Jesper Kjaergaard

Introduction: Recovery of consciousness after brain injury remains a major challenge in the intensive care unit (ICU), and pharmacological treatments that directly promote awakening from coma and other disorders of consciousness (DoC) are lacking. We hypothesise that simultaneously targeting the two core components of consciousness by pharmacological means—arousal with apomorphine and awareness with psilocybin—is safe in the ICU and may facilitate evidence of cerebral reserves after brain injury. Methods and analysis: This trial aims to evaluate the safety and potential efficacy of apomorphine and psilocybin in unresponsive ICU patients with brain injury. We will conduct a prospective, open-label, bicentric, phase 1b, dose-escalation study enrolling 80 ICU patients with DoC. Participants will be allocated to three dose-escalation cohorts. Cohort 1 (n=26) will receive 1 mg psilocybin, Cohort 2 (n=27) 10 mg psilocybin and Cohort 3 (n=27) 25 mg psilocybin. One hour after psilocybin, all patients will receive 2 mg subcutaneous apomorphine. Primary outcome is time to awakening within 30 days. Secondary outcomes are serious somatic and neuropsychiatric adverse events. Exploratory outcomes comprise changes in consciousness assessed by clinical scales, automated pupillometry, electroencephalography activity and functional outcome at 90 days. An independent Data Safety Monitoring Board will conduct interim analyses prior to dose escalations. Ethics and dissemination: The trial was authorised by the Danish Medical Research Ethics Committees and the Danish Medicines Agency through the Clinical Trials Information System (EU CT number 2023–503617-30-02). The study is considered to involve relatively low risk with the potential to improve future treatment options for DoC patients. If psilocybin and apomorphine are shown to be safe, this would justify a larger multicentre randomised trial to evaluate clinical efficacy. Findings will be disseminated through peer-reviewed journals and scientific conferences. Trial registration number: 2023–503617-30-02.

Background: Long forms of cardiac troponin T (cTnT) are promising markers that may differentiate myocardial infarction from other causes of acute and chronic myocardial injury. However, to understand the clinical utility of long cTnT, knowledge of the half-life (T½) is key. By using auto-transfusion in humans we determined the T½ of long forms of cTnT and compared long cTnT to a commercial high-sensitivity total cTnT assay. Methods: Patients with ST-segment-elevation-myocardial infarction were included within 24 h after revascularization and underwent plasmapheresis to obtain plasma with a high cTnT concentration. After at least 3 weeks, patients returned for an autologous plasma re-transfusion followed by repeated blood sampling. A novel assay measured long cTnT and a commercially available assay measured total cTnT. Results: We included 17 patients with median age 63 years (25th–75th percentiles 59–70), and 4 (24%) were female. The median concentrations after transfusion were 99 ng/L (54–125) for long cTnT vs 252 ng/L (233–322) for total cTnT. The median ratio of long cTnT to total cTnT was 0.39 (0.26–0.55) after transfusion and declined to 0.30 (0.20–0.44) after 60 min. Long cTnT displayed a 2-phase exponential decay, similar to what was observed for total cTnT but with shorter T½ both for the distribution phase [16 min (11–18) vs 22 min (20–24), P < 0.001] and the elimination phase [103 min (78–125) vs 133 min (114–168), P < 0.001]. Conclusion: The elimination of long forms of cTnT was faster than for total cTnT following re-transfusion. This understanding could aid in differentiating myocardial infarction from other causes of acute and chronic myocardial injury.

Background: Intermediate‐high risk pulmonary embolism ( PE ) represents a clinically challenging subgroup of acute PE , characterized by right ventricular dysfunction and increased risk of hemodynamic deterioration despite treatment with anticoagulation therapy. Although systemic thrombolysis may provide more rapid reperfusion, its use is limited by an increased risk of major bleeding. Catheter‐based treatment strategies have emerged as potential alternatives, but their comparative efficacy and safety remain uncertain. Objective: To assess the benefits and harms of catheter‐based treatment strategies compared with contemporary control regimens, including standard anticoagulation with or without systemic thrombolysis, in patients with intermediate‐high risk PE . Methods: This protocol outlines a systematic review with Bayesian pairwise meta‐analysis and network meta‐analysis of randomized clinical trials evaluating catheter‐based therapies for hospitalized patients with intermediate‐high risk PE . Eligible interventions include catheter‐directed thrombolysis, ultrasound‐assisted thrombolysis, and catheter‐based embolectomy. Comparators may include standard anticoagulation alone or in combination with systemic thrombolysis or other active control regimens reflecting standard of care. Searches will be conducted in relevant databases, supplemented by trial registries. Two reviewers will independently screen studies, extract data, and assess risk of bias using the Cochrane Risk of Bias 2 tool. Bayesian pairwise meta‐analyses and network meta‐analysis will be performed using weakly informative priors to synthesize direct and indirect evidence across interventions. Results will be reported as posterior effect estimates with 95% credible intervals. The primary outcome will be all‐cause mortality. Secondary and exploratory outcomes include major bleeding as defined according to the criteria of the International Society on Thrombosis and Haemostasis within 7 days, hospital length of stay, and change in RV/LV ratio within 48 h. GRADE assessments will be performed where applicable. Discussion: This review will synthesize direct and indirect randomized evidence on catheter‐based treatment strategies for intermediate‐high risk PE . The findings may help clarify the role of these interventions in contemporary management, inform future guideline recommendations, and identify persistent evidence gaps requiring further large‐scale randomized trials.

Background: Intensive care following resuscitation from out‐of‐hospital cardiac arrest (OHCA) is based on a set of interventions, all of which are intended to reduce anoxic brain injury and improve outcomes, including sedation, mechanical ventilation, circulatory optimization, and temperature control protocols. The backrest position impacts intracranial pressure and cerebral blood flow in traumatic brain injury, and the optimal position for improving outcomes after OHCA is unknown; guidelines advocate for an elevated backrest position. This trial compared outcomes of two backrest positions. Methods: The Danish Out‐of‐Hospital Cardiac Arrest (DANOHCA) trial is an investigator‐initiated, multicenter, randomized, controlled trial evaluating four interventions, including two different backrest positions, for improving outcomes. Comatose adult patients with OHCA of presumed cardiac cause and sustained return of spontaneous circulation will be included. Patients were randomized 1:1 to a backrest positioned at 5° or 35° straight elevation of backrest in the Semi‐Fowler's position (elevated lower limb position) during the initial 72 h or until extubation. The primary outcome was mortality within 90 days of cardiac arrest. Inclusion began in June 2023, and the study aims to include 1000 patients from five sites over an estimated time period of 3–4 years. Kaplan–Meier curves with Cox regression will be used for statistical analyses. The trial is registered at clinicaltrials.gov (identifier: NCT05895838) and euclinicaltrials.eu (2024‐515997‐28‐00). Perspectives: Post‐resuscitation care of comatose cardiac arrest is complex, and each part should be tested in randomized trials. This part of the DANOHCA trial will provide evidence on one of these factors, namely position of the patients' head relative to the heart. Trial Registration: EudraCT number 2016‐003265‐26; EU CTIS no 2024‐515997‐28‐00; ClinicalTrials.gov identifier: NCT05895838.

Background: The inflammatory response to whole‐body ischemia, as seen in comatose survivors after out‐of‐hospital cardiac arrest (OHCA), is associated with increased morbidity and mortality. Early high‐dose dexamethasone may dampen the inflammatory response, which may diminish secondary brain damage and other organ injury and decrease mortality. The aim is to evaluate the effect of high‐dose dexamethasone in post‐resuscitation care. Methods: The Danish Out‐of‐Hospital Cardiac Arrest (DANOHCA) trial is an investigator‐initiated, multicenter, randomized, controlled trial evaluating four post‐resuscitation interventions in adult patients resuscitated after OHCA including blinded early administration of high‐dose dexamethasone compared with placebo (isotonic saline). Adult OHCA patients with presumed cardiac etiology and sustained return of spontaneous circulation will be randomized 1:1 to receive 20 mg of dexamethasone or placebo immediately after inclusion in the trial and repeated the following two mornings for a total of three doses. The primary outcome is all‐cause mortality within 90 days using a log‐binomial regression analysis to estimate the relative risk of death from any cause between randomization and Day 90. Enrollment began in June 2023, with the aim to include 1000 patients at five sites in 3–4 years. The trial is registered at clinicaltrials.gov (identifier: NCT05895838) and euclinicaltrials.eu (2024‐515997‐28‐00). Perspectives: It is of paramount importance to optimize post‐resuscitation care through large‐scale randomized trials. Global ischemia–reperfusion–induced inflammatory response with resulting organ failures represents a possible target for interventions after OHCA. This part of the DANOHCA trial will provide new evidence on the impact of high‐dose dexamethasone in survivors of OHCA. Trial Registration: Clinical Trials Information System (CTIS): 2024‐515997‐28‐00

Background: Delirium is a frequent complication in comatose Out‐of‐Hospital Cardiac Arrest (OHCA) survivors requiring postresuscitation intensive care and is associated with higher mortality and longer hospitalization. Despite this, there is no established pharmacologic strategy for delirium prevention in OHCA survivors. This trial aims to evaluate if prophylactic use of olanzapine in comatose OHCA patients can reduce delirium incidence, thereby leading to a shorter duration of hospitalization. Methods: The Danish Out‐of‐Hospital Cardiac Arrest (DANOCHA) trial is an investigator‐initiated, multicenter, randomized, controlled trial evaluating four postresuscitation interventions in adult patients resuscitated after OHCA including administration of prophylactic olanzapine compared with placebo. Comatose adult patients with OHCA of presumed cardiac cause and sustained return of spontaneous circulation (> 20 min) will be randomized 1:1 to receive either 10 mg of olanzapine or placebo immediately after inclusion in the trial and the two following evenings for a total of three doses. The primary outcome is days alive and out of the hospital within 30 days after admission. Analysis of primary outcome will be analyzed using the Wilcoxon rank‐sum test. Results will be presented as medians with interquartile ranges and 95% confidence intervals for the median difference. Inclusion began in June 2023, and the study aims to include 1000 patients from five sites over an estimated time period of 3–4 years. The trial is registered at clinicaltrials.gov (identifier: NCT05895838) and euclinicaltrials.eu (2024‐515997‐28‐00). Perspectives: Optimizing postresuscitation care through large‐scale randomized trials is essential for improving outcomes of OHCA survivors. The findings from this part of the DANOHCA trial will provide evidence regarding the effects of prophylactic olanzapine in comatose OHCA survivors. Trial Registration: EudraCT no 2016‐003265‐26; EU CTIS no 2024‐515997‐28‐00; ClinicalTrials.gov identifier NCT05895838

Background: Post‐cardiac arrest care for patients resuscitated from out‐of‐hospital cardiac arrest (OHCA) includes multiple pharmacological and physiological interventions, yet optimal strategies to reduce post‐cardiac arrest syndrome–related morbidity and mortality remain uncertain. The DANOHCA (Danish Out‐of‐Hospital Cardiac Arrest) trial evaluates four such interventions—high‐dose dexamethasone, prophylactic olanzapine, elevated backrest position, and early wakeup—in a factorial trial framework. This manuscript presents the complete statistical analysis plan for analyses common to all four DANOHCA interventions. Methods: DANOHCA is an investigator‐initiated, multicenter, randomized, 2 × 2 × 2 × 2 factorial clinical trial enrolling comatose adult OHCA patients with a presumed cardiac etiology who achieve sustained return of spontaneous circulation, with randomization within 180 min of return of spontaneous circulation. Participants are co‐randomized to Dexamethasone versus placebo, olanzapine versus placebo, backrest elevation at 35° versus 5°, and early (≤ 6 h) versus late (28–36 h) wakeup, with pharmacological interventions blinded and physiological interventions open‐label. This statistical analysis plan specifies the primary and secondary outcomes, covariate adjustment, handling of missing data, assessments of interactions between interventions, and assumption checks, with all primary analyses conducted according to the intention‐to‐treat principle. The analysis plan is finalized prior to completion of randomization. Results: The primary outcomes are 90‐day all‐cause mortality for the dexamethasone and backrest interventions, and days alive outside hospital within 30 days for the olanzapine and early wakeup interventions, with common secondary and tertiary endpoints including mortality at later time points, neurological function, health‐related quality of life, organ function, and safety outcomes. Mixed‐effects regression models, Cox regression, stratified nonparametric tests, and prespecified sensitivity analyses will be applied to minimize bias and quantify intervention effects, including their associated uncertainties. Conclusion: This predefined statistical analysis plan provides a detailed, transparent framework for the primary analyses and reporting of the DANOHCA trial. Trial Registration: Clinical Trials Information System (CTIS): 2024‐515997‐28‐00

Background: Survivors of out‐of‐hospital cardiac arrest (OHCA) who remain comatose after return of spontaneous circulation are routinely sedated and mechanically ventilated during early post‐resuscitation care. Although prolonged sedation has traditionally been considered necessary, contemporary normothermia‐based temperature control allows earlier wake‐up call. The optimal timing of an early wake‐up call remains unknown and may influence overall mortality, neurological recovery, duration of mechanical ventilation, and length of hospital stay. Methods: The Danish Out‐of‐Hospital Cardiac Arrest (DANOHCA) trial (clinicaltrials.gov identifier: NCT05895838; and euclinicaltrials.eu, identifier: 2024–515,997–28‐00) is an investigator‐initiated, multicenter, randomized clinical trial using a 2 × 2 × 2 × 2 factorial design evaluating four interventions in patients resuscitated from OHCA. The present protocol describes the comparison of an early versus late wake‐up call strategy. Adult patients (≥ 18 years) with presumed cardiac‐cause of OHCA, sustained return of spontaneous circulation, and persistent unconsciousness on intensive care unit admission are randomized 1:1 to early wake‐up call (≤ 6 h after randomization) or late wake‐up call (28–36 h after randomization). Wake‐up call includes interruption of sedation, assessment of neurology, and may be followed by extubation if predefined neurological and respiratory criteria are fulfilled. The primary endpoint is days alive and out of hospital within 30 days after randomization. Analyses will follow a modified intention‐to‐treat principle. Perspectives: Optimizing post‐resuscitation care remains a cornerstone in managing comatose cardiac arrest survivors and improving outcomes. We hypothesize that sedation for 28–36 h leads to more days alive outside of the hospital in 30 days compared to sedation for ≤ 6 h. Trial Registration: EudraCT number: 2016‐003265‐26; EU CTIS no 2024‐515997‐28‐00; ClinicalTrials.gov identifier: NCT05895838.