ORCID Profile
0000-0002-6536-0504
Current Organisation
Rigshospitalet
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Publisher: Wiley
Date: 06-09-2022
DOI: 10.1111/AAS.14142
Abstract: Randomised clinical trials in critical care are prone to inconclusiveness owing, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Planned predictive enrichment based on secondary critical care data (often very rich with respect to both data types and temporal granularity) and causal inference methods may help overcome these challenges, but no overview exists about their use to this end. We will conduct a scoping review to assess the extent and nature of the use of causal inference from secondary data for planned predictive enrichment of randomised clinical trials in critical care. We will systematically search 10 general and specialty journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We will collect trial metadata (e.g., recruitment period and phase) and, when available, information pertaining to the focus of the review (predictive enrichment based on causal inference estimates from secondary data): causal inference methods, estimation techniques and software used types of patient populations data provenance, types and models and the availability of the data (public or not). The results will be reported in a descriptive manner. The outlined scoping review aims to assess the use of causal inference methods and secondary data for planned predictive enrichment in randomised critical care trials. This will help guide methodological improvements to increase the utility, and facilitate the use, of causal inference estimates when planning such trials in the future.
Publisher: Wiley
Date: 30-08-2023
DOI: 10.1111/AAS.14321
Abstract: Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real‐world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy‐three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3–3.4) years, and 83% of trials randomised less than 1000 participants. Thirty‐six trials (11%) were restricted to COVID‐19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.
Publisher: Wiley
Date: 23-10-2023
DOI: 10.1111/AAS.14345
Publisher: Springer Science and Business Media LLC
Date: 18-06-2023
Publisher: Wiley
Date: 09-02-2023
DOI: 10.1111/AAS.14205
Abstract: This rapid practice guideline provides evidence‐based recommendations for the use of awake proning in adult patients with acute hypoxemic respiratory failure due to COVID‐19. The panel included 20 experts from 12 countries, including one patient representative, and used a strict conflict of interest policy for potential financial and intellectual conflicts of interest. Methodological support was provided by the guidelines in intensive care, development, and evaluation (GUIDE) group. Based on an updated systematic review, and the grading of recommendations, assessment, development, and evaluation (GRADE) method we evaluated the certainty of evidence and developed recommendations using the Evidence‐to‐Decision framework. We conducted an electronic vote, requiring % agreement amongst the panel for a recommendation to be adopted. The panel made a strong recommendation for a trial of awake proning in adult patients with COVID‐19 related hypoxemic acute respiratory failure who are not invasively ventilated. Awake proning appears to reduce the risk of tracheal intubation, although it may not reduce mortality. The panel judged that most patients would want a trial of awake proning, although this may not be feasible in some patients and some patients may not tolerate it. However, given the high risk of clinical deterioration amongst these patients, awake proning should be conducted in an area where patients can be monitored by staff experienced in rapidly detecting and managing clinical deterioration. This RPG panel recommends a trial of awake prone positioning in patients with acute hypoxemic respiratory failure due to COVID‐19.
Publisher: Wiley
Date: 26-12-2020
DOI: 10.1111/AAS.13519
Abstract: 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. To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2022
Publisher: Wiley
Date: 30-01-2019
DOI: 10.1111/AAS.13326
Abstract: Health-related quality of life is often used as a patient-important outcome in randomized clinical trials in the intensive care unit setting. Missing data are a challenge in randomized clinical trials as they h er the interpretation of the results, but the extent and handling of missing health-related quality of life data are unknown. Therefore, we aim to describe and evaluate the extent, pattern, and handling of missing health-related quality of life data in randomized clinical trials conducted in the intensive care unit setting. We will conduct a systematic review of randomized clinical trials in intensive care patients that report health-related quality of life. We will systematically search the Cochrane Library, PubMed, excerpta medica database ovid, and cumulative index to nursing and allied health literature for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the preferred reporting items for systematic review and meta-analysis statement. We will extract information about missing data, including how the analyses and reporting of missing data were performed. We will assess the risk of systematic errors (bias) and compare the number of nonresponders vs responders in (a) low vs high risk of bias trials and in (b) small (n ≤ 100) vs large randomized clinical trials (n > 100). With this outlined systematic review, we will describe the handling of missing health-related quality of life data in randomized clinical trials in the intensive care unit setting and the impact on the interpretation of results. International Prospective Register of Systematic Reviews (PROSPERO): reg. no.: CRD42019118932.
Publisher: Wiley
Date: 12-08-2021
DOI: 10.1111/AAS.13953
Abstract: Patient and public involvement (PPI) in randomized clinical trials (RCTs) has increased in recent years but remains the exception rather than the rule. We aim to assess the frequency and extent of PPI in large, contemporary RCTs conducted in an intensive care setting. We will conduct a meta‐epidemiological study of RCTs conducted in intensive care settings published since 2019 and assess their use of PPI. We will extract trial characteristics and verify the use of PPI with trial authors unless specifically stated in the published paper. The primary outcome will be the proportion of trials that use PPI. Secondary outcomes will explore which groups are consulted, at which stage of the trial process this occurs, and by what means these opinions are collected and implemented. This meta‐epidemiological study will provide an important insight into the use of PPI in large, contemporary intensive care trials. We wish to reveal ways in which patient involvement could be incorporated more broadly and purposefully here and help to empower clinicians, researchers and patients to collaborate further on future research processes and goals.
Publisher: Wiley
Date: 20-09-2021
DOI: 10.1111/AAS.13941
Abstract: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID‐19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low‐dose hydrocortisone on patient‐centred outcomes in adults with COVID‐19 and severe hypoxia. In this multicentre, parallel‐group, placebo‐controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID‐19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID‐19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P = .79) mortality was 6/16 vs 2/14 and the number of serious adverse reactions 1/16 vs 0/14. In this trial of adults with COVID‐19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned s le size were enrolled. Trial registration : ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020‐001395‐15.
Publisher: Wiley
Date: 24-07-2019
DOI: 10.1111/AAS.13434
Abstract: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.
Publisher: Wiley
Date: 09-03-2021
DOI: 10.1111/AAS.13795
Abstract: 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. 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. 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.
Publisher: Wiley
Date: 30-07-2020
DOI: 10.1111/AAS.13673
Publisher: Wiley
Date: 25-02-2021
DOI: 10.1111/AAS.13793
No related grants have been discovered for Maj-Brit Kjær.