Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Effects of simulated sample sizes on mortality estimates-Protocol for a study in 3 randomised ICU trials.

BACKGROUND: An increasing number of trials are stopped earlier than originally planned. It has been suggested that trials stopped pre-maturely overestimate the treatment effect. With the outlined observational study, we aim to simulate the results of stopping trials before they reach their planned sample size to assess the effects on mortality estimates. METHODS AND STATISTICS: Based on 3 international, randomised clinical trials (RCTs) in critical care: Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, the Transfusion Requirements in Septic Shock (TRISS) trial and the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, we will estimate relative risks with 95% confidence intervals for the primary outcome 90-day mortality after the inclusion of each individual patient in each RCT. This will be presented graphically with the primary outcome as a function of the number of included patients. DISCUSSION: The outlined study will provide important knowledge about the effects of stopping critical care trials early. This may have important implications for patients, relatives, clinicians, researchers, guideline committee members and policy makers. ETHICS AND DISSEMINATION: We will use data from consenting patients enrolled in RCTs approved by the relevant ethical committees; this study requires no further permissions. We will report the results in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and submit the final approved manuscript to a peer-reviewed journal.

Out-of-hours intensive care unit admission and 90-day mortality: a Danish nationwide cohort study.

BACKGROUND: Mortality rates in critically ill adult patients admitted to the intensive care unit (ICU) remains high, and numerous patient- and disease-related adverse prognostic factors have been identified. In recent years, studies in a variety of emergency conditions suggested that outcome is dependent on the time of hospital admission. The importance of out-of-hours admission to the ICU has been sparsely evaluated and with ambiguous findings. We assessed the association between out-of-hours (16:00 to 07:00) and weekend admission to the ICU, respectively, and 90-day mortality in a nationwide cohort. METHODS: We included all Danish adult patients admitted to the ICU between 1 January 2011 and 30 June 2014, with an ICU stay > 24 h. The crude and adjusted association between out-of-hours and weekend admission and 90-day mortality was assessed (odds ratio (ORs) with 95% confidence intervals (CI)). RESULTS: A total of 44,797 patients were included, 53.3% were admitted out-of-hours, and 22.6% during weekends. Median age was 67 years (interquartile range (IQR) 55-76), and median SAPS II was 42 (IQR 30-54). Patients admitted in-hours vs. out-of-hours displayed a 90-day mortality rate of 41.0% vs. 44.2%. The adjusted association (OR with 95% CI) between out-of-hours admission and 90-day mortality was 1.07 (1.02-1.11), and the adjusted association (OR with 95% CI) between weekend admission and 90-day mortality was 1.10 (1.05-1.15). CONCLUSION: This nationwide study suggests that critically ill adult patients admitted to the ICU during weekends and out-of-hours, and with an ICU stay > 24 h are at slightly increased risk of mortality.

Empirical metronidazole for patients with severe bacterial infection: protocol for a systematic review.

INTRODUCTION: Anaerobic bacteria are believed to be common pathogens in severe infections. Yet, they are difficult to culture and consequently often unrecognised in clinical infections. Metronidazole is often used empirically for potential anaerobic infections, as the resistance to metronidazole is low. However, disadvantages of metronidazole use exist, including drug interactions, side effects and economical expenses. Currently, the balance between the benefits and harms of empirical metronidazole for severe bacterial infections is unknown. We aim to assess patient-important benefits and harms of empirical metronidazole vs. placebo or no treatment in adult patients with severe bacterial infection of any origin in a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. METHODS AND ANALYSIS: This protocol provides details on the planned systematic review, which will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome is all-cause mortality. Secondary outcomes include adverse events, secondary infections, use of life support, antibiotic resistance and hospital length of stay. We will conduct conventional meta-analyses, including predefined subgroup- and sensitivity analyses. Additionally, we will assess the risk of random errors by trial sequential analysis. ETHICS AND DISSEMINATION: Ethical approval is not needed, as the outlined review exclusively will include previously published data. We aim to publish in an international, peer-reviewed journal.

Untargeted antifungal therapy in adult patients with complicated intra-abdominal infection: a systematic review.

BACKGROUND: Systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in critically ill patients have provided conflicting results. We aimed to assess patient-important benefits and harms of untargeted antifungal therapy vs. placebo or no treatment in adult patients with complicated intra-abdominal infection. METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing untargeted antifungal therapy compared to placebo or no treatment in adults with complicated intra-abdominal infection. We used the Cochrane and GRADE methodologies and exclusively assessed patient-important outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. We performed conventional meta-analyses, including sensitivity and subgroup analyses, and trial sequential analysis to assess the risk of random errors and to estimate trial sequential analysis adjusted confidence intervals. RESULTS: We included six trials (1,067 patients) in the review, and four trials reported data on the predefined outcome measures and were included in the meta-analysis. Three of the four trials had high risk of bias. We observed no statistically significant difference in mortality (relative risk 0.58, 95% confidence interval 0.24-1.39) or in any of the other patient-important outcomes between untargeted antifungal treatment and placebo or no treatment (low/very low quality of evidence). Trial sequential analysis demonstrated lack of data and high risk of random errors. CONCLUSIONS: The quantity and quality of evidence supporting untargeted antifungal treatment in adult patients with complicated intra-abdominal infection are low to very low with no firm evidence for benefit or harm.

Corticosteroids and risk of gastrointestinal bleeding in critically ill adults: Protocol for a systematic review.

BACKGROUND: Corticosteroids are frequently prescribed to critically ill patients. However, their use may increase the risk of gastrointestinal (GI) bleeding, which is associated with morbidity and mortality. Accordingly, we aim to assess whether continued administration of corticosteroids for >24 hours increases the rate of GI bleeding in adult critically ill patients compared to placebo or no treatment. METHODS/DESIGN: We will conduct a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis. The participants will be adult (as defined in the included trials) critically ill patients. The intervention will be any corticosteroid administered systematically for >24 hours and the comparator will be placebo or no treatment. The primary outcome will be rate of clinically important GI bleeding. We will systematically search EMBASE, MEDLINE, Medline In-Process, Cochrane Library, Epistemonikos and trial registries for relevant literature, as well as perform a hand search. 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 risk of GI bleeding in adult critically ill patients treated with corticosteroids is unknown. Hence, there is need for a robust systematic review to assess this risk and provide clinicians with a clearer understanding of the strength and limitations of existing data.

Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with acute circulatory failure.

BACKGROUND: Adult critically ill patients often suffer from acute circulatory failure and those with low cardiac output may be treated with inotropic agents. The aim of this Scandinavian Society of Anaesthesiology and Intensive Care Medicine guideline was to present patient-important treatment recommendations on this topic. METHODS: This guideline was developed according to GRADE. We assessed the following subpopulations of patients with shock: (1) shock in general, (2) septic shock, (3) cardiogenic shock, (4) hypovolemic shock, (5) shock after cardiac surgery, and (6) other types of shock, including vasodilatory shock. We assessed patient-important outcome measures, including mortality and serious adverse reactions. RESULTS: For all patients, we suggest against the routine use of any inotropic agent, including dobutamine, as compared to placebo/no treatment (very low quality of evidence). For patients with shock in general, and in those with septic and other types of shock, we suggest using dobutamine rather than levosimendan or epinephrine (very low quality of evidence). For patients with cardiogenic shock and in those with shock after cardiac surgery, we suggest using dobutamine rather than milrinone (very low quality of evidence). For the other clinical questions, we refrained from giving any recommendations or suggestions. CONCLUSIONS: We suggest against the routine use of any inotropic agent in adult patients with shock. If used, we suggest using dobutamine rather than other inotropic agents for the majority of patients, however, the quality of evidence was very low, implying high uncertainty on the balance between the benefits and harms of inotropic agents.

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.

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

BACKGROUND: Intensive care unit (ICU) mortality prediction scores deteriorate over time, and their complexity decreases clinical applicability and commonly causes problems with missing data. We aimed to develop and internally validate a new and simple score that predicts 90-day mortality in adults upon acute admission to the ICU: the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU). METHODS: We used data from an international cohort of 2139 patients acutely admitted to the ICU and 1947 ICU patients with severe sepsis/septic shock from 2009 to 2016. We performed multiple imputations for missing data and used binary logistic regression analysis with variable selection by backward elimination, followed by conversion to a simple point-based score. We assessed the apparent performance and validated the score internally using bootstrapping to present optimism-corrected performance estimates. RESULTS: The SMS-ICU comprises seven variables available in 99.5% of the patients: two numeric variables: age and lowest systolic blood pressure, and five dichotomous variables: haematologic malignancy/metastatic cancer, acute surgical admission and use of vasopressors/inotropes, respiratory support and renal replacement therapy. Discrimination (area under the receiver operating characteristic curve) was 0.72 (95% CI: 0.71-0.74), overall performance (Nagelkerke's R2 ) was 0.19 and calibration (intercept and slope) was 0.00 and 0.99, respectively. Optimism-corrected performance was similar to apparent performance. CONCLUSIONS: The SMS-ICU predicted 90-day mortality with reasonable and stable performance. If performance remains adequate after external validation, the SMS-ICU could prove a valuable tool for ICU clinicians and researchers because of its simplicity and expected very low number of missing values.

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.

Therapeutic bronchoscopy vs. standard of care in acute respiratory failure: a systematic review.

BACKGROUND: We aimed to assess patient-important benefits and harms of therapeutic bronchoscopy vs. standard of care (no bronchoscopy) in critically ill patients with acute respiratory failure (ARF). METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) according to the Cochrane Handbook and GRADE methodology, including a predefined protocol (PROSPERO no. CRD42016046235). We included randomized clinical trials (RCTs) comparing therapeutic bronchoscopy to standard of care in critically ill patients with ARF. Two reviewers independently assessed trials for inclusion, extracted data and assessed risk of bias. Risk ratios (RR) with 95% confidence intervals (CI) were estimated by conventional meta-analysis. The risk of random errors was assessed by TSA. Exclusively patient-important outcomes were evaluated. RESULTS: We included five trials (n = 212); all were judged as having high risk of bias. There was no difference in all-cause mortality between therapeutic bronchoscopy and standard of care (TSA adjusted RR 0.39; 95% CI 0.14 to 1.07; I2 0%), and only 3% of the required information size had been accrued. There was no difference in ICU length of stay. A shorter duration of mechanical ventilation was suggested by conventional meta-analysis, however TSA highlighted that only 42% of the required information size had been accrued, indicating high risk of random errors. No trials reported data on adverse events, hospital length of stay, quality of life or performance status. CONCLUSIONS: The quantity and quality of evidence supporting therapeutic bronchoscopy in critically ill patients with ARF is very low with no firm evidence for benefit or harm.

Use of life support in acutely admitted ICU patients. An international cohort study.

BACKGROUND: Use of life support in intensive care unit (ICU) patients has been associated with increased risk of poor outcome. The prognostic importance of the duration of support is less studied. We assessed the use of life support and the association between its duration and 90-day mortality in a contemporary cohort of acutely admitted adult ICU patients. METHODS: We performed a post-hoc analysis of the SUP-ICU 7-day inception cohort study (n = 1034), which was conducted in 97 ICUs in 11 countries. We included patients with an ICU stay of 3 days or more. We assessed the use of life support during the first 3 days in ICU and the crude and adjusted association between its duration and 90-day mortality using logistic regression analyses. RESULTS: We included 690 patients; their 90-day mortality was 23%. During the first 3 days in ICU mechanical ventilation was used in 65%, vasopressors/inotropes in 57% and renal replacement therapy in 13%. Renal replacement therapy for 3 days or more was associated with a higher 90-day mortality as compared with 1 day of renal replacement therapy [odds ratio 6.5 (95% confidence interval 1.3 to 32.8)]. For mechanical ventilation and vasopressors/inotropes the odds ratios were 2.2 [0.9 to 5.3] and 1.2 [0.5 to 2.6], respectively. CONCLUSIONS: Among acutely admitted adult ICU patients, a higher number of days of renal replacement therapy in the initial ICU stay were associated with increased risk of death within 90 days. We did not observe such an association for mechanical ventilation or vasopressor/inotropic therapy.

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.

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.

Risk factors for reintervention after surgery for perforated gastroduodenal ulcer.

BACKGROUND: Perforated gastroduodenal ulcer carries a high mortality rate. Need for reintervention after surgical repair is associated with worse outcome, but knowledge on risk factors for reintervention is limited. The aim was to identify prognostic risk factors for reintervention after perforated gastroduodenal ulcer in a nationwide cohort. METHODS: All patients treated surgically for perforated gastroduodenal ulcer in Denmark between 2003 and 2014 were included using data from the Danish Clinical Register of Emergency Surgery. Potential risk factors for reintervention were assessed, and their crude and adjusted associations calculated by the competing risks subdistribution hazards approach. RESULTS: A total of 4086 patients underwent surgery for perforated gastroduodenal ulcer during the study interval. Median age was 71·1 (i.q.r. 59·6-81·0) years and the overall 90-day mortality rate was 30·8 per cent (1258 of 4086). Independent risk factors for reintervention were: male sex (adjusted hazard ratio (HR) 1·46, 95 per cent c.i. 1·20 to 1·78), in-hospital perforation (adjusted HR 1·36, 1·11 to 1·68), high BMI (adjusted HR 1·49, 1·10 to 2·01), high ASA physical status grade (adjusted HR 1·54, 1·23 to 1·94), shock on admission (adjusted HR 1·40, 1·13 to 1·74), surgical delay (adjusted HR 1·07, 1·02 to 1·14) and other co-morbidity (adjusted HR 1·24, 1·02 to 1·51). Preadmission use of steroids (adjusted HR 0·59, 0·41 to 0·84) and age above 70 years (adjusted HR 0·72, 0·59 to 0·89) were associated with a reduced risk of reoperation. CONCLUSION: Obese men with coexisting diseases and high disease severity who have surgery for gastroduodenal perforation are at increased risk of reoperation.

Scandinavian SSAI clinical practice guideline on choice of first-line vasopressor for patients with acute circulatory failure.

BACKGROUND: Adult critically ill patients often suffer from acute circulatory failure, necessitating use of vasopressor therapy. The aim of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force for Acute Circulatory Failure was to present clinically relevant, evidence-based treatment recommendations on this topic. METHODS: This guideline was developed according to standards for trustworthy guidelines, including a systematic review of the literature and use of the GRADE methodology for assessment of the quality of evidence and for moving from evidence to recommendations. We assessed the following subpopulations of patients with acute circulatory failure: 1) shock in general, 2) septic shock, 3) cardiogenic shock, 4) hypovolemic shock and 5) other types of shock, including vasodilatory shock. We assessed patient-important outcome measures, including mortality, serious adverse reactions and quality-of-life. RESULTS: For patients with shock in general and those with septic shock, we recommend using norepinephrine rather than dopamine, and we suggest using norepinephrine rather than epinephrine, vasopressin analogues, and phenylephrine. For patients with cardiogenic shock and those with hypovolemic shock, we suggest using norepinephrine rather than dopamine, and we provide no recommendations/suggestions of norepinephrine vs. epinephrine, vasopressin analogues, and phenylephrine. For patients with other types of shock, including vasodilatory shock, we suggest using norepinephrine rather than dopamine, epinephrine, vasopressin analogues, and phenylephrine. CONCLUSIONS: We recommend using norepinephrine rather than other vasopressors as first-line treatment for the majority of adult critically ill patients with acute circulatory failure.

Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome.

BACKGROUND: The objective of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force on fluid and drug therapy in adults with acute respiratory distress syndrome (ARDS) was to provide clinically relevant, evidence-based treatment recommendations according to standards for trustworthy guidelines. METHODS: The guideline was developed according to standards for trustworthy guidelines, including a systematic review of the literature and use of the GRADE methodology for assessment of the quality of evidence and for moving from evidence to recommendations. RESULTS: A total of seven ARDS interventions were assessed. We suggest fluid restriction in patients with ARDS (weak recommendation, moderate quality evidence). Also, we suggest early use of neuromuscular blocking agents (NMBAs) in patients with severe ARDS (weak recommendation, moderate quality evidence). We recommend against the routine use of other drugs, including corticosteroids, beta2 agonists, statins, and inhaled nitric oxide (iNO) or prostanoids in adults with ARDS (strong recommendations: low- to high-quality evidence). These recommendations do not preclude the use of any drug or combination of drugs targeting underlying or co-existing disorders. CONCLUSION: This guideline emphasizes the paucity of evidence of benefit - and potential for harm - of common interventions in adults with ARDS and highlights the need for prudence when considering use of non-licensed interventions in this patient population.

Surgical complications after open and laparoscopic surgery for perforated peptic ulcer in a nationwide cohort.

BACKGROUND: Surgery for perforated peptic ulcer (PPU) is associated with a risk of complications. The frequency and severity of reoperative surgery is poorly described. The aims of the present study were to characterize the frequency, procedure-associated risk and mortality associated with reoperation after surgery for PPU. METHODS: All patients treated surgically for PPU in Denmark between 2011 and 2013 were included. Baseline and clinical data, including 90-day mortality and detailed information on reoperative surgery, were collected from the Danish Clinical Register of Emergency Surgery. Distribution frequencies of reoperation stratified by type of surgical approach (laparoscopy or open) were reported. The crude and adjusted risk associations between surgical approach and reoperation were assessed by regression analysis and reported as odds ratio (OR) with 95 per cent c.i. Sensitivity analyses were carried out. RESULTS: A total of 726 patients were included, of whom 238 (32·8 per cent) were treated laparoscopically and 178 (24·5 per cent) had a laparoscopic procedure converted to laparotomy. Overall, 124 (17·1 per cent) of 726 patients underwent reoperation. A persistent leak was the most frequent cause (43 patients, 5·9 per cent), followed by wound dehiscence (34, 4·7 per cent). The crude risk of reoperative surgery was higher in patients who underwent laparotomy and those with procedures converted to open surgery than in patients who had laparoscopic repair: OR 1·98 (95 per cent c.i. 1·19 to 3·27) and 2·36 (1·37 to 4·08) respectively. The difference was confirmed when adjusted for age, surgical delay, co-morbidity and American Society of Anesthesiologists fitness grade. However, the intention-to-treat sensitivity analysis (laparoscopy including conversions) demonstrated no significant difference in risk. The risk of death within 90 days was greater in patients who had reoperation: crude and adjusted OR 1·53 (1·00 to 2·34) and 1·06 (0·65 to 1·72) respectively. CONCLUSION: Reoperation was necessary in almost one in every five patients operated on for PPU. Laparoscopy was associated with lower risk of reoperation than laparotomy or a converted procedure. However, there was a risk of bias, including confounding by indication.

Randomized multicentre feasibility trial of intermediate care versus standard ward care after emergency abdominal surgery (InCare trial).

BACKGROUND: Emergency abdominal surgery carries a considerable risk of death and postoperative complications. Early detection and timely management of complications may reduce mortality. The aim was to evaluate the effect and feasibility of intermediate care compared with standard ward care in patients who had emergency abdominal surgery. METHODS: This was a randomized clinical trial carried out in seven Danish hospitals. Eligible for inclusion were patients with an Acute Physiology And Chronic Health Evaluation (APACHE) II score of at least 10 who were ready to be transferred to the surgical ward within 24 h of emergency abdominal surgery. Participants were randomized to either intermediate care or standard surgical ward care after surgery. The primary outcome was 30-day mortality. RESULTS: In total, 286 patients were included in the modified intention-to-treat analysis. The trial was terminated after the interim analysis owing to slow recruitment and a lower than expected mortality rate. Eleven (7·6 per cent) of 144 patients assigned to intermediate care and 12 (8·5 per cent) of 142 patients assigned to ward care died within 30 days of surgery (odds ratio 0·91, 95 per cent c.i. 0·38 to 2·16; P = 0·828). Thirty (20·8 per cent) of 144 patients assigned to intermediate care and 37 (26·1 per cent) of 142 assigned to ward care died within the total observation period (hazard ratio 0·78, 95 per cent c.i. 0·48 to 1·26; P = 0·310). CONCLUSION: Postoperative intermediate care had no statistically significant effect on 30-day mortality after emergency abdominal surgery, nor any effect on secondary outcomes. The trial was stopped prematurely owing to slow recruitment and a much lower than expected mortality rate among the enrolled patients. REGISTRATION NUMBER: NCT01209663 (http://www.clinicaltrials.gov).

Anaesthesia care with and without tracheal intubation during emergency endoscopy for peptic ulcer bleeding: a population-based cohort study.

BACKGROUND: Emergency upper gastrointestinal bleeding is a common condition with high mortality. Most patients undergo oesophagogastroduodenoscopy (OGD), but no universally agreed approach exists to the type of airway management required during the procedure. We aimed to compare anaesthesia care with tracheal intubation (TI group) and without airway instrumentation (monitored anaesthesia care, MAC group) during emergency OGD. METHODS: This was a prospective, nationwide, population-based cohort study during 2006-13. Emergency OGDs performed under anaesthesia care were included. End points were 90 day mortality (primary) and length of stay in hospital (secondary). Associations between exposure and outcomes were assessed in logistic and linear regression models, adjusted for the following potential confounders: shock at admission, level of anaesthetic expertise present, ASA score, Charlson comorbidity index score, BMI, age, sex, alcohol use, referral origin (home or in-hospital), Forrest classification, ulcer localization, and postoperative care. RESULTS: The study group comprised 3580 patients under anaesthesia care: 2101 (59%) for the TI group and 1479 (41%) for the MAC group. During the first 90 days after OGD, 18.9% in the TI group and 18.4% in the MAC group died, crude odds ratio=1.03 [95% confidence interval (CI)=0.87-1.23, P=0.701], adjusted odds ratio=0.95 (95% CI=0.79-1.15, P=0.590). Patients in the TI group stayed slightly longer in hospital [mean 8.16 (95% CI=7.63-8.60) vs 7.63 days (95%=CI 6.92-8.33), P=0.108 in adjusted analysis]. CONCLUSIONS: In this large population-based cohort study, anaesthesia care with TI was not different from anaesthesia care without airway instrumentation in patients undergoing emergency OGD in terms of 90 day mortality and length of hospital stay.