ORCID Profile
0000-0003-4544-0619
Current Organisations
IT University of Copenhagen
,
Zealand University Hospital
,
Region Zealand
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-07-2022
DOI: 10.1097/CCM.0000000000005637
Abstract: Randomized clinical trials (RCTs) conducted in adult ICU patients increasingly include patient-important outcomes other than mortality. This comes with challenges regarding outcome choices/definitions, handling of deceased patients and missing data in analyses, and choices of effect measures and statistical methods due to complex distributions. This scoping review aimed to characterize how these challenges are handled in relevant contemporary RCTs. We systematically searched 10 selected journals for RCTs conducted primarily in adult ICU patients published between 1 January 2018 and 5 May 2022 reporting at least one patient-important outcome other than mortality, including “days alive without”…-type outcomes, functional/cognitive/neurologic outcomes, health-related quality of life (HRQoL) outcomes, and ordinal/other outcomes. Abstracts and full-texts were assessed independently and in duplicate by two reviewers. Data were extracted independently and in duplicate by two reviewers using predefined and pilot-tested extraction forms and subsequently categorized to facilitate analysis. We included 687 outcomes from 167 RCTs, with 32% of RCTs using a patient-important outcome other than mortality as a (co-)primary outcome, most frequently “days alive without”…-type outcomes. Many different functional/cognitive/neurologic (103) and HRQoL (29) outcomes were reported. Handling of deceased patients varied, with analyses frequently restricted to survivors only for functional/cognitive/neurologic (62%) and HRQoL (89%) outcomes. Follow-up was generally longer and missing data proportions higher for functional/cognitive/neurologic and HRQoL outcomes. Most outcomes were analyzed using nonparametric tests (31%), linear regression/ t tests (27%), chi-square–like tests (12%), and proportional odds logistic regression (9%), often without presentation of actual treatment effects estimates (38%). In this s le of RCTs, substantial variation in practice and suboptimal methodological choices were observed. This calls for increased focus on standardizing outcome choices and definitions, adequate handling of missing data and deceased patients in analyses, and use of statistical methods quantifying effect sizes.
Publisher: Wiley
Date: 16-08-2020
DOI: 10.1111/AAS.13679
Publisher: Wiley
Date: 23-11-2019
DOI: 10.1111/AAS.13501
Abstract: 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. 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. 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 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.
Publisher: Massachusetts Medical Society
Date: 29-12-2022
Publisher: Wiley
Date: 14-05-2018
Abstract: The hydrogen evolution reaction (HER) is a fundamental process in electrocatalysis and plays an important role in energy conversion for the development of hydrogen-based energy sources. However, the considerably slow rate of the HER in alkaline conditions has hindered advances in water splitting techniques for high-purity hydrogen production. Differing from well documented acidic HER, the mechanistic aspects of alkaline HER are yet to be settled. A critical appraisal of alkaline HER electrocatalysis is presented, with a special emphasis on the connection between fundamental surface electrochemistry on single-crystal models and the derived molecular design principle for real-world electrocatalysts. By presenting some typical ex les across theoretical calculations, surface characterization, and electrochemical experiments, we try to address some key ongoing debates to deliver a better understanding of alkaline HER at the atomic level.
Publisher: Wiley
Date: 15-08-2019
DOI: 10.1111/AAS.13453
Abstract: Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU-acquired delirium. AID-ICU is an investigator-initiated, pragmatic, international, randomised, blinded, parallel-group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol lacebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post-randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation mortality, health-related quality-of-life and cognitive function at 1-year follow-up. A s le size of 1000 patients is required to detect a 7-day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%. The AID-ICU trial is based on gold standard methodology applied to a large s le of clinically representative patients and will provide pivotal high-quality data on the benefits and harms of haloperidol for the treatment ICU-acquired delirium.
Publisher: Wiley
Date: 31-05-2022
DOI: 10.1111/AAS.14091
Abstract: Delirium is highly prevalent in the intensive care unit (ICU) and is associated with high morbidity and mortality. The antipsychotic haloperidol is the most frequently used agent to treat delirium although this is not supported by solid evidence. The agents intervening against delirium in the intensive care unit (AID‐ICU) trial investigates the effects of haloperidol versus placebo for the treatment of delirium in adult ICU patients. This protocol describes the secondary, pre‐planned Bayesian analyses of the primary and secondary outcomes up to day 90 of the AID‐ICU trial. We will use Bayesian linear regression models for all count outcomes and Bayesian logistic regression models for all dichotomous outcomes. We will adjust for stratification variables (site and delirium subtype) and use weakly informative priors supplemented with sensitivity analyses using sceptical priors. We will present results as absolute differences (mean differences and risk differences) and relative differences (ratios of means and relative risks). Posteriors will be summarised using median values as point estimates and percentile‐based 95% credibility intervals. Probabilities of any benefit/harm, clinically important benefit/harm and clinically unimportant differences will be presented for all outcomes. The results of this secondary, pre‐planned Bayesian analysis will complement the primary frequentist analysis of the AID‐ICU trial and facilitate a nuanced and probabilistic interpretation of the trial results.
Publisher: Wiley
Date: 13-07-2022
DOI: 10.1111/AAS.14108
Abstract: ICU admission due to COVID‐19 may result in cognitive and physical impairment. We investigated the long‐term cognitive and physical status of Danish ICU patients with COVID‐19. We included all patients with COVID‐19 admitted to Danish ICUs between March 10 and May 19, 2020. Patients were the contacted prospectively at 6 and 12 months for follow‐up. Our primary outcomes were cognitive function and frailty at 6 and 12 months after ICU admission, estimated by the Mini Montreal Cognitive Assessment, and the Clinical Frailty Scale. Secondary outcomes were 6‐ and 12‐month mortality, health‐related quality of life (HRQoL) assessed by EQ‐5D‐5L, functional status (Barthel activities of daily living and Lawton–Brody instrumental activities of daily living), and fatigue (Fatigue Assessment Scale). The study had no information on pre‐ICU admission status for the participants. A total of 326 patients were included. The 6‐ and 12‐month mortality was 37% and 38%, respectively. Among the 204 six‐month survivors, 105 (51%) participated in the 6‐month follow‐up among the 202 twelve‐month survivors, 95 (47%) participated in the 12‐month follow‐up. At 6 months, cognitive scores indicated impairment for 26% (95% confidence interval [CI], 11.4–12.4) and at 12 months for 17% (95% CI, 12.0–12.8) of participants. Frailty was indicated in 20% (95% CI, 3.4–3.9) at 6 months, and for 18% (95% CI, 3.3–3.8) at 12 months. Fatigue was reported by 52% at 6 months, and by 47% at 12 months. For HRQoL, moderate, severe, or extreme health problems were reported by 28% at 6 months, and by 25% at 12 months. Long‐term cognitive, functional impairment was found in up to one in four of patients surviving intensive care for COVID‐19. Fatigue was present in nearly half the survivors at both 6 and 12 months. However, pre‐ICU admission status of the patients was unknown.
Publisher: Wiley
Date: 13-07-2020
DOI: 10.1111/AAS.13661
Publisher: Wiley
Date: 14-02-2018
DOI: 10.1111/AAS.13088
Abstract: 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. 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. 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. 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.
Publisher: SAGE Publications
Date: 2023
DOI: 10.1177/11786329231166519
Abstract: When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials (2) conducting randomised clinical trials and (3) analysing randomised clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2023
DOI: 10.1186/S13054-023-04621-4
Abstract: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. We included 11 RCTs with 15 comparisons ( n = 2200) five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89 96.7% CI 0.77 to 1.03 I 2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94 96.7% CI 0.81 to 1.10 I 2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration : CRD42017081133, date of registration 28 November 2017.
No related grants have been discovered for Ole Mathiesen.