compared with placebo in acutely admitted, adult ICU patients with delirium for the primary and most secondary outcomes., Author(s): Nina C. Andersen-Ranberg [sup.1] [sup.2], Lone Musaeus Poulsen [sup.1] [sup.2], Anders Perner [sup.2] [sup.3], Johanna Hästbacka [sup.4], Matthew Morgan [sup.5], Giuseppe Citerio [sup.6] [sup.7], Marie Oxenbøll Collet [sup.2] [sup.3], [...]

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 ([euro]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., Author(s): Christine Marie Bækø Halling [sup.1], Morten Hylander Møller [sup.2] [sup.3], Søren Marker [sup.2] [sup.3], Mette Krag [sup.4], Jakob Kjellberg [sup.1], Anders Perner [sup.2] [sup.3], Dorte Gyrd-Hansen [sup.5] Author Affiliations: [...]

Purpose Motivated by a new randomized trial (the PEPTIC trial) that raised the issue of an increase in mortality with proton pump inhibitors (PPIs) relative to histamine-2 receptor antagonists (H2RAs), we updated our prior systematic review and network meta-analysis (NMA) addressing the impact of pharmacological gastrointestinal bleeding prophylaxis in critically ill patients. Methods We searched for randomized controlled trials that examined the efficacy and safety of gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. We performed Bayesian random-effects NMA and conducted analyses using all PEPTIC data as well as a restricted analysis using only PEPTIC data from high compliance centers. We used the GRADE approach to quantify absolute effects and assess the certainty of evidence. Results Seventy-four trials enrolling 39 569 patients proved eligible. Both PPIs (risk ratio (RR) 1.03, 95% credible interval 0.93 to 1.14, moderate certainty) and H2RAs (RR 0.98, 0.89 to 1.08, moderate certainty) probably have little or no impact on mortality compared with no prophylaxis. There may be no important difference between PPIs and H2RAs on mortality (RR 1.05, 0.97 to 1.14, low certainty), the 95% credible interval of the complete analysis has not excluded an important increase in mortality with PPIs. Both PPIs (RR 0.46, 0.29 to 0.66) and H2RAs (RR 0.67, 0.48 to 0.94) probably reduce clinically important gastrointestinal bleeding; the magnitude of reduction is probably greater in PPIs than H2RAs (RR 0.69, 0.45 to 0.93), and the difference may be important in higher, but not lower bleeding risk patients. PPIs (RR 1.08, 0.88 to 1.45, low certainty) and H2RAs (RR 1.07, 0.85 to 1.37, low certainty) may have no important impact on pneumonia compared with no prophylaxis. Conclusion This updated NMA confirmed that PPIs and H2RAs are most likely to have a similar effect on mortality compared to each other and compared to no prophylaxis; however, the possibility that PPIs may slightly increase mortality cannot be excluded (low certainty evidence). PPIs and H2RAs probably achieve important reductions in clinically important gastrointestinal bleeding; for higher bleeding risk patients, the greater benefit of PPIs over H2RAs may be important. PPIs or H2RAs may not result in important increases in pneumonia but the certainty of evidence is low., Author(s): Ying Wang [sup.1], Long Ge [sup.2], Zhikang Ye [sup.1], Reed A. Siemieniuk [sup.1] [sup.3], Annika Reintam Blaser [sup.4] [sup.5], Xin Wang [sup.6], Anders Perner [sup.7], Morten H. Møller [sup.7], [...]

Author(s): Anders Perner [sup.1], Bharath Kumar Tirupakuzhi Vijayaraghavan [sup.2], Balasubramanian Venkatesh [sup.3] Author Affiliations: (1) grid.5254.6, 0000 0001 0674 042X, Department of Intensive Care, Rigshospitalet, University of Copenhagen, , Copenhagen, [...]

Author(s): Alexander P. Vlaar [sup.1] [sup.9] , Simon Oczkowski [sup.2] [sup.3] [sup.4] , Gavin J. Murphy [sup.5] , Anders Perner [sup.6] , Gordon Guyatt [sup.2] [sup.3] [sup.4] , Joanna C. [...]

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 [greater than or equal to] 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., Author(s): Anders Granholm [sup.1], Linan Zeng [sup.2] [sup.3], Joanna Colleen Dionne [sup.3] [sup.4], Anders Perner [sup.1] [sup.5], Søren Marker [sup.1] [sup.5], Mette Krag [sup.1] [sup.5], Robert MacLaren [sup.6], Zhikang Ye [...]

Author(s): José Castela Forte [sup.1] [sup.2], Anders Perner [sup.3], Iwan C. C. van der Horst [sup.2] Author Affiliations: (1) 0000 0004 0407 1981, grid.4830.f, Bernoulli Institute for Mathematics, Computer Science [...]

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., Author(s): Søren Marker [sup.1] [sup.2], Anders Perner [sup.1] [sup.2], Jørn Wetterslev [sup.2] [sup.3], Mette Krag [sup.1] [sup.2], Theis Lange [sup.4] [sup.5], Matt P. Wise [sup.6], Mark Borthwick [sup.7], Stepani Bendel [...]

While guidelines provide important information on how to approach a patient in septic shock, 'many challenges remain' for the management of these patients. In this narrative review, the panel discusses the challenges in identifying the right hemodynamic target, optimization of fluid therapy, selection of vasopressor agents, identification of patients who may benefit from inotropic agents or on the contrary beta-blockade, and use of steroids. The place for microcirculation-targeted therapy is debated as well as the use of alternative techniques (blood purification) and therapies (vitamin C). The implications of hemodynamic alterations on antibiotic doses is discussed. Finally, the specific challenges in low- and middle-income countries are addressed. Ongoing trials address some of these challenges, but many uncertainties will remain, and individualized therapies based on careful clinical assessment will continue to be essential to optimizing the care of patients with septic shock., Author(s): Daniel De Backer [sup.1], Maurizio Cecconi [sup.2], Jeffrey Lipman [sup.3], Flavia Machado [sup.4], Sheila Nainan Myatra [sup.5], Marlies Ostermann [sup.6], Anders Perner [sup.7], Jean-Louis Teboul [sup.8], Jean-Louis Vincent [sup.9], [...]

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., Author(s): Marija Barbateskovic [sup.1] [sup.2], Søren Marker [sup.2] [sup.3], Anders Granholm [sup.3], Carl Thomas Anthon [sup.3], Mette Krag [sup.3], Janus Christian Jakobsen [sup.1] [sup.2] [sup.4], Anders Perner [sup.2] [sup.3], Jørn [...]

Author(s): Anders Perner [sup.1], Simon Finfer [sup.2] Author Affiliations: (1) grid.475435.4, Department of Intensive Care, Rigshospitalet, University of Copenhagen, , Copenhagen, Denmark (2) 0000 0004 4902 0432, grid.1005.4, Malcolm Fisher [...]

Purpose To assess the effect of low dose corticosteroids on outcomes in adults with septic shock. Methods We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay. Results There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89-1.08, p = 0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91-1.02, p = 0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90-1.02, p = 0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03-2.70, p = 0.04, I.sup.2 = 78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) -1.52 days; 95% CI -1.71 to -1.32, p < 0.0001], duration of mechanical ventilation (MD -1.38 days; 95% CI -1.96 to -0.80, p < 0.0001), and ICU stay (MD -0.75 days; 95% CI -1.34 to -0.17, p = 0.01) were shorter with corticosteroids versus placebo. Conclusions In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037., Author(s): Sofie Louise Rygård [sup.1], Ethan Butler [sup.2], Anders Granholm [sup.1], Morten Hylander Møller [sup.1] [sup.3], Jeremy Cohen [sup.4] [sup.5], Simon Finfer [sup.6] [sup.9], Anders Perner [sup.1] [sup.3], John Myburgh [...]

Hypovolemia is frequent in patients with sepsis and may contribute to worse outcome. The management of these patients is impeded by the low quality of the evidence for many of the specific components of the care. In this paper, we discuss recent advances and controversies in this field and give expert statements for the management of hypovolemia in patients with sepsis including triggers and targets for fluid therapy and volumes and types of fluid to be given. Finally, we point to unanswered questions and suggest a roadmap for future research., Author(s): Anders Perner [sup.1], Maurizio Cecconi [sup.2], Maria Cronhjort [sup.3], Michael Darmon [sup.4] [sup.5] [sup.6], Stephan M. Jakob [sup.7], Ville Pettilä [sup.8], Iwan C. C. van der Horst [sup.9] Author [...]

Purpose Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During storage, the RBCs and storage medium undergo changes, which may have clinical consequences. Several trials now have assessed these consequences, and we reviewed the present evidence on the effects of shorter versus longer storage time of transfused RBCs on outcomes in ICU patients. Methods We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials including adult ICU patients transfused with fresher versus older or standard issue blood. Results We included seven trials with a total of 18,283 randomised ICU patients; two trials of 7504 patients were judged to have low risk of bias. We observed no effects of fresher versus older blood on death (relative risk 1.04, 95% confidence interval (CI) 0.97-1.11; 7349 patients; TSA-adjusted CI 0.93-1.15), adverse events (1.26, 0.76-2.09; 7332 patients; TSA-adjusted CI 0.16-9.87) or post-transfusion infections (1.07, 0.96-1.20; 7332 patients; TSA-adjusted CI 0.90-1.27). The results were unchanged by including trials with high risk of bias. TSA confirmed the results and the required information size was reached for mortality for a relative risk change of 20%. Conclusions We may be able to reject a clinically meaningful effect of RBC storage time on mortality in transfused adult ICU patients as our trial sequential analyses reject a 10% relative risk change in death when comparing fresher versus older blood for transfusion., Author(s): Sofie L. Rygård [sup.1], Andreas B. Jonsson [sup.1], Martin B. Madsen [sup.1], Anders Perner [sup.1] [sup.4], Lars B. Holst [sup.1], Pär I. Johansson [sup.3], Jørn Wetterslev [sup.2] [sup.4] Author [...]

Purpose Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients. Methods We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers. Results Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies. Conclusions Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question., Author(s): Waleed Alhazzani [sup.1] [sup.2], Fayez Alshamsi [sup.3], Emilie Belley-Cote [sup.2], Diane Heels-Ansdell [sup.2], Romina Brignardello-Petersen [sup.2], Mustafa Alquraini [sup.1], Anders Perner [sup.4], Morten Hylander Møller [sup.4], Mette Krag [sup.4], [...]