Publications by authors named "Jørn Wetterslev"

258 Publications

Letter the editor: serious methodological concerns about a recently published meta-analysis on oxygen therapy.

J Intensive Care 2021 Dec 7;9(1):72. Epub 2021 Dec 7.

Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.

In a recent paper, Chen et al. report the findings of a systematic review with meta-analysis concerning conservative versus conventional oxygen therapy for critically ill patients. We wish to commend the authors for their interest in the matter. However, the authors appear to misquote findings, fail to report results for all specified analyses, do not identify all relevant trials, have post hoc changed the eligibility criteria, and have seemingly switched directions of effects in analyses of secondary outcomes. These issues have led to incorrect conclusions concerning the effects of targeted oxygen therapy in critically ill patients.
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http://dx.doi.org/10.1186/s40560-021-00573-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649324PMC
December 2021

Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.

Acta Anaesthesiol Scand 2022 01 20;66(1):76-84. Epub 2021 Sep 20.

Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.

Background: Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage.

Methods: In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO ) of 8 kPa (lower oxygenation group) or a PaO of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients.

Results: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant.

Conclusions: Targeting a PaO of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial.

Trial Registration Number: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.
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http://dx.doi.org/10.1111/aas.13977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653379PMC
January 2022

Participants with mild, moderate, or severe pain following total hip arthroplasty. A sub-study of the PANSAID trial on paracetamol and ibuprofen for postoperative pain treatment.

Scand J Pain 2021 04 6;21(2):384-392. Epub 2021 Jan 6.

Department of Anaesthesiology, Centre for Anaesthesiological Research, Zealand University Hospital, Køge, Denmark.

Objectives: In this sub-study of the 'Paracetamol and Ibuprofen in Combination' (PANSAID) trial, in which participants were randomised to one of four different non-opioids analgesic regimen consisting of paracetamol, ibuprofen, or a combination of the two after planned primary total hip arthroplasty, our aims were to investigate the distribution of participants' pain (mild, moderate or severe), integrate opioid use and pain to a single score (Silverman Integrated Approach (SIA)-score), and identify preoperative risk factors for severe pain.

Methods: We calculated the proportions of participants with mild (VAS 0-30 mm), moderate (VAS 31-60 mm) or severe (VAS 61-100 mm) pain and the SIA-scores (a sum of rank-based percentage differences from the mean rank in pain scores and opioid use, ranging from -200 to 200%). Using logistic regression with backwards elimination, we investigated the association between severe pain and easily obtainable preoperative patient characteristics.

Results: Among 556 participants from the modified intention-to-treat population, 33% (95% CI: 26-42) (Group Paracetamol + Ibuprofen (PCM + IBU)), 28% (95% CI: 21-37) (Group Paracetamol (PCM)), 23% (95% CI: 17-31) (Group Ibuprofen (IBU)), and 19% (95% CI: 13-27) (Group Half Strength-Paracetamol + Ibuprofen (HS-PCM + IBU)) experienced mild pain 6 h postoperatively during mobilisation. Median SIA-scores during mobilisation were: Group PCM + IBU: -48% (IQR: -112 to 31), Group PCM: 40% (IQR: -31 to 97), Group IBU: -5% (IQR: -57 to 67), and Group HS-PCM + IBU: 6% (IQR: -70 to 74) (overall difference: p=0.0001). Use of analgesics before surgery was the only covariate associated with severe pain (non-opioid: OR 0.50, 95% CI: 0.29-0.82, weak opioid 0.56, 95% CI: 0.28-1.16, reference no analgesics before surgery, p=0.02).

Conclusions: Only one third of participants using paracetamol and ibuprofen experienced mild pain after total hip arthroplasty and even fewer experienced mild pain using each drug alone as basic non-opioid analgesic treatment. We were not able, in any clinically relevant way, to predict severe postoperative pain. A more extensive postoperative pain regimen than paracetamol, ibuprofen and opioids may be needed for a large proportion of patients having total hip arthroplasty. SIA-scores integrate pain scores and opioid use for the individual patient and may add valuable information in acute pain research.
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http://dx.doi.org/10.1515/sjpain-2020-0141DOI Listing
April 2021

Higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit.

Emergencias 2021 08;33(4):309-311

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Dinamarca. Centre for Research in Intensive Care, Department 7831, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Dinamarca.

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August 2021

Carotid endarterectomy with patch angioplasty versus primary closure in patients with symptomatic and significant stenosis: a systematic review with meta-analyses and trial sequential analysis of randomized clinical trials.

Syst Rev 2021 05 6;10(1):139. Epub 2021 May 6.

Department of Vascular Surgery, ZGT, Hospital Group Twente, Almelo/Hengelo, the Netherlands.

Background: Patch angioplasty in conventional carotid endarterectomy is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke compared with primary closure. A systematic review of randomized clinical trials is needed to compare outcomes (benefits and harms) of both techniques.

Methods: Searches (CENTRAL, PubMed/MEDLINE, EMBASE, and other databases) were last updated 3rd of January 2021. We included randomized clinical trials comparing carotid endarterectomy with patch angioplasty versus primary closure of the arterial wall in patients with a symptomatic and significant (> 50%) carotid stenosis. Primary outcomes are defined as all-cause mortality and serious adverse events.

Results: We included 12 randomized clinical trials including 2187 participants who underwent 2335 operations for carotid stenosis comparing carotid endarterectomy with patch closure (1280 operations) versus carotid endarterectomy with primary closure (1055 operations). Meta-analysis comparing carotid endarterectomy with patch angioplasty versus carotid endarterectomy with primary closure may potentially decrease the number of patients with all-cause mortality (RR 0.53; 95% CI 0.26 to 1.08; p = 0.08, best-case scenario for patch), serious adverse events (RR 0.73; 95% CI 0.56 to 0.96; p = 0.02, best-case scenario for patch), and the number of restenosis (RR 0.41; 95% CI 0.23 to 0.71; p < 0.01). Trial sequential analysis demonstrated that the required information sizes were far from being reached for these patient-important outcomes. All the patient-relevant outcomes were at low certainty of evidence according to The Grading of Recommendations Assessment, Development, and Evaluation.

Conclusions: This systematic review showed no conclusive evidence of a difference between carotid endarterectomy with patch angioplasty versus primary closure of the arterial wall on all-cause mortality, < 30 days mortality, < 30 days stroke, or any other serious adverse events. These conclusions are based on data from 15 to 35 years ago, obtained in trials with very low certainty according to GRADE, and should be interpreted cautiously. Therefore, we suggest conducting new randomized clinical trials patch angioplasty versus primary closure in carotid endarterectomy in symptomatic patients with an internal carotid artery stenosis of 50% or more. Such trials ought to be designed according to the Standard Protocol Items: Recommendations for Interventional Trials statement (Chan et al., Ann Intern Med 1:200-7, 2013) and reported according to the Consolidated Standards of Reporting Trials statement (Schulz et al., 7, 2010). Until conclusive evidence is obtained, the standard of care according to guidelines should not be abandoned.

Systematic Review Registration: PROSPERO CRD42014013416 . Review protocol publication 2019 DOI: https://doi.org/10.1136/bmjopen-2018-026419 .
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http://dx.doi.org/10.1186/s13643-021-01692-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103619PMC
May 2021

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

J Clin Epidemiol 2021 07 6;135:29-41. Epub 2021 Feb 6.

Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Capital Region of Denmark, Denmark.

Objective: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions.

Study Design And Setting: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups.

Results: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters.

Conclusion: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.
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http://dx.doi.org/10.1016/j.jclinepi.2021.01.023DOI Listing
July 2021

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

N Engl J Med 2021 04 20;384(14):1301-1311. Epub 2021 Jan 20.

From the Department of Anesthesia and Intensive Care, Aalborg University Hospital, Aalborg University, Aalborg (O.L.S., T.L.K., S.A.R., J.B., A.E.S.E., A.-S.H.L., R.L.P., E.C., T.C.G., M.T.B., B.S.R.), Zealand University Hospital, Køge (L.M.P., S.E., J.P.L., C.A., C.B.M.), Rigshospitalet (A.P., B.A.B., J. Wetterslev, I.-L.J., M.H.M., L.Q., M.-B.N.K.) and the Section of Biostatistics, Department of Public Health (T.L.), University of Copenhagen, Bispebjerg, and Frederiksberg Hospital (C.S.M., M. Hjort, L.K.B.) and the Copenhagen Trial Unit (J. White, J.E.), Copenhagen, Nordsjaellands Hospital, Hillerod (M.H.B., M.S.-L., M.K.K., M. Hindborg), Randers Hospital, Randers (T.G., H.B.), Aarhus University Hospital, Skejby North, Aarhus (L.H.M.Ø., M.A.T.), Zealand University Hospital, Roskilde (T.H., B.U.), Viborg Hospital, Viborg (C.G.S., N.M.-N.), Kolding Hospital, Kolding (A.C.B., M. Bäcklund), Hvidovre Hospital, Hvidovre (U.G.P.), Herlev Hospital, Herlev (A.S.A.), Horsens Hospital, Horsens (L.B.), Herning Hospital, Herning (R.R.W.), Holbæk Hospital, Holbæk (S.B.T.), and Slagelse Hospital, Slagelse (S.A.I.) - all in Denmark; the Department of Intensive Care and Department of Clinical Research, University of Basel, Basel (M.S., A.H., C.E.G., N.Z.), and the Department of Intensive Care, Inselspital, University of Bern, Bern (J.C.S.) - both in Switzerland; the Department of Perioperative, Intensive Care and Pain Medicine, Helsinki University Hospital, Helsinki (M.B., M.O.); the Department of Critical Care, University Medical Center Groningen, Groningen, the Netherlands (F.K., W.D.); the Departments of Anesthesia and Intensive Care and of Clinical Research, Rikshospitalet, Oslo University Hospital, Oslo (J.H.L., T.N.A.); the Department of Intensive Care, Cardiff University Hospital of Wales, Cardiff, United Kingdom (M.M.); and the Department of Anesthesia and Intensive Care, Landspitali University Hospital, Reykjavik, Iceland (K.M.T.).

Background: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao) would result in lower mortality than using a higher target.

Methods: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days.

Results: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24).

Conclusions: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).
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http://dx.doi.org/10.1056/NEJMoa2032510DOI Listing
April 2021

Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus in adult patients with aneurysmal subarachnoid haemorrhage: a systematic review.

BMJ Open 2020 11 26;10(11):e040722. Epub 2020 Nov 26.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.

Objectives: To summarise the evidence on benefits and harms of prompt closure versus gradual weaning of external ventricular drainage (EVD) in patients with hydrocephalus following aneurysmal subarachnoid haemorrhage (aSAH) based on randomised clinical trials (RCTs) in humans.

Setting: RCTs comparing prompt closure versus gradual weaning of EVD in adult patients with hydrocephalus following aSAH were included.

Participants: Patients aged equal to or greater than 18 years with an EVD due to hydrocephalus following aSAH were eligible for inclusion.

Primary And Secondary Outcome Measures: Primary outcomes were all-cause mortality, any serious adverse event, rate of ventriculoperitoneal (VP) shunt placement and quality of life. Secondary outcomes were patients with shunt failure, hospital and neuro intensive care unit (NICU) length of stay (LOS) and complications related to treatment with an EVD. Data permitted report of rate of VP shunt placement, and hospital and NICU LOS.

Results: Six studies were assessed in full text. One RCT with 81 patients was included. Rate of VP shunt placement was 63.4% in the rapid weaning group (ie, prompt closure of the EVD; 41 patients) and 62.5% in the gradual weaning group (40 patients; p=0.932). LOS in hospital and NICU was significantly shorter in the rapidly weaned group compared with the gradually weaned group (mean 19.1 vs 21.5 days in hospital (p=0.03); and mean 14.1 vs 16.9 days in NICU (p=0.0002)). Data were insufficient to conduct meta-analysis, trial sequential analysis or subgroup analysis of heterogeneity and sensitivity. One RCT is currently ongoing.

Conclusions: We found insufficient evidence to favour any of the two strategies for EVD discontinuation in patients with hydrocephalus following aSAH.

Prospero Registration Number: CRD42018108801.
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http://dx.doi.org/10.1136/bmjopen-2020-040722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692827PMC
November 2020

Effect of low vs high haemoglobin transfusion trigger on cardiac output in patients undergoing elective vascular surgery: Post-hoc analysis of a randomized trial.

Acta Anaesthesiol Scand 2021 03 7;65(3):302-312. Epub 2020 Dec 7.

Department of Anaesthesia, Zealand University Hospital Roskilde, Roskilde, Denmark.

Background: During vascular surgery, restricted red-cell transfusion reduces frontal lobe oxygen (ScO ) saturation as determined by near-infrared spectroscopy. We evaluated whether inadequate increase in cardiac output (CO) following haemodilution explains reduction in ScO .

Methods: This is a post-hoc analysis of data from the Transfusion in Vascular surgery (TV) Trial where patients were randomized on haemoglobin drop below 9.7 g/dL to red-cell transfusion at haemoglobin below 8.0 (low-trigger) vs 9.7 g/dL (high-trigger). Fluid administration was guided by optimizing stroke volume. We compared mean intraoperative levels of CO, haemoglobin, oxygen delivery, and CO at nadir ScO with linear regression adjusted for age, operation type and baseline. Data for 46 patients randomized before end of surgery were included for analysis.

Results: The low-trigger resulted in a 7.1% lower mean intraoperative haemoglobin level (mean difference, -0.74 g/dL; P < .001) and reduced volume of red-cell transfused (median [inter-quartile range], 0 [0-300] vs 450 mL [300-675]; P < .001) compared with the high-trigger group. Mean CO during surgery was numerically 7.3% higher in the low-trigger compared with the high-trigger group (mean difference, 0.36 L/min; 95% confidence interval (CI.95), -0.05 to 0.78; P = .092; n = 42). At the nadir ScO -level, CO was 11.9% higher in the low-trigger group (mean difference, 0.58 L/min; CI.95, 0.10-1.07; P = .024). No difference in oxygen delivery was detected between trial groups (MD, 1.39 dL /min; CI.95, -6.16 to 8.93; P = .721).

Conclusion: Vascular surgical patients exposed to restrictive RBC transfusion elicit the expected increase in CO making it unlikely that their potentially limited cardiac capacity explains the associated ScO decrease.
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http://dx.doi.org/10.1111/aas.13733DOI Listing
March 2021

Risk factors for long-term cognitive impairment in ICU survivors: A multicenter, prospective cohort study.

Acta Anaesthesiol Scand 2021 01 12;65(1):92-99. Epub 2020 Sep 12.

Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Denmark.

Purpose: To describe the incidence of and risk factors for impaired cognitive function in intensive care unit (ICU) survivors. We hypothesized that age, severity of illness, and days in coma, delirium, mechanical ventilation in the ICU would be associated with impaired cognitive function.

Methods: We included all adults, alive 6 months after acute admission to one of the 24 Danish ICUs participating in the AID-ICU cohort study. Trained professionals assessed cognitive function in patients' homes or in outpatient clinics using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 6 months after ICU admission. Potential risk factors for cognitive impairment were analyzed with linear regression models.

Results: In total, 237 ICU patients were alive 6 months after ICU admission and did not meet the exclusion criteria. A total of 106 patients completed the cognitive assessment. The median RBANS global cognitive score was 76 (interquartile range, 62-91), and 52% had a global cognitive score 1.5 SD below the normative mean and 36% displayed a global cognitive score 2 SD below the normative mean, similar to that of Alzheimer's disease. Higher age was associated with poorer RBANS global cognitive score (estimate -0.35 [95% confidence interval -0.63 to -0.07] per year).

Conclusions: In this multicenter study of adult ICU survivors, cognitive impairment was frequent and severe in those assessed at 6 months. Higher age was a risk factor for cognitive impairment, but events related to the ICU stay were not associated with poorer cognitive performance at 6 months.
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http://dx.doi.org/10.1111/aas.13692DOI Listing
January 2021

Arterial oxygen tensions in mechanically ventilated ICU patients and mortality: a retrospective, multicentre, observational cohort study.

Br J Anaesth 2020 04 7;124(4):420-429. Epub 2020 Feb 7.

Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Centre for Research in Intensive Care, Copenhagen, Denmark.

Background: Supplemental oxygen therapy is commonly required for respiratory failure requiring mechanical ventilation in the ICU. However, hyperoxaemia may be injurious and may increase mortality. We evaluated the relationship amongst the degree of hyperoxaemia and changes in fraction of inspired oxygen (Fio) in response to hyperoxaemia, as well as associations with mortality in mechanically ventilated ICU patients.

Methods: We retrospectively identified all invasively mechanically ventilated patients admitted to five ICUs, and retrieved all oxygen tension (Pao) and Fio data. We assessed the time between arterial blood gas (ABG) samples, proportions of patients with hyperoxaemia, and changes in Fio when hyperoxaemia was present. The primary outcome was the association between Pao (assessed by mechanically ventilated exposure-time-divided area under the curve [AUC]) and mortality (in-ICU and post-ICU discharge) using a multistate illness-death model with transition intensities estimated by Cox proportional hazards models.

Results: We assessed 177 769 ABG analyses obtained from 4998 patients between January 2012 and June 2016. The median time between ABGs was 3 h (inter-quartile range: 2-4 h); the median Pao was 11.3 kPa (9.8-13.6 kPa), and Fio was 0.40 (0.35-0.50). Hyperoxaemia (Pao >13.7 kPa) was present in 23.9% of the ABGs, and hyperoxaemia seemed to be disregarded when Fio was <0.40, as >50% of these Fio values were not subsequently reduced. AUC Pao >16.0 kPa was associated with increased ICU mortality (adjusted hazard ratio: 1.75; 95% confidence interval: 1.28-2.40).

Conclusions: In mechanically ventilated ICU patients, hyperoxaemia was common. Although oxygen supplementation was often reduced when hyperoxaemia was observed, several patients remained hyperoxaemic. Hyperoxaemia was associated with increased ICU mortality in these patients.
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http://dx.doi.org/10.1016/j.bja.2019.12.039DOI Listing
April 2020

Higher vs Lower Oxygenation Strategies in Acutely Ill Adults: A Systematic Review With Meta-Analysis and Trial Sequential Analysis.

Chest 2021 01 17;159(1):154-173. Epub 2020 Jul 17.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, University of Copenhagen, Denmark; Centre for Research in Intensive Care, Rigshospitalet, University of Copenhagen, Denmark.

Background: Liberal oxygen supplementation is often used in acute illness but has, in some studies, been associated with harm.

Research Question: The goal of this study was to assess the benefits and harms of higher vs lower oxygenation strategies in acutely ill adults.

Study Design And Methods: This study was an updated systematic review with meta-analysis and Trial Sequential Analysis (TSA) of randomized clinical trials. A clear differentiation (separation) was made between a higher (liberal) oxygenation and a lower (conservative) oxygenation strategy and their effects on all-cause mortality, serious adverse events, quality of life, lung injury, sepsis, and cardiovascular events at time points closest to 90 days in acutely ill adults.

Results: The study included 50 randomized clinical trials of 21,014 participants; 36 trials with a total of 20,166 participants contributed data to the analyses. Meta-analysis and TSAs showed no difference between higher and lower oxygenation strategies in trials at overall low risk of bias except for blinding: mortality relative risk (RR), 0.98 (95% CI, 0.89-1.09; TSA-adjusted CI, 0.86-1.12; low certainty evidence); serious adverse events RR, 0.99 (95% CI, 0.89-1.12; TSA-adjusted CI, 0.83-1.19; low certainty evidence). The corresponding summary estimates including trials with overall low and high risk of bias showed similar results. No difference was found between higher and lower oxygenation strategies in meta-analyses and TSAs regarding quality of life, lung injury, sepsis, and cardiovascular events (very low certainty evidence).

Interpretation: No evidence was found of beneficial or harmful effects of higher vs lower oxygenation strategies in acutely ill adults (low to very low certainty evidence).

Clinical Trial Registration: PROSPERO; No.: CRD42017058011; URL: https://www.crd.york.ac.uk/prospero/.
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http://dx.doi.org/10.1016/j.chest.2020.07.015DOI Listing
January 2021

Response.

Chest 2020 07 2;158(1):428. Epub 2020 Jul 2.

Centre for Research in Intensive Care (CRIC), Copenhagen, Denmark; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.chest.2020.02.031DOI Listing
July 2020

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.

Acta Anaesthesiol Scand 2020 10 13;64(9):1357-1364. Epub 2020 Jul 13.

Centre for Research in Intensive Care (CRIC), Copenhagen, Denmark.

Background: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial.

Methods: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables.

Conclusion: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.
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http://dx.doi.org/10.1111/aas.13661DOI Listing
October 2020

Long-term mortality in the Intermediate care after emergency abdominal surgery (InCare) trial-A post-hoc follow-up study.

Acta Anaesthesiol Scand 2020 09 29;64(8):1100-1105. Epub 2020 May 29.

Herlev Anaesthesia Critical and Emergency Care Science Unit (ACES), Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.

Background: Patients undergoing emergency abdominal surgery are at high risk of post-operative complications. Although post-operative treatment at an intermediate care unit may improve early outcome, there is a lack of studies on the long-term effects of such therapy. The aim of this study was to assess the long-term effect of intermediate care versus standard surgical ward care on mortality in the Intermediate Care After Emergency Abdominal Surgery (InCare) trial.

Methods: We included adult patients undergoing emergency major laparoscopy or laparotomy with an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 10 or more, who participated in the InCare trial from October 2010 to November 2012. In the InCare trial, patients were randomized to either post-operative intermediate care or standard surgical ward care. The primary outcome was time to death within 6 years after surgery. We assessed mortality with Coxregression analysis.

Results: A total of 286 patients were included. The all-cause 6-year landmark mortality was 52.8% (76 of 144 patients) in the intermediate care group and 47.9% (68 of 142 patients) in the ward care group. There was no statistically significant difference in mortality risk between the two groups (hazard ratio 1.06 (95% confidence interval 0.76-1.47), P = .73).

Conclusion: We found no statistically significant difference in 6-year mortality between patients randomized to post-operative intermediate care or ward care after emergency abdominal surgery. However, we detected an absolute mortality risk reduction of 5% in favour of ward care, possibly due to random error.
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http://dx.doi.org/10.1111/aas.13613DOI Listing
September 2020

Eversion technique versus conventional endarterectomy with patch angioplasty in carotid surgery: protocol for a systematic review with meta-analyses and trial sequential analysis of randomised clinical trials.

BMJ Open 2020 04 19;10(4):e030503. Epub 2020 Apr 19.

Department of Vascular Surgery, Ikazia Hospital, Rotterdam, The Netherlands.

Introduction: Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of patch angioplasty to restore the arterial wall after longitudinal endarterectomy is, to date, not unequivocally proven to be superior to eversion technique. A systematic review is needed for evaluation of benefits and harms of the eversion technique versus the traditional endarterectomy with patch angioplasty in patients with symptomatic carotid stenosis.

Methods And Outcomes: The review will be conducted according to this protocol following the recommendations of the 'Cochrane Handbook for Systematic Reviews' and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Randomised clinical trials comparing eversion technique versus endarterectomy with patch angioplasty in patients with a symptomatic stenosis of the internal carotid artery will be included. Primary outcomes are all-cause mortality rate, health-related quality of life and serious adverse events. Secondary outcomes are 30-day stroke and mortality rate, symptomatic arterial restenosis or occlusion and non-serious adverse events. The databases Cochrane Central Register of Controlled Trials, PubMed/MEDLINE and EMBASE will be searched (November 2019). We will primarily base our conclusions on meta-analyses of trials with overall low-risk of bias. We will use trial sequential analysis to assist the evaluation of imprecision in Grading of Recommendations, Assessment, Development and Evaluation. However, if pooled point estimates of all trials are similar to pooled point estimates of trials with overall low risk of bias and there is lack of a statistical significant interaction between estimates from trials with overall high risk of bias and trials with overall low risk of bias we will consider the trial sequential analysis adjusted precision of the estimate achieved in all trials as the result of our meta-analyses.

Ethics And Dissemination: The proposed systematic review will collect and analyse data from published studies, therefore, ethical approval is not required. The results of the review will be disseminated by publication in a peer-review journal and submitted for presentation at conferences.

Prospero Registration Number: CRD42019119361.
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http://dx.doi.org/10.1136/bmjopen-2019-030503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245381PMC
April 2020

The PANSAID randomized clinical trial: A pre-planned 1-year follow-up regarding harm.

Acta Anaesthesiol Scand 2020 08 23;64(7):910-912. Epub 2020 Apr 23.

Centre for Anaesthesiological Research, Department of Anaesthesiology, Zealand University Hospital, Køge, Denmark.

Background: Limiting harm from postoperative pain treatment is important. However, long-term follow-up from acute pain trials are rare. The aim of the study was to provide long-term follow-up data regarding harm from the "Paracetamol and Ibuprofen in Combination" (PANSAID) trial.

Methods: In this preplanned long-term follow-up study from the PANSAID trial, we used data from Danish national health registries (the Danish National Patient Registry and the Danish Civil Registration System) in addition to the 90-day follow-up in the original trial. The primary outcome was 1-year proportion of patients with one or more serious adverse events.

Results: One-year follow-up was complete for 551 patients (99%). We found three additional patients with one or more serious adverse events in the 1-year follow-up compared with the 90-day follow-up. The relative risk of having one or more serious adverse event when randomized to ibuprofen compared with paracetamol was 1.40 (95% CI: 0.84-2.33, P = .20).

Conclusion: We found no statistically significant difference in 1-year serious adverse events between patients randomized to ibuprofen compared with paracetamol in patients having planned primary total hip arthroplasty. There were few additional events from the 90-day follow-up to the 1-year follow-up.
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http://dx.doi.org/10.1111/aas.13597DOI Listing
August 2020

The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: Detailed statistical analysis plan.

Acta Anaesthesiol Scand 2020 07 4;64(6):847-856. Epub 2020 Mar 4.

Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.

Background: No solid evidence exists on optimal oxygenation targets in intensive care patients. The handling oxygenation targets in the intensive care unit (HOT-ICU) trial assesses the effects of a targeted arterial oxygen tension of 8 vs 12 kPa on 90-day mortality in acutely admitted adult patients with hypoxaemic respiratory failure. This article describes the detailed statistical analysis plan for the predefined outcomes and supplementary analyses in the HOT-ICU trial.

Methods: The trial will include 2928 patients to be able to detect or reject a true 20% relative risk reduction in the primary outcome of 90-day all-cause mortality with an α of 5% and a β of 10%. Analyses of the primary and secondary outcomes will be conducted according to the intention-to-treat principle and adjusted for stratification variables. The primary outcome and dichotomous secondary outcomes will be analysed using a generalised linear model with a log-link and binomial error distribution. For the primary outcome, a 95% confidence interval (CI) not including 1.00 for the risk ratio will be considered statistically significant. Continuous secondary outcomes will be analysed using a generalised linear model or nonparametric test. CIs adjusted for the multiple secondary outcomes not including the null effect will be considered statistically significant. One planned interim analysis has been conducted.

Conclusions: The HOT-ICU trial and the pre-planned statistical analyses are designed to minimise bias and produce high quality data on the effects of a lower vs a higher oxygenation target throughout ICU admission in acutely admitted adult patients with hypoxaemic respiratory failure.

Registration: ClinicalTrials.gov identifier: NCT03174002, date of registration: June 2, 2017. European clinical trials database, EudraCT number 2017-000632-34.
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http://dx.doi.org/10.1111/aas.13569DOI Listing
July 2020

Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta-analysis and trial sequential analysis.

Acta Anaesthesiol Scand 2020 07 5;64(6):714-728. Epub 2020 Mar 5.

Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Acutely ill patients are at risk of stress-related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients.

Methods: We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). The primary outcomes were all-cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials.

Results: We included 65 comparisons from 62 trials (n = 9713); 43 comparisons were from intensive care units. Only three trials (n = 3596) had overall low risk of bias. We did not find an effect on all-cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA-adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA-adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health-related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses.

Conclusions: We did not observe a difference in all-cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive.

Study Registration: PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.
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http://dx.doi.org/10.1111/aas.13568DOI Listing
July 2020

Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how.

BMJ Evid Based Med 2021 Jun 27;26(3):121-126. Epub 2020 Jan 27.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.
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http://dx.doi.org/10.1136/bmjebm-2019-111268DOI Listing
June 2021

Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis.

Chest 2020 06 23;157(6):1478-1496. Epub 2020 Jan 23.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Collaboration for Research in Intensive Care, Copenhagen, Denmark.

Objective: IV fluids are recommended during the initial management of sepsis, but the quality of evidence is low, and clinical equipoise exists. We aimed to assess patient-important benefits and harms of lower vs higher fluid volumes in adult patients with sepsis.

Methods: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized clinical trials of IV fluid volume separation in adult patients with sepsis. We adhered to our published protocol; the Cochrane handbook; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and the Grading of Recommendations Assessment, Development and Evaluation statements. The primary outcomes were all-cause mortality, serious adverse events (SAEs), and quality of life.

Results: We included nine trials (n = 637); all were published after 2015 and had an overall high risk of bias. We found no statistically significant difference between lower vs higher fluid volumes in all-cause mortality (relative risk [RR], 0.87; 95% CI, 0.69-1.10; I = 0%; TSA-adjusted CI, 0.34-2.22) or SAEs (RR, 0.91; 95% CI, 0.78-1.05; I = 0%; TSA-adjusted CI, 0.68-1.21). No trials reported on quality of life. We did not find differences in the secondary or exploratory outcomes. The quality of evidence was very low across all outcomes.

Conclusions: In this systematic review, we found very low quantity and quality of evidence supporting the decision on the volumes of IV fluid therapy in adults with sepsis.

Trial Registry: ClinicalTrials.gov; No.: NCT03668236; URL: www.clinicaltrials.gov.
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June 2020

Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial.

Intensive Care Med 2020 04 14;46(4):717-726. Epub 2020 Jan 14.

Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present.

Methods: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots.

Results: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63).

Conclusions: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS.

Gov Identifier: NCT02467621.
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http://dx.doi.org/10.1007/s00134-019-05903-8DOI Listing
April 2020

Hyperoxia and antioxidants during major non-cardiac surgery and risk of cardiovascular events: Protocol for a 2 × 2 factorial randomised clinical trial.

Acta Anaesthesiol Scand 2020 03 26;64(3):400-409. Epub 2019 Dec 26.

Department of Anaesthesia and Intensive Care, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Myocardial injury after non-cardiac surgery occurs in a high number of patients, resulting in increased mortality in the post-operative period. The use of high inspiratory oxygen concentrations may cause hyperoxia, which is associated with impairment of coronary blood flow. Furthermore, the surgical stress response increases reactive oxygen species, which is involved in several perioperative complications including myocardial injury and death. Avoidance of hyperoxia and substitution of reactive oxygen species scavengers may be beneficial. Our primary objective is to examine the effect of oxygen and added antioxidants for prevention of myocardial injury assessed by area under the curve for troponin measurements during the first three post-operative days.

Methods: The VIXIE trial (VitamIn and oXygen Interventions and cardiovascular Events) is an investigator-initiated, blinded, 2 × 2 factorial multicentre clinical trial. We include 600 patients with cardiovascular risk factors undergoing major non-cardiac surgery. Participants are randomised to an inspiratory oxygen fraction of 0.80 or 0.30 during and for 2 hours after surgery and either an intravenous bolus of vitamin C and an infusion of N-acetylcysteine or matching placebo of both. The primary outcome is the area under the curve for high-sensitive cardiac troponin release during the first three post-operative days as a marker of the extent of myocardial injury. Secondary outcomes are mortality, non-fatal myocardial infarction and non-fatal serious adverse events within 30 days.

Perspective: The current trial will provide further evidence for clinicians on optimal administration of perioperative oxygen in surgical patients with cardiovascular risks and the clinical effects of two common antioxidants.
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http://dx.doi.org/10.1111/aas.13518DOI Listing
March 2020

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

Acta Anaesthesiol Scand 2020 03 26;64(3):410-416. Epub 2019 Dec 26.

Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes.

Aim: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial.

Methods: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function.

Discussion: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.
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http://dx.doi.org/10.1111/aas.13519DOI Listing
March 2020

DEBATE-statistical analysis plans for observational studies.

BMC Med Res Methodol 2019 12 9;19(1):233. Epub 2019 Dec 9.

Department of Intensive Care, University of Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands.

Background: All clinical research benefits from transparency and validity. Transparency and validity of studies may increase by prospective registration of protocols and by publication of statistical analysis plans (SAPs) before data have been accessed to discern data-driven analyses from pre-planned analyses.

Main Message: Like clinical trials, recommendations for SAPs for observational studies increase the transparency and validity of findings. We appraised the applicability of recently developed guidelines for the content of SAPs for clinical trials to SAPs for observational studies. Of the 32 items recommended for a SAP for a clinical trial, 30 items (94%) were identically applicable to a SAP for our observational study. Power estimations and adjustments for multiplicity are equally important in observational studies and clinical trials as both types of studies usually address multiple hypotheses. Only two clinical trial items (6%) regarding issues of randomisation and definition of adherence to the intervention did not seem applicable to observational studies. We suggest to include one new item specifically applicable to observational studies to be addressed in a SAP, describing how adjustment for possible confounders will be handled in the analyses.

Conclusion: With only few amendments, the guidelines for SAP of a clinical trial can be applied to a SAP for an observational study. We suggest SAPs should be equally required for observational studies and clinical trials to increase their transparency and validity.
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http://dx.doi.org/10.1186/s12874-019-0879-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902479PMC
December 2019

Higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit.

Cochrane Database Syst Rev 2019 11 27;2019(11). Epub 2019 Nov 27.

Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Blegdamsvej 9, Copenhagen, Denmark, DK-2100.

Background: The mainstay treatment for hypoxaemia is oxygen therapy, which is given to the vast majority of adults admitted to the intensive care unit (ICU). The practice of oxygen administration has been liberal, which may result in hyperoxaemia. Some studies have indicated an association between hyperoxaemia and mortality, whilst other studies have not. The ideal target for supplemental oxygen for adults admitted to the ICU is uncertain. Despite a lack of robust evidence of effectiveness, oxygen administration is widely recommended in international clinical practice guidelines. The potential benefit of supplemental oxygen must be weighed against the potentially harmful effects of hyperoxaemia.

Objectives: To assess the benefits and harms of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU.

Search Methods: We identified trials through electronic searches of CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, BIOSIS Previews, CINAHL, and LILACS. We searched for ongoing or unpublished trials in clinical trials registers. We also scanned the reference lists of included studies. We ran the searches in December 2018.

Selection Criteria: We included randomized controlled trials (RCTs) that compared higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU. We included trials irrespective of publication type, publication status, and language. We included trials with a difference between the intervention and control groups of a minimum 1 kPa in partial pressure of arterial oxygen (PaO), minimum 10% in fraction of inspired oxygen (FiO), or minimum 2% in arterial oxygen saturation of haemoglobin/non-invasive peripheral oxygen saturation (SaO/SpO). We excluded trials randomizing participants to hypoxaemia (FiO below 0.21, SaO/SpO below 80%, and PaO below 6 kPa) and to hyperbaric oxygen.

Data Collection And Analysis: Three review authors independently, and in pairs, screened the references retrieved in the literature searches and extracted data. Our primary outcomes were all-cause mortality, the proportion of participants with one or more serious adverse events, and quality of life. None of the trials reported the proportion of participants with one or more serious adverse events according to the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) criteria. Nonetheless, most trials reported several serious adverse events. We therefore included an analysis of the effect of higher versus lower fraction of inspired oxygen, or targets using the highest reported proportion of participants with a serious adverse event in each trial. Our secondary outcomes were lung injury, acute myocardial infarction, stroke, and sepsis. None of the trials reported on lung injury as a composite outcome, however some trials reported on acute respiratory distress syndrome (ARDS) and pneumonia. We included an analysis of the effect of higher versus lower fraction of inspired oxygen or targets using the highest reported proportion of participants with ARDS or pneumonia in each trial. To assess the risk of systematic errors, we evaluated the risk of bias of the included trials. We used GRADE to assess the overall certainty of the evidence.

Main Results: We included 10 RCTs (1458 participants), seven of which reported relevant outcomes for this review (1285 participants). All included trials had an overall high risk of bias, whilst two trials had a low risk of bias for all domains except blinding of participants and personnel. Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding mortality at the time point closest to three months (risk ratio (RR) 1.18, 95% confidence interval (CI) 1.01 to 1.37; I = 0%; 4 trials; 1135 participants; very low-certainty evidence). Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding serious adverse events at the time point closest to three months (estimated highest proportion of specific serious adverse events in each trial RR 1.13, 95% CI 1.04 to 1.23; I = 0%; 1234 participants; 6 trials; very low-certainty evidence). These findings should be interpreted with caution given that they are based on very low-certainty evidence. None of the included trials reported any data on quality of life at any time point. Meta-analysis indicated no evidence of a difference between higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation on lung injury at the time point closest to three months (estimated highest reported proportion of lung injury RR 1.03, 95% CI 0.78 to 1.36; I = 0%; 1167 participants; 5 trials; very low-certainty evidence). None of the included trials reported any data on acute myocardial infarction or stroke, and only one trial reported data on the effects on sepsis.

Authors' Conclusions: We are very uncertain about the effects of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU on all-cause mortality, serious adverse events, and lung injuries at the time point closest to three months due to very low-certainty evidence. Our results indicate that oxygen supplementation with higher versus lower fractions or oxygenation targets may increase mortality. None of the trials reported the proportion of participants with one or more serious adverse events according to the ICH-GCP criteria, however we found that the trials reported an increase in the number of serious adverse events with higher fractions or oxygenation targets. The effects on quality of life, acute myocardial infarction, stroke, and sepsis are unknown due to insufficient data.
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http://dx.doi.org/10.1002/14651858.CD012631.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880382PMC
November 2019

Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis.

J Clin Med 2019 Nov 21;8(12). Epub 2019 Nov 21.

Department of Critical Care, University Medical Center Groningen, Groningen 9713 GZ, The Netherlands.

International guidelines recommend low-molecular-weight heparin (LMWH) as first-line pharmacological option for the prevention of venous thromboembolism (VTE) in many patient categories. Guidance on the optimal prophylactic dose is lacking. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials to assess benefits and harms of low-dose LMWH versus placebo or no treatment for thrombosis prophylaxis in patients at risk of VTE. PubMed, Cochrane Library, Web of Science, and Embase were searched up to June 2019. Results were presented as relative risk (RR) with conventional and TSA-adjusted confidence intervals (CI). Forty-four trials with a total of 22,579 participants were included. Six (14%) had overall low risk of bias. Low-dose LMWH was not statistically significantly associated with all-cause mortality (RR 0.99; 95%CI 0.85-1.14; TSA-adjusted CI 0.89-1.16) but did reduce symptomatic VTE (RR 0.62; 95%CI 0.48-0.81; TSA-adjusted CI 0.44-0.89) and any VTE (RR 0.61; 95%CI 0.50-0.75; TSA-adjusted CI 0.49-0.82). Analyses on major bleeding (RR 1.07; 95%CI 0.72-1.59), as well as serious adverse events (SAE) and clinically relevant non-major bleeding were inconclusive. There was very low to moderate-quality evidence that low-dose LMWH for thrombosis prophylaxis did not decrease all-cause mortality but reduced the incidence of symptomatic and asymptomatic VTE, while the analysis of the effects on bleeding and adverse events remained inconclusive.
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http://dx.doi.org/10.3390/jcm8122039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947554PMC
November 2019

Haloperidol for the treatment of delirium in critically ill patients: A systematic review with meta-analysis and Trial Sequential Analysis.

Acta Anaesthesiol Scand 2020 02 23;64(2):254-266. Epub 2019 Nov 23.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark.

Background: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium.

Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomized clinical trials (RCTs) assessing the effects of haloperidol vs any intervention on all-cause mortality, serious adverse reactions/events, days alive without delirium, health-related quality of life (HRQoL), cognitive function and delirium severity in critically ill patients with delirium. We also report on QTc prolongation, delirium resolution and extrapyramidal symptoms.

Results: We included 8 RCTs with 11 comparisons (n = 951). We adjudicated one trial as having overall low risk of bias. Three trials used rescue haloperidol; excluding these, we did not find an effect of haloperidol vs control on all-cause mortality (RR 1.01; 95% CI 0.33-3.06; I  = 0%; 112 participants; 3 trials; 4 comparisons; very low certainty) or delirium severity (SMD -0.15; 95% CI -0.61-0.30; I  = 27%; 134 participants; 3 trials; 4 comparisons; very low certainty). No trials reported adequately on serious adverse reactions/events. Only one trial reported on days alive without delirium, cognitive function and QTc prolongation, and no trials reported on HRQoL. Sensitivity analyses, including trials using rescue haloperidol, did not change the results.

Conclusions: The evidence for the use of haloperidol to treat critically ill patients with delirium is sparse, of low quality and inconclusive. We therefore have no certainty regarding any beneficial, harmful or neutral effects of haloperidol in these patients.
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http://dx.doi.org/10.1111/aas.13501DOI Listing
February 2020

Considerations on the strengths and limitations of using disease-related mortality as an outcome in clinical research.

BMJ Evid Based Med 2021 Jun 25;26(3):127-130. Epub 2019 Oct 25.

Copenhagen Trial Unit, Centre for Clinical Intervention Research,Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Disease-related mortality (eg, cardiovascular mortality or breast-cancer mortality) is often used as an outcome in randomised clinical trials and systematic reviews. The rationale why disease-related mortality might be used in addition to, or instead of, all-cause mortality seems to be that disease-related mortality may more readily detect the experimental intervention effects. Disease-related mortality is theoretically what most interventions aim at influencing; disease-related intervention effects are not 'diluted' by events unrelated to the disease that may be occurring in both the experimental group and the control group (eg, traffic accidents). Intervention-effect estimates are indeed theoretically diluted and affected if events unrelated to the disease or the trial interventions are occurring. Although sounding attractive, we will in the present paper consider the several methodological limitations of using disease-related mortality instead of all-cause mortality as an outcome. When mortality is a relevant outcome, we recommend using all-cause mortality as a primary outcome and disease-specific mortality as a secondary or exploratory outcome depending on power.
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http://dx.doi.org/10.1136/bmjebm-2018-111154DOI Listing
June 2021
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