The DIFFMASK score for predicting difficult facemask ventilation: a cohort study of 46,804 patients.

Facemask ventilation is an essential part of airway management. Correctly predicting difficulties in facemask ventilation may reduce the risk of morbidity and mortality among patients at risk. We aimed to develop and evaluate a weighted risk score for predicting difficult facemask ventilation during anaesthesia. We analysed a cohort of 46,804 adult patients who were assessed pre-operatively airway for 13 predictors of difficult airway management and subsequently underwent facemask ventilation during general anaesthesia. We developed the Difficult Facemask (DIFFMASK) score in two consecutive steps: first, a multivariate regression analysis was performed; and second, the regression coefficients of the adjusted regression model were converted into a clinically applicable weighted point score. The predictive accuracy of the DIFFMASK score was evaluated by assessment of receiver operating characteristic curves. The prevalence of difficult facemask ventilation was 1.06% (95%CI 0.97-1.16). Following conversion of regression coefficients into 0, 1, 2 or 3 points, the cumulated DIFFMASK score ranged from 0 to 18 points and the area under the receiver operating characteristic curve was 0.82. The Youden index indicated a sum score ≥ 5 as an optimal cut-off value for prediction of difficult facemask ventilation giving a sensitivity of 85% and specificity of 59%. The DIFFMASK score indicated that a score of 6-10 points represents a population of patients who may require heightened attention when facemask ventilation is planned, compared with those patients who are obviously at a high- or low risk of difficulties. The DIFFMASK score may be useful in a clinical context but external, prospective validation is needed.

Effects of avoidance or use of neuromuscular blocking agents on outcomes in tracheal intubation: a Cochrane systematic review.

Cohort studies have indicated that avoidance of neuromuscular blocking agents (NMBA) is a risk factor for difficult tracheal intubation. However, the impact of avoiding NMBA on tracheal intubation, possible adverse effects, and postoperative discomfort has not been evaluated in a systematic review of randomised trials. We searched several databases for trials published until January 2017. We included randomised controlled trials comparing the effect of avoiding vs using NMBA. Two independent authors assessed risk of bias and extracted data. The risk of random errors was assessed by trial sequential analysis (TSA). We included 34 trials (3565 participants). In the four trials judged to have low risk of bias, there was an increased risk of difficult tracheal intubation with no use of NMBA [random-effects model, risk ratio (RR) 13.27, 95% confidence interval (CI) 8.19-21.49, P<0.00001, TSA-adjusted CI 1.85-95.04]. The result was confirmed when including all trials, (RR 5.00, 95% CI 3.49-7.15, P<0.00001, TSA-adjusted CI 1.20-20.77). There was a significant risk of upper airway discomfort or injury by avoiding NMBA (RR=1.37, 95% CI 1.09-1.74, P=0.008, TSA-adjusted CI 1.00-1.86). None of the trials reported mortality. Avoiding NMBA was significantly associated with difficult laryngoscopy, (RR 2.54, 95% CI 1.53-4.21, P=0.0003, TSA-adjusted CI 0.27-21.75). In a clinical context, one must balance arguments for using NMBA when performing tracheal intubation.

Perioperative hyperoxia and post-operative cardiac complications in adults undergoing non-cardiac surgery: Systematic review protocol.

BACKGROUND: Oxygen therapy is used liberally for all patients undergoing anaesthesia. Recent studies have raised concerns that it may not be without complications when arterial oxygen concentrations reach supranormal concentrations (hyperoxia). Studies of oxygen therapy have raised concerns that the risk of myocardial injury and infarction is elevated in patients with hyperoxia due to vasoconstriction and formation of reactive oxygen species. Due to lack of symptoms or silent ischaemia, post-operative myocardial injury may be missed clinically. In some studies, perioperative hyperoxia has been linked to increased long-term mortality, but cardiac complications are sparsely evaluated. The aim of this review is to summarize current evidence to assess the risk and benefits of perioperative hyperoxia on post-operative cardiac complications. METHODS: This systematic review will include meta-analyses and Trial Sequential Analyses. We will include randomized clinical trials with patients undergoing non-cardiac surgery if the allocation separates patients into a target of either higher (above 0.60) or lower (below 0.40) inspired oxygen fraction. To minimize the risk of systematic error, we will assess the risk of bias of the included trials using the Cochrane Risk of Bias Tool. The overall quality of evidence for each outcome will be assessed with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE). DISCUSSION: This systematic review will provide data on a severe, albeit rare, potential risk of oxygen therapy. We will do a trial sequential analysis to assess the robustness of results as well as help estimate the required patient size for future clinical trials.

Oxygen supplementation for critically ill patients-A protocol for a systematic review.

BACKGROUND: In critically ill patients, hypoxaemia is a common clinical manifestation of inadequate gas exchange in the lungs. Supplemental oxygen is therefore given to all critically ill patients. This can result in hyperoxaemia, and some observational studies have identified harms with hyperoxia. The objective of this systematic review is to critically assess the evidence of randomised clinical trials on the effects of higher versus lower inspiratory oxygen fractions or targets of arterial oxygenation in critically ill adult patients. METHODS: We will search for randomised clinical trials in major international databases. Two authors will independently screen and select references for inclusion using Covidence, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager and Trial Sequential Analysis. To assess the quality of the evidence, we will create a 'Summary of Findings' table containing our primary and secondary outcomes using the GRADE assessment. DISCUSSION: Supplemental oxygen administration is widely recommended in international guidelines despite lack of robust evidence of its effectiveness. To our knowledge, no systematic review of randomised clinical trials has investigated the effects of oxygen supplementation in critically ill patients. This systematic review will provide reliable evidence to better inform future trialists and decision-makers on clinical practice on supplemental oxygen administration in critically ill patients.

Systematic overview and critical appraisal of meta-analyses of interventions in intensive care medicine.

RATIONALE: Meta-analysed intervention effect estimates are perceived to represent the highest level of evidence. However, such effects and the randomized clinical trials which are included in them need critical appraisal before the effects can be trusted. OBJECTIVE: Critical appraisal of a predefined set of all meta-analyses on interventions in intensive care medicine to assess their quality and assessed the risks of bias in those meta-analyses having the best quality. METHODS: We conducted a systematic search to select all meta-analyses of randomized clinical trials on interventions used in intensive care medicine. Selected meta-analyses were critically appraised for basic scientific criteria, (1) presence of an available protocol, (2) report of a full search strategy, and (3) use of any bias risk assessment of included trials. All meta-analyses which qualified these criteria were scrutinized by full "Risk of Bias in Systematic Reviews" ROBIS evaluation of 4 domains of risks of bias, and a "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" PRISMA evaluation. RESULTS: We identified 467 meta-analyses. A total of 56 meta-analyses complied with these basic scientific criteria. We scrutinized the risks of bias in the 56 meta-analyses by full ROBIS evaluation and a PRISMA evaluation. Only 4 meta-analyses scored low risk of bias in all the 4 ROBIS domains and 41 meta-analyses reported all 27 items of the PRISMA checklist. CONCLUSION: In contrast with what might be perceived as the highest level of evidence only 0.9% of all meta-analyses were judged to have overall low risk of bias.

Haloperidol for delirium in critically ill patients - protocol for a systematic review.

BACKGROUND: In the intensive care unit, the prevalence of delirium is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer intensive care unit stay, increased long-term mortality, and cognitive impairment. Thus, the burden of delirium for patients, relatives, and societies is considerable. The objective of this systematic review was to critically access the evidence of randomised clinical trials on the effects of haloperidol vs. placebo or any other agents for delirium in critically ill patients. METHODS: We will search for randomised clinical trials in the following databases: Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, and Allied and Complementary Medicine Database. Two authors will independently screen and select references for inclusion using Covidence, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager, STATA 15, and Trial Sequential. ANALYSIS: The aim of this study was to assess the quality of the evidence, we will create a 'Summary of Findings' table containing our primary and secondary outcomes using the GRADE assessment. DISCUSSION: Our ambition with this systematic review is to provide reliable and powered evidence to better inform decision makers on the use of or future trials with haloperidol for the management of delirium in critically ill patients.

Stress ulcer prophylaxis in adult intensive care unit patients - a protocol for a systematic review.

BACKGROUND: In the intensive care unit (ICU), stress ulcer prophylaxis with proton pump inhibitors or histamine-2-receptor antagonists is standard of care although gastrointestinal bleeding remains uncommon. It remains unknown whether its use is associated with benefits or harms and the quality of evidence supporting the use of stress ulcer prophylaxis has been questioned. Accordingly, the objective of this systematic review was to critically assess the evidence from randomized clinical trials on the benefits and harms of stress ulcer prophylaxis vs. placebo or no prophylaxis in adult ICU patients. METHODS: We will systematically search for randomized clinical trials in major international databases. Two authors will independently screen and select trials for inclusion, extract data and assess the methodological quality using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will perform conventional meta-analyses using Review Manager, and STATA 15, and we will assess the risk of random errors using Trial Sequential Analysis. Also, we will assess and report the overall quality of evidence for all outcomes according to GRADE. DISCUSSION: The evidence on the benefits and harms of stress ulcer prophylaxis in adult ICU patients is unclear and an updated systematic review is warranted as new trials have been published. To control risks of systematic and random errors, we will use Cochrane and GRADE methodology and Trial Sequential Analysis. Our ambition with this systematic review is to provide updated, reliable and precise data to better inform decision makers on the use of stress ulcer prophylaxis in adult ICU patients.

Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study.

BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP.

Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

BACKGROUND: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. METHODS: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. RESULTS: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2 ) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2 ); and 23% preferred SaO2 . Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. CONCLUSION: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.

Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses.

Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended.

Higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial.

BACKGROUND: Using a restrictive transfusion strategy appears to be safe in sepsis, but there may be subgroups of patients who benefit from transfusion at a higher haemoglobin level. We explored if subgroups of patients with septic shock and anaemia had better outcome when transfused at a higher vs. a lower haemoglobin threshold. METHODS: In post-hoc analyses of the full trial population of 998 patients from the Transfusion Requirements in Septic Shock (TRISS) trial, we investigated the intervention effect on 90-day mortality in patients with severe comorbidity (chronic lung disease, haematological malignancy or metastatic cancer), in patients who had undergone surgery (elective or acute) and in patients with septic shock as defined by the new consensus definition: lactate above 2 mmol/l and the need for vasopressors to maintain a mean arterial pressure above 65 mmHg. RESULTS: The baseline characteristics were mostly similar between the two intervention groups in the different subgroups. There were no differences in the intervention effect on 90-day mortality in patients with chronic lung disease (test of interaction P = 0.31), haematological malignancy (P = 0.47), metastatic cancer (P = 0.51), in those who had undergone surgery (P = 0.99) or in patients with septic shock by the new definition (P = 0.20). CONCLUSION: In exploratory analyses of a randomized trial in patients with septic shock and anaemia, we observed no survival benefit in any subgroups of transfusion at a haemoglobin threshold of 90 g/l vs. 70 g/l.

Low vs. high haemoglobin trigger for transfusion in vascular surgery: protocol for a randomised trial.

BACKGROUND: In patients with cardiovascular disease, guidelines for administration of red blood cells (RBC) are mainly based on studies outside the vascular surgical setting with the recommendation to use a haemoglobin (hb) trigger-level lower than by guidelines from The European Society for Vascular Surgery. Restricting RBC transfusion may affect blood O2 transport with a risk for development of tissue ischaemia and postoperative complications. METHODS: In a single-centre, open-label, assessor blinded trial, 58 vascular surgical patients (> 40 years of age) awaiting open surgery of the infrarenal aorta or infrainguinal arterial bypass surgery undergo a web-based randomisation to one of two groups: perioperative RBC transfusion triggered by hb < 8 g/dl or hb < 9.7 g/dl. Administration of fluid follows an individualised strategy by optimising cardiac stroke volume and near-infrared spectroscopy determines tissue oxygenation. Serious adverse event rates are: myocardial injury (troponin-I ≥ 45 ng/l or ischaemic electrocardiographic findings at day 30), acute kidney injury, death, stroke and severe transfusion reactions. A follow-up visit takes place 30 days after surgery and a follow-up of serious adverse events in the Danish National Patient Register within 90 days is pending. DISCUSSION: This trial is expected to determine whether a RBC transfusion triggered by hb < 9.7 g/dl compared with hb < 8 g/dl results in adequate separation of postoperative hb levels, transfusion of more RBC units and maintains a higher tissue oxygenation. The results will inform the design of a multicentre trial for evaluation of important postoperative outcomes.

Effects of hydroxyethyl starch 130/0.42 vs. Ringer's acetate on cytokine levels in severe sepsis.

BACKGROUND: The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased 90-day mortality with hydroxyethyl starch (HES) 130/0.42 vs. Ringer's acetate. To explore the underlying pathophysiology, we compared early changes in plasma cytokine concentrations between patients resuscitated with HES vs. Ringer's acetate. METHODS: In a subgroup of 226 patients from the 6S trial, we calculated delta plasma concentrations of tumour necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-10 from randomization to day 2. We used multiple linear and logistic regression analyses to assess differences between the groups and associations between delta cytokine concentrations and 90-day mortality, respectively. RESULTS: Baseline characteristics and day 2 mortality were comparable between the groups. We observed similar delta cytokine concentrations in the HES vs. Ringer's group (mean difference in delta TNF-α: -1.5 pg/ml (95% CI, -4.9 to 1.9), P = 0.39; IL-6: 36.0 pg/ml (-24.1 to 96.1), P = 0.24; IL-10: -3.9 pg/ml (-21.1 to 28.9), P = 0.76). In all included patients, we observed a linear relationship between increases in TNF-α and 90-day mortality (P = 0.005). CONCLUSION: Resuscitation with HES 130/0.42 vs. Ringer's acetate did not appear to affect plasma concentrations of TNF-α, IL-6 or IL-10 differently during the first days after randomization into the 6S trial. In the overall cohort, increases in TNF-α were associated with increased 90-day mortality. Although interpretation should be done with caution, it seems unlikely that the increased mortality observed with the use HES in the 6S trial is signalled by early changes in three biomarkers of systemic inflammation.

Lower vs. higher fluid volumes in sepsis-protocol for a systematic review with meta-analysis.

BACKGROUND: Intravenous fluid administration with crystalloids is recommended in the initial management of sepsis. However, the quality of evidence supporting the recommendation on fluid volumes is low, and clinical equipoise exists. Potential benefits of restricting fluid volumes has been suggested, but the overall benefit or harm in patients with sepsis is unknown. Accordingly, we aim to assess patient-important benefits and harms of lower vs. higher fluid volumes in resuscitation of adult patients with sepsis. METHODS/DESIGN: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials comparing different strategies to obtain separation in fluid volumes or balances during resuscitation of adult patients with sepsis. 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 Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: The outlined systematic review will provide important data on how patient-important outcomes are affected by higher vs. lower resuscitation fluid volumes in adults with sepsis. Using trial sequential analysis to assess the risk of random errors will increase the validity of the summary estimates calculated and help estimate the required information size for future trials.

Effects of red blood cell storage time on transfused patients in the ICU-protocol for a systematic review.

BACKGROUND: Patients in the intensive care unit (ICU) are often anaemic due to blood loss, impaired red blood cell (RBC) production and increased RBC destruction. In some studies, more than half of the patients were treated with RBC transfusion. During storage, the RBC and the storage medium undergo changes, which lead to impaired transportation and delivery of oxygen and may also promote an inflammatory response. Divergent results on the clinical consequences of storage have been reported in both observational studies and randomised trials. Therefore, we aim to gather and review the present evidence to assess the effects of shorter vs. longer storage time of transfused RBCs for ICU patients. METHODS: We will conduct a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials, and also include results of severe adverse events from large observational studies. Participants will be adult patients admitted to an ICU and treated with shorter vs. longer stored RBC units. We will systematically search the Cochrane Library, MEDLINE, Embase, BIOSIS, CINAHL and Science Citation Index for relevant literature, and we will follow the recommendation by the Cochrane Collaboration and the Preferred Reporting Items for Systemtic Review and Meta-Analysis (PRISMA)-statement. We will assess the risk of bias and random errors, and we will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the overall quality of evidence. CONCLUSION: We need a high-quality systematic review to summarise the clinical consequences of RBC storage time among ICU patients.

Effects of fluid restriction on measures of circulatory efficacy in adults with septic shock.

BACKGROUND: The haemodynamic consequences of fluid resuscitation in septic shock have not been fully elucidated. Therefore, we assessed circulatory effects in the first 24 h of restriction of resuscitation fluid as compared to standard care in intensive care unit (ICU) patients with septic shock. METHODS: This was a post-hoc analysis of the multicentre CLASSIC randomised trial in which patients with septic shock, who had received the initial fluid resuscitation, were randomised to a protocol restricting resuscitation fluid or a standard care protocol in nine ICUs. The highest plasma lactate, highest dose of noradrenaline, and the urinary output were recorded in five time frames in the first 24 h after randomisation. We used multiple linear mixed effects models to compare the two groups. RESULTS: We included all 151 randomised patients; the cumulated fluid resuscitation volume in the first 24 h after randomisation was median 500 ml (Interquartile range (IQR) 0-1500) and 1250 ml (500-2500) in the fluid restriction group and standard care group, respectively. The estimated differences in the fluid restriction group vs. the standard care group were 0.1 mM (95% confidence interval -0.7 to 0.9; P = 0.86) for lactate, 0.01 µg/kg/min (-0.02 to 0.05; P = 0.48) for dose of noradrenaline, and -0.1 ml/kg/h (-0.3 to 0.2; P = 0.70) for urinary output during the first 24 h after randomisation. CONCLUSIONS: We observed no indications of worsening of measures of circulatory efficacy in the first 24 h of restriction of resuscitation fluid as compared with standard care in adults with septic shock who had received initial resuscitation.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.

The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis.

Acute respiratory distress syndrome is associated with high mortality and morbidity. Inhaled nitric oxide has been used to improve oxygenation but its role remains controversial. Our primary objective in this systematic review was to examine the effects of inhaled nitric oxide administration on mortality in adults and children with acute respiratory distress syndrome. We included all randomised, controlled trials, irrespective of date of publication, blinding status, outcomes reported or language. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effect of inhaled nitric oxide. There was no statistically significant effect of inhaled nitric oxide on longest follow-up mortality (inhaled nitric oxide group 250/654 deaths (38.2%) vs. control group 221/589 deaths (37.5%; relative risk (95% CI) 1.04 (0.9-1.19)). We found a significant improvement in PaO2 /FI O2 ratio at 24 h (mean difference (95% CI) 15.91 (8.25-23.56)), but not at 48 h or 72 h, while four trials indicated improved oxygenation in the inhaled nitric oxide group at 96 h (mean difference (95% CI) 14.51 (3.64-25.38)). There were no statistically significant differences in ventilator-free days, duration of mechanical ventilation, resolution of multi-organ failure, quality of life, length of stay in intensive care unit or hospital, cost-benefit analysis and methaemoglobin and nitrogen dioxide levels. There was an increased risk of renal impairment (risk ratio (95% CI) 1.59 (1.17-2.16)) with inhaled nitric oxide. In conclusion, there is insufficient evidence to support inhaled nitric oxide in any category of critically ill patients with acute respiratory distress syndrome despite a transient improvement in oxygenation, since mortality is not reduced and it may induce renal impairment.

Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta-analysis and trial sequential analysis.

Coagulopathy and severe bleeding are associated with high mortality. We evaluated haemostatic treatment guided by the functional viscoelastic haemostatic assays, thromboelastography or rotational thromboelastometry in bleeding patients. We searched for randomised, controlled trials irrespective of publication status, publication date, blinding status, outcomes published or language from date of inception to 5 January 2016 in six bibliographic databases. We included 17 trials (1493 participants), most involving cardiac surgery. Thromboelastography or rotational thromboelastometry seemed to reduce overall mortality compared to any of our comparisons (3.9% vs. 7.4%, RR (95% CI) 0.52 (0.28-0.95); I2 = 0%, 8 trials, 717 participants). However, the quality of evidence is graded as low due to the high risk of bias, heterogeneity, imprecision and low event rate. Thromboelastography or rotational thromboelastometry significantly reduced the proportion of patients transfused with red blood cells (RR (95% CI) 0.86 (0.79-0.94); I2 = 0%, 10 trials, 832 participants), fresh frozen plasma (RR (95% CI) 0.57 (0.33-0.96); I2 = 86%, 10 trials, 832 participants) and platelets (RR (95% CI) 0.73 (0.60-0.88); I2 = 0%, 10 studies, 832 participants). There was no difference in proportion needing surgical re-interventions (RR (95% CI) 0.75 (0.50-1.10); I2 = 0%, 9 trials, 887 participants). Trial sequential analysis of mortality suggests that only 54% of the required information size has been reached so far. Transfusion strategies guided by thromboelastography or rotational thromboelastometry may reduce the need for blood products in patients with bleeding, but the results are mainly based on trials of elective cardiac surgery involving cardiopulmonary bypass, with low-quality evidence.

Prediction of difficult mask ventilation using a systematic assessment of risk factors vs. existing practice - a cluster randomised clinical trial in 94,006 patients.

We compared implementation of systematic airway assessment with existing practice of airway assessment on prediction of difficult mask ventilation. Twenty-six departments were cluster-randomised to assess eleven risk factors for difficult airway management (intervention) or to continue with their existing airway assessment (control). In both groups, patients predicted as a difficult mask ventilation and/or difficult intubation were registered in the Danish Anaesthesia Database, with a notational summary of airway management. The trial's primary outcome was the respective incidence of unpredicted difficult and easy mask ventilation in the two groups. Among 94,006 patients undergoing mask ventilation, the incidence of unpredicted difficult mask ventilation in the intervention group was 0.91% and 0.88% in the control group; (OR) 0.98 (95% CI 0.66-1.44), p = 0.90. The incidence of patients predicted difficult to mask ventilate, but in fact found to be easy ('falsely predicted difficult') was 0.64% vs. 0.35% (intervention vs. control); OR 1.56 (1.01-2.42), p = 0.045. In the intervention group, 86.3% of all difficult mask ventilations were not predicted, compared with a higher proportion 91.2% in the control group, OR 0.61 (0.41-0.91), p = 0.016. The systematic intervention did not alter the overall incidence of unpredicted difficult mask ventilations, but of the patients who were found to be difficult to mask ventilate, the proportion predicted was higher in the intervention group than in the control group. However, this was at a 'cost' of increasing the number of mask ventilations falsely predicted to be difficult.