Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial.

BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.

Tramadol for chronic pain in adults: protocol for a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.

BACKGROUND: Chronic pain in adults is a frequent clinical symptom with a significant impact on patient well-being. Therefore, sufficient pain management is of utmost importance. While tramadol is a commonly used pain medication, the quality of evidence supporting its use has been questioned considering the observed adverse events. Our objective will be to assess the benefits and harms of tramadol compared with placebo or no intervention for chronic pain. METHODS/DESIGN: We will conduct a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis to assess the beneficial and harmful effects of tramadol in any dose, formulation, or duration. We will accept placebo or no intervention as control interventions. We will include adult participants with any type of chronic pain, including cancer-related pain. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and BIOSIS for relevant literature. We will follow the recommendations by Cochrane and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors ('bias') and random errors ('play of chance') will be assessed. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: Although tramadol is often being used to manage chronic pain conditions, the beneficial and harmful effects of this intervention are unknown. The present review will systematically assess the current evidence on the benefits and harms of tramadol versus placebo or no intervention to inform clinical practice and future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019140334.

Ivabradine for coronary artery disease and/or heart failure-a protocol for a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Coronary artery disease and heart failure are both highly prevalent diseases with a global prevalence of 93 million and 40 million. These patients are at increased risk of morbidity and mortality. The management of these patients involves medical therapy, and both diseases can be treated using the heart rate-lowering drug ivabradine. However, the evidence regarding the use of ivabradine in the treatment of coronary artery disease and/or heart failure is unclear. Our objective is to assess the beneficial and harmful effects of ivabradine in the treatment of coronary artery disease and/or heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P), and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ivabradine in the treatment of coronary artery disease and/or heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS in order to identify relevant trials. We will begin the searches in February 2019. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our primary conclusions will be based on the results from the primary outcomes at low risk of bias. Extracted data will be analysed using Review Manager 5.3 and Trial Sequential Analysis 0.9.5.10. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: The systematic review will have the potential to aid clinicians in decision-making regarding ivabradine and to benefit patients with coronary artery disease and/or heart failure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018112082.

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.

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.

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.

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.

Effects of using the simplified airway risk index vs usual airway assessment on unanticipated difficult tracheal intubation - a cluster randomized trial with 64,273 participants.

BACKGROUND: Unanticipated difficult intubation remains a challenge in anaesthesia. The Simplified Airway Risk Index (SARI) is a multivariable risk model consisting of seven independent risk factors for difficult intubation. Our aim was to compare preoperative airway assessment based on the SARI with usual airway assessment. METHODS: From 01.10.2012 to 31.12.2013, 28 departments were cluster-randomized to apply the SARI model or usual airway assessment. The SARI group implemented the SARI model. The Non-SARI group continued usual airway assessment, thus reflecting a group of anaesthetists' heterogeneous individual airway assessments. Preoperative prediction of difficult intubation and actual intubation difficulties were registered in the Danish Anaesthesia Database for both groups. Patients who were preoperatively scheduled for intubation by advanced techniques (e.g. video laryngoscopy; flexible optic scope) were excluded from the primary analysis. Primary outcomes were the proportions of unanticipated difficult and unanticipated easy intubation. RESULTS: A total of 26 departments (15 SARI and 11 Non-SARI) and 64 273 participants were included. In the primary analyses 29 209 SARI and 30 305 Non-SARI participants were included.In SARI departments 2.4% (696) of the participants had an unanticipated difficult intubation vs 2.4% (723) in Non-SARI departments. Odds ratio (OR) adjusted for design variables was 1.03 (95% CI: 0.77-1.38). The proportion of unanticipated easy intubation was 1.42% (415) in SARI departments vs 1.00% (302) in Non-SARI departments. Adjusted OR was 1.26 (0.68-2.34). CONCLUSIONS: Using the SARI compared with usual airway assessment we detected no statistical significant changes in unanticipated difficult- or easy intubations. CLINICAL TRIAL REGISTRATION: NCT01718561.

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).

Effects of cognitive therapy versus interpersonal psychotherapy in patients with major depressive disorder: a systematic review of randomized clinical trials with meta-analyses and trial sequential analyses.

BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetime at tremendous suffering and cost. Cognitive therapy and interpersonal psychotherapy are treatment options, but their effects have only been limitedly compared in systematic reviews. METHOD: Using Cochrane systematic review methodology we compared the benefits and harm of cognitive therapy versus interpersonal psychotherapy for major depressive disorder. Trials were identified by searching the Cochrane Library's CENTRAL, Medline via PubMed, EMBASE, Psychlit, PsycInfo, and Science Citation Index Expanded until February 2010. Continuous outcome measures were assessed by mean difference and dichotomous outcomes by odds ratio. We conducted trial sequential analysis to control for random errors. RESULTS: We included seven trials randomizing 741 participants. All trials had high risk of bias. Meta-analysis of the four trials reporting data at cessation of treatment on the Hamilton Rating Scale for Depression showed no significant difference between the two interventions [mean difference -1.02, 95% confidence interval (CI) -2.35 to 0.32]. Meta-analysis of the five trials reporting data at cessation of treatment on the Beck Depression Inventory showed comparable results (mean difference -1.29, 95% CI -2.73 to 0.14). Trial sequential analysis indicated that more data are needed to definitively settle the question of a differential effect. None of the included trial reported on adverse events. CONCLUSIONS: Randomized trials with low risk of bias and low risk of random errors are needed, although the effects of cognitive therapy and interpersonal psychotherapy do not seem to differ significantly regarding depressive symptoms. Future trials should report on adverse events.