Incidence and assessment of delirium following open cardiac surgery; A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis sought i) to provide an overview of the incidence of delirium following open cardiac surgery and ii) to investigate how incidences of delirium are associated with different assessment tools. METHODS AND RESULTS: A systematic search of studies investigating delirium following open cardiac surgery were conducted in Medline (Ovid), EMBASE, PsycINFO, CiNAHL and the Cochrane Database. Only studies with patients diagnosed or screened with a validated tool were included. Studies published from 2005 to 2021 were included in the meta-analysis.Of 7,126 individual studies retrieved, 106 met the inclusion criteria for the meta-analysis, hereof 31% of high quality. The weighted pooled incidence of delirium following open cardiac surgery across all studies was 23% (95% CI 20-26%), however we found a considerable heterogeneity (I2 = 99%), which could not be explained by subgroups or further sensitivity analyses. The most commonly applied screening tool for delirium is CAM/CAM-ICU. The lowest estimates of delirium were found by applying the Delirium Observation Scale (incidence 14%, 95% CI 8-20%), and the highest estimates in studies using "other" screening tools (Organic Brain Symptom Scale, Delirium Symptom Interview) pooled incidence of 43%, (95% CI 19 - 66%), however, only two studies applied these. CONCLUSION: Delirium following open cardiac surgery remains a complication with a high incidence of overall 23%, when applying a validated tool for screening or diagnosis. Nevertheless, this systematic review and meta-analyses highlight the significant inconsistency in current evidence regarding assessment tools and regimens. REGISTRATION: Prospero CRD42020215519.

Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study.

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy. METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent. RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891). CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

Immediate inflammatory response to mechanical circulatory support in a porcine model of severe cardiogenic shock.

BACKGROUND: In selected cases of cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is combined with trans valvular micro axial flow pumps (ECMELLA). Observational studies indicate that ECMELLA may reduce mortality but exposing the patient to two advanced mechanical support devices may affect the early inflammatory response. We aimed to explore inflammatory biomarkers in a porcine cardiogenic shock model managed with V-A ECMO or ECMELLA. METHODS: Fourteen landrace pigs had acute myocardial infarction-induced cardiogenic shock with minimal arterial pulsatility by microsphere embolization and were afterwards managed 1:1 with either V-A ECMO or ECMELLA for 4 h. Serial blood samples were drawn hourly and analyzed for serum concentrations of interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha, and serum amyloid A (SAA). RESULTS: An increase in IL-6, IL-8, and SAA levels was observed during the experiment for both groups. At 2-4 h of support, IL-6 levels were higher in ECMELLA compared to V-A ECMO animals (difference: 1416 pg/ml, 1278 pg/ml, and 1030 pg/ml). SAA levels were higher in ECMELLA animals after 3 and 4 h of support (difference: 401 ng/ml and 524 ng/ml) and a significant treatment-by-time effect of ECMELLA on SAA was identified (p = 0.04). No statistical significant between-group differences were observed in carotid artery blood flow, urine output, and lactate levels. CONCLUSIONS: Left ventricular unloading with Impella during V-A ECMO resulted in a more extensive inflammatory reaction despite similar end-organ perfusion.

Haemodynamic implications of VA-ECMO vs. VA-ECMO plus Impella CP for cardiogenic shock in a large animal model.

AIMS: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) with profound left ventricular (LV) failure is associated with inadequate LV emptying. To unload the LV, VA-ECMO can be combined with Impella CP (ECMELLA). We hypothesized that ECMELLA improves cardiac energetics compared with VA-ECMO in a porcine model of cardiogenic shock (CS). METHODS AND RESULTS: Land-race pigs (weight 70 kg) were instrumented, including a LV conductance catheter and a carotid artery Doppler flow probe. CS was induced with embolization in the left main coronary artery. CS was defined as reduction of ≥50% in cardiac output or mixed oxygen saturation (SvO2) or a SvO2 < 30%. At CS VA-ECMO was initiated and embolization was continued until arterial pulse pressure was <10 mmHg. At this point, Impella CP was placed in the ECMELLA arm. Support was maintained for 4 h. CS was induced in 15 pigs (VA-ECMO n = 7, ECMELLA n = 8). At time of CS MAP was <45 mmHg in both groups, with no difference at 4 h (VA-ECMO 64 mmHg ± 11 vs. ECMELLA 55 mmHg ± 21, P = 0.08). Carotid blood flow and arterial lactate increased from CS and was similar in VA-ECMO and ECMELLA [239 mL/min ± 97 vs. 213 mL/min ± 133 (P = 0.6) and 5.2 ± 3.3 vs. 4.2 ± 2.9 mmol/ (P = 0.5)]. Pressure-volume area (PVA) was significantly higher with VA-ECMO compared with ECMELLA (9567 ± 1733 vs. 6921 ± 5036 mmHg × mL/min × 10-3, P = 0.014). Total diureses was found to be lower in VA-ECMO compared with ECMELLA [248 mL (179-930) vs. 506 mL (418-2190); P = 0.005]. CONCLUSIONS: In a porcine model of CS, we found lower PVA, with the ECMELLA configuration compared with VA-ECMO, indicating better cardiac energetics without compromising systemic perfusion.

Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma.

BACKGROUND: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. METHODS: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). RESULTS: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. CONCLUSION: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

Lower versus higher blood pressure targets in comatose patients resuscitated from out-of-hospital cardiac arrest-Protocol for a secondary Bayesian analysis of the box trial.

BACKGROUND: The management of blood pressure targets during intensive care after out-of-hospital cardiac arrest (OHCA) remains a topic of debate. The blood Pressure and Oxygenation Targets After OHCA (BOX) trial explored the efficacy of two different blood pressure targets in 789 patients during intensive care after OHCA. In the primary frequentist analysis, no statistically significant differences were found for neurological outcome after 90 days. METHODS: This protocol outlines secondary Bayesian analyses of 365-day all-cause mortality and two secondary outcomes: neurological outcome after 365 days, and plasma neuron-specific enolase, a biomarker of brain injury, after 48 h. We will employ adjusted Bayesian logistic and linear regressions, presenting results as relative and absolute differences with 95% confidence intervals. We will use weakly informative priors for the primary analyses, and skeptical and evidence-based priors (where available) in sensitivity analyses. Exact probabilities for any benefit/harm will be presented for all outcomes, along with probabilities of clinically important benefit/harm (risk differences larger than 2%-points absolute) and no clinically important differences for the binary outcomes. We will assess whether heterogeneity of treatment effects on mortality is present according to lactate at admission, time to return of spontaneous circulation, primary shockable rhythm, age, hypertension, and presence of ST-elevation myocardial infarction. DISCUSSION: This secondary analysis of the BOX trial aim to complement the primary frequentist analysis by quantifying the probabilities of beneficial or harmful effects of different blood pressure targets. This approach seeks to provide clearer insights for researchers and clinicians into the effectiveness of these blood pressure management strategies in acute medical conditions, particularly focusing on mortality, neurological outcomes, and neuron-specific enolase.

Health-related quality of life and cognitive function after out-of-hospital cardiac arrest; a comparison of prehospital return-of-spontaneous circulation and refractory arrest managed with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for selected refractory out-of-hospital cardiac arrest (OHCA) is increasingly used. Detailed knowledge of health-related quality of life (HRQoL) and long-term cognitive function is limited. HRQoL and cognitive function were assessed in ECPR-survivors and OHCA-survivors with prehospital return of spontaneous circulation after standard advanced cardiac life support (sACLS). METHODS: Fifteen ECPR-survivors and 22 age-matched sACLS-survivors agreed to participate in this follow-up study. Participants were examined with echocardiography, 6-minute walk test, and neuropsychological testing, and answered HRQoL (EQ-5D-5L and Short Form 36 (SF-36)), and mental health questionnaires. RESULTS: Most patients were male (73 % and 82 %) and median age at follow-up was similar between groups (55 years and 60 years). Low flow time was significantly longer for ECPR-survivors (86 min vs. 15 min) and lactate levels were significantly higher (14.1 mmol/l vs. 3.9 mmol/l). No between-group difference was found in physical function nor in cognitive function with scores corresponding to the 23rd worst percentile of the general population. SACLS-survivors had HRQoL on level with the Danish general population while ECPR-survivors scored lower in both EQ-5D-5L (index score 0.73 vs. 0.86, p = 0.03, visual analog scale: 70 vs. 84, p = 0.04) and in multiple SF-36 health domains (role physical, bodily pain, general health, and mental health). CONCLUSIONS: Despite substantially longer low flow times with thrice as high lactate levels, ECPR-survivors were similar in cognitive and physical function compared to sACLS-survivors. Nonetheless, ECPR-survivors reported lower HRQoL overall and related to mental health, pain management, and the perception of limitations in physical role.

Invasive mechanical ventilation in cardiogenic shock complicating acute myocardial infarction: A contemporary Danish cohort analysis.

PURPOSE: Invasive mechanical ventilation (IMV) is widely used in patients with cardiogenic shock following acute myocardial infarction (AMICS), but evidence to guide practice remains sparse. We sought to evaluate trends in the rate of IMV utilization, applied settings, and short term-outcome of a contemporary cohort of AMICS patients treated with IMV according to out-of-hospital cardiac arrest (OHCA) at admission. METHODS: Consecutive AMICS patients receiving IMV in an intensive care unit (ICU) at two tertiary centres between 2010 and 2017. Data were analysed in relation to OHCA. RESULTS: A total of 1274 mechanically ventilated AMICS patients were identified, 682 (54%) with OHCA. Frequency of IMV increased during the study period, primarily due to higher occurrence of OHCA admissions. Among 566 patients with complete ventilator data, positive-end-expiratory pressure, inspired oxygen fraction, and minute ventilation during the initial 24 h in ICU were monitored. No differences were observed between 30-day survivors and non-survivors with OHCA. In non-OHCA, these ventilator requirements were significantly higher among 30-day non-survivors (P for all<0.05), accompanied by a lower PaO2/FiO2 ratio (median 143 vs. 230, P < 0.001) and higher arterial lactate levels (median 3.5 vs. 1.5 mmol/L, P < 0.001) than survivors. Physiologically normal PaO2 and pCO2 levels were achieved in all patients irrespective of 30-day survival and OHCA status. CONCLUSION: In the present contemporary cohort of AMICS patients, physiologically normal blood gas values were achieved both in OHCA and non-OHCA in the early phase of admission. However, increased demand of ventilatory support was associated with poorer survival only in non-OHCA patients.

Perioperative treatment with tranexamic acid in melanoma (PRIME): protocol for a Danish multicentre randomised controlled trial investigating the prognostic and treatment-related impact of the plasminogen-plasmin pathway.

INTRODUCTION: Inflammation is a hallmark of cancer and is involved in tumour growth and dissemination. However, the hallmarks of cancer are also the hallmarks of wound healing, and modulating the wound inflammatory response and immune contexture in relation to cancer surgery may represent effective targets of therapies.Repurposing anti-inflammatory drugs in a cancer setting has gained increasing interest in recent years. Interestingly, the known and thoroughly tested antifibrinolytic drug tranexamic acid reduces the risk of bleeding, but it is also suggested to play important roles in anti-inflammatory pathways, improving wound healing and affecting anti-carcinogenic mechanisms.As a novel approach, we will conduct a randomised controlled trial using perioperative treatment with tranexamic acid, aiming to prevent early relapses by >10% for patients with melanoma. METHODS AND ANALYSIS: Design: investigator-initiated parallel, two-arm, randomised, blinded, Danish multicentre superiority trial. PATIENTS: ≥T2 b melanoma and eligible for sentinel lymph node biopsy (n=1204).Project drug: tranexamic acid or placebo. TREATMENT: before surgery (intravenous 15 mg/kg) and daily (peroral 1000 mg x 3) through postoperative day 4. PRIMARY OUTCOME: relapse within 2 years after surgery.Primary analysis: risk difference between the treatment arms (χ2 test). SECONDARY OUTCOMES: postoperative complications, adverse events and survival.Inclusion period: summer 2023 to summer 2026. ETHICS AND DISSEMINATION: The trial will be initiated during the summer of 2023 and is approved by the National Committee on Health Research Ethics, the Danish Medicine Agency, and registered under the Data Protection Act. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Patients included in the study will adhere to normal Danish treatment protocols and standards of care, and we expect only mild and temporary side effects. Positive and negative results will be published in peer-reviewed journals, with authorships adhering to the Vancouver rules. TRIAL REGISTRATION NUMBER: NCT05899465; ClinicalTrials.gov Identifier.

Combined effects of targeted blood pressure, oxygenation, and duration of device-based fever prevention after out-of-hospital cardiac arrest on 1-year survival: post hoc analysis of a randomized controlled trial.

BACKGROUND: The "Blood Pressure and Oxygenation Targets in Post Resuscitation Care" (BOX) trial investigated whether a low versus high blood pressure target, a restrictive versus liberal oxygenation target, and a shorter versus longer duration of device-based fever prevention in comatose patients could improve outcomes. No differences in rates of discharge from hospital with severe disability or 90-day mortality were found. However, long-term effects and potential interaction of the interventions are unknown. Accordingly, the objective of this study is to investigate both individual and combined effects of the interventions on 1-year mortality rates. METHODS: The BOX trial was a randomized controlled two-center trial that assigned comatose resuscitated out-of-hospital cardiac arrest patients to the following three interventions at admission: A blood pressure target of either 63 mmHg or 77 mmHg; An arterial oxygenation target of 9-10 kPa or 13-14 kPa; Device-based fever prevention administered as an initial 24 h at 36 °C and then either 12 or 48 h at 37 °C; totaling 36 or 72 h of temperature control. Randomization occurred in parallel and simultaneously to all interventions. Patients were followed for the occurrence of death from all causes for 1 year. Analyzes were performed by Cox proportional models, and assessment of interactions was performed with the interventions stated as an interaction term. RESULTS: Analysis for all three interventions included 789 patients. For the intervention of low compared to high blood pressure targets, 1-year mortality rates were 35% (138 of 396) and 36% (143 of 393), respectively, hazard ratio (HR) 0.92 (0.73-1.16) p = 0.47. For the restrictive compared to liberal oxygenation targets, 1-year mortality rates were 34% (135 of 394) and 37% (146 of 395), respectively, HR 0.92 (0.73-1.16) p = 0.46. For device-based fever prevention for a total of 36 compared to 72 h, 1-year mortality rates were 35% (139 of 393) and 36% (142 of 396), respectively, HR 0.98 (0.78-1.24) p = 0.89. There was no sign of interaction between the interventions, and accordingly, no combination of randomizations indicated differentiated treatment effects. CONCLUSIONS: There was no difference in 1-year mortality rates for a low compared to high blood pressure target, a liberal compared to restrictive oxygenation target, or a longer compared to shorter duration of device-based fever prevention after cardiac arrest. No combination of the interventions affected these findings. Trial registration ClinicalTrials.gov NCT03141099, Registered 30 April 2017.

PD-L1 is a biomarker of real-world clinical outcomes for anti-CTLA-4 plus anti-PD-1 or anti-PD-1 monotherapy in metastatic melanoma.

BACKGROUND: Metastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. METHODS: We conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. RESULTS: We identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52-0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94-2.11, p = 0.101; MSS: HR 1.21, CI 0.70-2.11, p = 0.49; OS: HR 1.17, CI 0.68-2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53-0.93, p = 0.013; and HR 0.54, CI 0.37-0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50-1.02, p = 0.065; and HR 0.79, CI 0.51-1.21, p = 0.278) or OS (HR 0.78, CI 0.56-1.08, p = 0.135; and HR 0.81, CI 0.54-1.21, p = 0.305) compared to monotherapy. CONCLUSION: Our findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression.

DIFFERENCES IN MANAGEMENT AND PROGNOSTICATION OF CARDIOGENIC SHOCK PATIENTS IN THE PRESENCE AND ABSENCE OF OUT-OF-HOSPITAL CARDIAC ARREST.

ABSTRACT: Background: The clinical spectrum of acute myocardial infarction complicated by cardiogenic shock (AMICS) varies. Out-of-hospital cardiac arrest (OHCA) can be the first sign of cardiac failure, whereas others present with various degrees of hemodynamic instability (non-OHCA). The aim of the present study was to explore differences in prehospital management and characteristics of survivors and nonsurvivors in AMICS patients with OHCA or non-OHCA. Methods: Data analysis was based on patient data from the RETROSHOCK cohort comprising consecutive AMICS patients admitted to two tertiary cardiac centers between 2010 and 2017. Results: 1,716 AMICS patients were included and 42% presented with OHCA. Mortality in OHCA patients was 47% versus 57% in the non-OHCA group. Almost all OHCA patients were intubated before admission (96%). In the non-OHCA group, prehospital intubation (25%) was associated with a better survival ( P < 0.001). Lactate level on admission demonstrated a linear relationship with mortality in OHCA patients. In non-OHCA, probability of death was higher for any given lactate level <12 mmol/L compared with OHCA. However, a lactate level >7 mmol/L in non-OHCA did not increase mortality odds any further. Conclusion: Mortality was almost doubled for any admission lactate level up to 7 mmol/L in non-OHCA patients. Above this level, mortality remained unchanged in non-OHCA patients but continued to increase in OHCA patients. Prehospital intubation was performed in almost all OHCA patients but only in one of four patients without OHCA. Early intubation in non-OHCA patients was associated with a better outcome.

Survival and neurological outcome after bystander versus lay responder defibrillation in out-of-hospital cardiac arrest: A sub-study of the BOX trial.

BACKGROUND AND AIM: Bystander defibrillation is associated with increased survival with good neurological outcome after out-of-hospital cardiac arrest (OHCA). Dispatch of lay responders could increase defibrillation rates, however, survival with good neurological outcome in these remain unknown. The aim was to compare long-term survival with good neurological outcome in bystander versus lay responder defibrillated OHCAs. METHODS: This is a sub-study of the BOX trial, which included OHCA patients from two Danish tertiary cardiac intensive care units from March 2017 to December 2021. The main outcome was defined as 3-month survival with good neurological performance (Cerebral Performance Category of 1or 2, on a scale from 1 (good cerebral performance) to 5 (death or brain death)). For this study EMS witnessed OHCAs were excluded. RESULTS: Of the 715 patients, a lay responder arrived before EMS in 125 cases (16%). In total, 81 patients were defibrillated by a lay responder (11%), 69 patients by a bystander (10%) and 565 patients by the EMS staff (79%). The 3-month survival with good neurological outcome was 65% and 81% in the lay responder and bystander defibrillated groups, respectively (P = 0.03). CONCLUSION: In patients with OHCA, 3-month survival with good neurological outcome was higher in bystander defibrillated patients compared with lay responder defibrillated patients.

Treatment effects of blood pressure targets and hemodynamics according to initial blood lactate levels in comatose out-of-hospital cardiac arrest patients - A sub study of the BOX trial.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) survivors remaining comatose are often circulatory unstable with high mortality in the first days following resuscitation. Elevated lactate will reflect the severity and duration of hypoperfusion in cardiac arrest. Further, the severity of hypoperfusion could modify the effect on survival of different mean arterial blood pressure (MAP) targets. METHODS: In this sub-study of the BOX trial, adult successfully resuscitated comatose OHCA patients (n = 789) with a presumed cardiac cause were randomized to a MAP target of 63 mmHg vs. 77 mmHg. Patients were arbitrarily grouped in low-lactate: <25% of sample, medium-lactate: 25%-75%, and high >75 percentile according to blood lactate levels at hospital arrival as a surrogate of the severity of hypoperfusion. Invasive hemodynamic evaluations were performed using an arterial catheter and pulmonary artery catheter (PAC), and data from admission to 48 hours (h) were recorded. Logistic regression analysis evaluated whether lactate levels (as continuous and categorical) modify the effect of MAP targets on mortality at 365 days. RESULTS: The three lactate groups had initial lactate levels of low-lactate: <2.9 mmol/L, medium-lactate: 2.9-7.9 mmol/L, and high-lactate > 7.9 mmol/L. All patients were randomized to a 63 mmHg or 77 mmHg MAP target. The proportion of patients in the high-MAP target group was 100/201 (50%), 178/388 (46%), and 114/197 (58%) for low, medium, and high-lactate groups respectively. At admission, the high-lactate groups had a lower MAP compared to the medium-lactate (2.6 mmHg (95% CI: 0.1-5.0 mmHg, p = 0.02), and the low-lactate group, (3.6 mmHg (95% CI: 0.8-6.5 mmHg, p < 0.01). Accordingly, the vasoactive inotropic score was 79% (95%CI: 42%-124%%) higher with increasing initial lactate level (High-lactate vs. low-lactate) with the largest difference at 6 hours (110.6% (95%CI: 54.4%-187.2%) higher in high-lactate patients). No difference in the cardiac index or systemic vascular resistance was observed between lactate groups. The initial lactate level (continuous) modified the effect of the two MAP targets (p = 0.04). In the highest lactate group, the mortality was 100/197 (51%), and with an odds ratio (OR): 1.7 (95%CI: 0.9-3.0) if randomized to MAP 77 mmHg compared to MAP 63 mmHg. In the lowest lactate group, the mortality was 35/201(17%) and similar if randomized to a MAP target of 77 mmHg (OR: 1.1 (95% CI: 0.5-2.3)). CONCLUSION: Comatose OHCA patients with high initial lactate levels required more vasoactive drugs on the first two days of ICU admission to meet the blood pressure target and had a poorer prognosis. No indication that aiming for a higher MAP target is beneficial in patients with an initial high lactate level was found, however, given the post-hoc nature of this study, these results should be considered hypothesis-generating.

Impact of blood pressure targets on central hemodynamics during intensive care after out-of-hospital cardiac arrest.

OBJECTIVES: The aim was to investigate the advanced hemodynamic effects of the two MAP-targets during intensive care on systemic hemodynamics in comatose patients after cardiac arrest. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Primary vasopressor used was per protocol norepinephrine. Hemodynamic monitoring was done with pulmonary artery catheters (PAC) and measurements were made on predefined time points. The primary endpoint of this substudy was the difference in cardiac index within 48 h from a repeated measurements-mixed model. Secondary endpoints included systemic vascular resistance index (SVRI), heart rate, and stroke volume index. PATIENTS: Comatose survivors after out-of-hospital cardiac arrest. INTERVENTIONS: The "Blood pressure and oxygenations targets after out-of-hospital cardiac arrest (BOX)"-trial was a randomized, controlled, double-blinded, multicenter-study comparing targeted mean arterial pressure (MAP) of 63 mmHg (MAP63) vs 77 mmHg (MAP77). MEASUREMENTS AND MAIN RESULTS: Among 789 randomized patients, 730 (93%) patients were included in the hemodynamic substudy. From PAC-insertion (median 1 hours after ICU-admission) and the next 48 hours, the MAP77-group received significantly higher doses of norepinephrine (mean difference 0.09 µg/kg/min, 95% confidence interval (CI) 0.07-0.11, pgroup < 0.0001). Cardiac index was significantly increased (0.20 L/min/m2 (CI 0.12-0.28), pgroup < 0.0001) as was SVRI with an overall difference of (43 dynes m2/s/cm5 (CI 7-79); pgroup = 0.02). Heart rate was increased in the MAP77-group (4 beats/minute; CI 2-6, pgroup < 0.003), but stroke volume index was not (pgroup = 0.10). CONCLUSIONS: Targeted MAP at 77 mmHg compared to 63 mmHg resulted in a higher dose of norepinephrine, increased cardiac index and SVRI. Heart rate was also increased, but stroke volume index was not affected by a higher blood pressure target.

Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity.

Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1TBM/TBM (TRAF6 Binding Mutant = TBM) mice causes fatal inflammation and autoimmunity, but the involved targets and underlying molecular mechanisms are unknown. We genetically rendered a single MALT1 substrate, the RNA-binding protein (RBP) Roquin-1, insensitive to MALT1 cleavage. These Rc3h1Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1TBM/TBM mice. Mechanistically, we show how antigen/MHC recognition is translated by MALT1 into Roquin cleavage and derepression of Roquin targets. Increasing T cell receptor (TCR) signals inactivated Roquin more effectively, and only high TCR strength enabled derepression of high-affinity targets to promote Th17 differentiation. Induction of experimental autoimmune encephalomyelitis (EAE) revealed increased cleavage of Roquin-1 in disease-associated Th17 compared to Th1 cells in the CNS. T cells from Rc3h1Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκBNS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1Mins/Mins mice were protected from EAE. These data demonstrate how TCR signaling and MALT1 activation utilize graded cleavage of Roquin to differentially regulate target mRNAs that control T cell activation and differentiation as well as the development of autoimmunity.

Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies.

BACKGROUND: The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. METHODS: In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria. RESULTS: We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. CONCLUSIONS: The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Blood Pressure and Oxygen Targets on Kidney Injury After Cardiac Arrest.

BACKGROUND: Acute kidney injury (AKI) represents a common and serious complication to out-of-hospital cardiac arrest. The importance of post-resuscitation care targets for blood pressure and oxygenation for the development of AKI is unknown. METHODS: This is a substudy of a randomized 2-by-2 factorial trial, in which 789 comatose adult patients who had out-of-hospital cardiac arrest with presumed cardiac cause and sustained return of spontaneous circulation were randomly assigned to a target mean arterial blood pressure of either 63 or 77 mm Hg. Patients were simultaneously randomly assigned to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa or a liberal oxygenation target of a Pao2 of 13 to 14 kPa. The primary outcome for this study was AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) classification in patients surviving at least 48 hours (N=759). Adjusted logistic regression was performed for patients allocated to high blood pressure and liberal oxygen target as reference. RESULTS: The main population characteristics at admission were: age, 64 (54-73) years; 80% male; 90% shockable rhythm; and time to return of spontaneous circulation, 18 (12-26) minutes. Patients allocated to a low blood pressure and liberal oxygen target had an increased risk of developing AKI compared with patients with high blood pressure and liberal oxygen target (84/193 [44%] versus 56/187 [30%]; adjusted odds ratio, 1.87 [95% CI, 1.21-2.89]). Multinomial logistic regression revealed that the increased risk of AKI was only related to mild-stage AKI (KDIGO stage 1). There was no difference in risk of AKI in the other groups. Plasma creatinine remained high during hospitalization in the low blood pressure and liberal oxygen target group but did not differ between groups at 6- and 12-month follow-up. CONCLUSIONS: In comatose patients who had been resuscitated after out-of-hospital cardiac arrest, patients allocated to a combination of a low mean arterial blood pressure and a liberal oxygen target had a significantly increased risk of mild-stage AKI. No difference was found in terms of more severe AKI stages or other kidney-related adverse outcomes, and creatinine had normalized at 1 year after discharge. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099.

Quantitative pupillometry for neuroprognostication in comatose post-cardiac arrest patients: A protocol for a predefined sub-study of the Blood pressure and Oxygenations Targets after Out-of-Hospital Cardiac Arrest (BOX)-trial.

Background: Resuscitation guidelines propose a multimodal prognostication strategy algorithm at ≥72 hours after the return of spontaneous circulation to evaluate neurological outcome for unconscious cardiac arrest survivors. Even though guidelines suggest quantitative pupillometry for assessing pupillary light reflex, threshold values are not yet validated.This study aims to validate pre-specified thresholds of quantitative pupillometry by quantitatively assessing the percentage reduction of pupillary size (qPLR) <4% and Neurological Pupil index (NPi) ≤2 and in predicting unfavorable neurological outcome. Both as an isolated predictor and combined with guideline-suggested neuron-specific enolase (NSE) threshold >60 µg L-1 in the current prognostication strategy algorithm. Methods: We conduct this pre-planned diagnostic sub-study in the randomized, controlled, multicenter clinical trial "Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial". Blinded to treating physicians and outcome assessors, measurements of qPLR and NPi are obtained from cardiac arrest survivors at time points (±6 hours) of admission, after 24, 48, and 72 hours, or until the time of awakening or death. Discussion: This study will be the largest prospective study investigating the predictive performance of automated quantitative pupillometry in unconscious patients resuscitated from cardiac arrest. We will test specific threshold values of NPi ≤2 and qPLR <4% to predict unfavorable outcome following cardiac arrest. The validation of pupillometry alone and combined with NSE with the criteria of the current prognostication strategy algorithm will hopefully increase the level of evidence and support clinical neuroprognostication with automated quantitative pupillometry in unconscious post-cardiac arrest patients. Trial registration: Registered March 30, 2017, at ClinicalTrials.gov (Identifier: NCT03141099).