Sebastian Wiberg

Background: Intensive care unit (ICU) delirium is a multifactorial acute brain dysfunction associated with prolonged hospitalization, increased morbidity and mortality, and higher healthcare costs. Despite these substantial negative impacts of delirium, the optimal prevention and treatment strategies are unclear. Olanzapine, an atypical antipsychotic drug, is commonly used for delirium management. We will perform an updated systematic review and meta‐analysis to assess the benefits and harms of olanzapine for the prevention and treatment of ICU delirium. Methods: This protocol is developed in accordance with the recommendations of The Cochrane Collaboration and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis Protocols (PRISMA‐P) guidelines. We will include all randomized clinical trials (RCTs) evaluating prophylactic or therapeutic olanzapine versus any comparator, including pharmacological, non‐pharmacological, placebo, or routine care/no specific delirium‐directed intervention (treated as a single comparator) in ICU patients. Observational studies will be included solely to address potential harms. We will systematically search the following databases: Embase, MEDLINE, The Cochrane Library, Web of Science, CINAHL, Scopus, and PsycINFO, as well as clinical trial registries. We will perform meta‐analysis and trial sequential analysis (TSA) to investigate the risk of both Type I and II errors. We will assess the risk of bias using the Cochrane Risk of Bias tool (RoB‐2). The quality of trials will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The review is registered in the PROSPERO database (CRD420261474813). Outcomes: The primary outcome is days alive and out of the hospital. The secondary outcomes include all‐cause mortality at 90 days, number of CAM‐ICU (Confusion Assessment Method for the Intensive Care Unit) negative days at 30 days, number of days without pharmacological treatment for delirium other than study drug during the intervention period and serious intervention‐related harms. Discussion: This protocol outlines the methodology we will use in a systematic review with meta‐analysis designed to evaluate the beneficial and harmful effects of olanzapine for prevention and treatment of delirium in ICU patients. The findings of the systematic review will be disseminated through peer‐reviewed publication. We hope this review will inform future RCTs and improve clinical practice.

Introduction: Myocardial injury is a significant contributor to 30‐day mortality after cardiac surgery with cardiopulmonary bypass. We aimed to investigate the association between mean arterial pressure, norepinephrine use during the aorta cross‐clamp period, and aorta cross‐clamp duration with myocardial injury during cardiopulmonary bypass‐assisted open‐heart surgery. Method: We identified all adults (≥ 18 years) undergoing coronary artery bypass grafting on cardiopulmonary bypass at Rigshospitalet, Copenhagen, between January 1st 2018 and December 31st 2019. The primary outcome was the change from baseline in creatine kinase myocardial band during the first 18 postoperative hours. Exposures included mean arterial pressure, norepinephrine use during the aorta cross‐clamp period, and aorta cross‐clamp duration. Associations were investigated using linear mixed‐effect models. Results: A total of 1443 patients were included in the analysis. Patients treated with norepinephrine during the aortic cross‐clamp period had 19% (95% CI: 9.0%–29%; p < 0.001) higher creatine kinase myocardial band postoperatively compared with those not treated with norepinephrine. Higher mean arterial pressure was not significantly associated with creatine kinase myocardial band (3.0%, 95% CI: −2.0% to 9%; p = 0.20). Patients treated with norepinephrine with a mean arterial pressure above the median (39 mmHg) had similar creatine kinase myocardial band levels compared to patients not treated with norepinephrine with a mean arterial pressure below the median, with a difference of 2% (95% CI: −0.18% to 0.22%, p = 0.80). Creatine kinase myocardial band increased by 12% (95% CI: 10%–14%; p < 0.001) for each 15‐min increase in aortic cross‐clamp duration. Conclusion: This retrospective observational study suggested a possible link between norepinephrine use and myocardial injury during cardiopulmonary bypass‐assisted open‐heart surgery, while mean arterial pressure appeared to have no impact. Further randomized controlled trials are necessary. Editorial Comment: In this single center retrospective cohort analysis, intraoperative cardiac surgery management factors were analyzed along with postoperative cardiac injury marker levels. Associations for aortic cross‐clamp time, noradrenaline use during this, and mean arterial pressures are presented for post‐op creatine kinase MB levels.

Aims: Biomarkers of endothelial activation and damage are elevated after out-of-hospital cardiac arrest (OHCA). Elevated plasma concentrations of syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule 1 (PECAM-1) reflect glycocalyx degradation, endothelial cell injury, and endothelial junction disruption, respectively. Interleukin 6 (IL-6) plays an important role in the inflammatory mechanisms that cause endothelial damage, and inhibiting IL-6 with tocilizumab may attenuate endothelial damage. The present study examines the effect of tocilizumab on endothelial biomarkers and their prognostic value in comatose resuscitated OHCA patients. Methods and results: The ‘IL-6 Inhibition for Modulating Inflammation after Cardiac Arrest’ (IMICA) trial included 80 comatose OHCA patients who were randomized to receive tocilizumab (8 mg/kg) or placebo. Blood samples were drawn sequentially at hospital admission (0 h) and after 24, 48, and 72 h for biomarker measurements. Syndecan-1 concentrations declined over time in both groups; however, the reduction was significantly less in the tocilizumab group (all P < 0.003). No significant between-group differences were observed for sTM or PECAM-1. In prognostic analyses, baseline PECAM-1 had an AUROC of 0.71 (95% CI 0.59–0.83) for prediction of 30-day mortality. Syndecan-1 and sTM had no predictive value (AUROC 0.61 and 0.53, respectively). Conclusion: Plasma syndecan-1 decline was less pronounced in comatose OHCA patients treated with tocilizumab, without affecting sTM or PECAM-1. This contrasts with previous IMICA findings of reduced systemic inflammation, vasopressor use, and myocardial injury, suggesting a complex relationship between inflammation and endothelial injury. Finally, PECAM-1 levels already at hospital admission had a moderate predictive value for mortality. Clinical trial registration: The trial is registered at clinicaltrials.gov (NCT03863015).

Introduction: Patients undergoing anterior cruciate ligament (ACL) reconstruction experience substantial postoperative pain, which delays recovery and leads to both immediate and long-term opioid use. In other knee procedures, infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) has demonstrated analgesic and opioid reducing effects. However, the effect in patients undergoing ACL reconstruction has not been investigated. We aimed to investigate the real-world effect of IPACK in patients undergoing ACL reconstruction on immediate postoperative opioid consumption. Participants: In this single-centre difference-in-differences cohort study, all patients who underwent ACL reconstruction surgery at Bispebjerg Hospital, Denmark, from 1 February 2024 to 30 June 2025 are included. The study further includes a similar reference cohort, comprising all patients who underwent trochleaplasty, Elmslie-Trillat, or medial patellofemoral ligament reconstruction during the same period, and at the same hospital. Intervention: The primary exposure is the implementation of IPACK as part of perioperative management for ACL reconstruction on 1 January 2025. The IPACK was performed under ultrasound guidance, immediately before surgery, administering 20 mL of ropivacaine 0.5% between the popliteal artery and the posterior knee capsule. Outcomes: The primary outcome is the cumulative opioid consumption from surgical incision to 2 hours postoperatively. Secondary outcomes include the cumulative opioid consumption from incision to 24 hours postoperatively, the worst reported pain score at 0-24h postoperatively, occurrence of postoperative nausea or vomiting (PONV) 0-24h postoperatively, length of PACU stay, length of hospital stay, and nerve injuries. As an exploratory outcome, carbon dioxide emissions will be investigated. Statistical analysis: The main analysis will be a standard two-way fixed effects DiD regression assessing the changes occurring at the time of implementation of IPACK in the ACL cohort, with adjustment for the underlying time trend. Continuous outcomes are reported as mean difference (95% confidence interval [CI]), and binary outcomes as absolute and relative risks (95% CI).

Background: Intraoperative hypotension is a common occurrence in patients undergoing anaesthesia, although there is no standardised definition of hypotension. International consensus statements provide some guidelines for the management of intraoperative hypotension, but general clinical practice is unknown. We aimed to survey anaesthesiologists' values and preferences regarding intraoperative blood pressure management, including whether they would support future research on this topic. Methods: We conducted an international, online survey of routine practice and opinion. The target population was anaesthesiologists who regularly anaesthetise adult patients. Results are reported descriptively and in accordance with the Consensus‐Based Checklist for Reporting of Survey Studies (CROSS) checklist. Results: A total of 1640 anaesthesiologists from 11 European countries participated in the survey. The majority of respondents were specialists (1322 of 1640, 80.6%, 95% CI 78.7–82.6). Almost all respondents worked in public hospitals (1613 of 1640, 98.4%). The overall response rate was 22.7%. Most respondents reported using absolute mean arterial pressure as their main unit of measurement to quantify hypotension (1098 of 1640, 67.0%, 95% CI 64.6–69.2). Respondents were most likely to initiate vasoactive treatment at a mean arterial pressure below 60 or 65 mmHg. Chronic arterial hypertension, traumatic brain injury and surgical procedures involving head‐up positioning of the patient were the three most common scenarios where respondents would raise their threshold for treatment. Most respondents considered the establishment of safe intraoperative blood pressure thresholds a critical research question, and almost all respondents (1509 of 1640, 92.0%) indicated a willingness to randomise patients to specific blood pressure targets. For 72.9% (1196 of 1640), the lowest acceptable mean arterial pressure for randomisation was 60 mmHg. Respondents were also interested in the comparison of efficacy and safety of vasoactive agents, and the most sought‐after comparison was phenylephrine versus noradrenaline (1252 of 1640, 76.3%). The willingness of respondents to administer these agents in peripheral venous access differed according to geography. Conclusion: In this international survey, mean arterial pressures of 60 or 65 mmHg were the most commonly reported blood pressure thresholds leading to initiation of treatment with vasoactive agents. Almost all respondents indicated patient groups for whom they would alter their treatment threshold, namely those suffering from chronic arterial hypertension, those undergoing surgery in a head‐up position, and patients with traumatic brain injury. The majority of respondents supported future trials establishing optimal mean arterial pressure threshold and choice of vasoactive agent. We noticed a geographical variation in willingness to administer vasoactive agents in peripheral venous access. Editorial Comment: This survey of anaesthesiologists from European countries queried practitioner perceptions of blood pressure management in adults during anaesthesia with focus on hypotension. Queries and responses also concerned circumstances and blood pressure levels which clinicians report being willing to treat actively, and how they might do this practically.

Aims: Intermediate high-risk pulmonary embolism (PE) is associated with increased risk of haemodynamic deterioration and death, but balancing the risk of thrombolytics or catheter-based treatment and efficacy has been challenging. This trial compared the additional efficacy of catheter-based ultrasound low-dose thrombolysis (USAT) over intravenous low-dose thrombolysis or heparin alone. Methods and results: In an investigator-initiated randomized clinical multicentre trial, we randomized 210 adult patients with acute, intermediate high-risk PE admitted to emergency departments in two regions of Denmark. Patients were allocated 1:1:1 to one of three treatment strata: low-dose thrombolysis (20 mg alteplase administered over 6 h) by USAT, by intravenous administration, or heparin alone. The efficacy of the interventions was assessed by comparing the refined Modified Miller Score, rmMS, (0–40 points, higher score indicating higher thrombus burden) from CT angiographies performed at baseline and 48–96 h post-randomization. Two comparisons were investigated: the reduction of rmMS with low-dose thrombolysis (USAT or intravenously) compared to heparin alone and the reduction of rmMS with low-dose thrombolysis administered by USAT compared to the intravenous route. The safety endpoint included the risk of bleeding. We included 210 patients with acute PE, 49% were female, the mean age was 70 (IQR 62–76), and the mean body mass index was 30 (26–34). Compared to heparin alone, low-dose thrombolysis reduced the rmMS by 3.6 points (95% CI 2.2–5.0, P < 0.001), but the reduction in rmMS was not different in the ultrasound-assisted thrombolysis (USAT) vs. the intravenous route, mean difference −0.1 (95% CI: −1.9–1.7), P = 0.88. Bleeding complications were numerically more frequent with low-dose thrombolysis, albeit not statistically significant. No differences in other outcomes were observed. Conclusion: Low-dose thrombolysis reduced thrombus burden more than heparin alone in patients with acute intermediate high-risk PE. However, USAT did not show greater thrombus reduction than intravenous thrombolysis. The rate of death and risk of bleeding complications were increased with low-dose thrombolysis. Trial Registration: clinicaltrials.gov, NCT04088292.