First-In-Man Trial of ß3-Adrenoceptor Agonist Treatment in Chronic Heart Failure: Impact on Diastolic Function.

ABSTRACT: Diastolic dysfunction (DD) in heart failure is associated with increased myocardial cytosolic calcium and calcium-efflux through the sodium-calcium exchanger depends on the sodium gradient. Beta-3-adrenoceptor (ß3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, ß3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction, New York Heart Association II-III, and left ventricular ejection fraction <40% to receive the ß3-AR agonist mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended heart failure therapy. We performed echocardiography and cardiac computed tomography and measured N-terminal probrain natriuretic peptide at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59 ± 11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between the groups by echocardiography (E/e' placebo: 13 ± 7 to 13 ± 5, P = 0.21 vs. mirabegron: 12 ± 6 to 13 ± 8, P = 0.74, between-group follow-up difference 0.2 [95% CI, -3 to 4], P = 0.89) or cardiac computed tomography (left atrial volume index: between-group follow-up difference 9 mL/m 2 [95% CI, -3 to 19], P = 0.15). DD gradings did not change within or between the groups following 2 algorithms ( P = 0.72, P = 0.75). N-terminal probrain natriuretic peptide remained unchanged in both the groups ( P = 0.74, P = 0.64). In patients with HF with reduced ejection fraction, no changes were identified in diastolic measurements, gradings or biomarker after ß3-AR stimulation compared with placebo. The findings add to the previous literature questioning the role of impaired Na + -Ca 2+ -mediated calcium export as a major culprit in DD. NCT01876433.

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.

BACKGROUND: Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS: Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS: The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome. CONCLUSIONS: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.

The Glucagon-Like Peptide-1 Analog Exenatide Increases Blood Glucose Clearance, Lactate Clearance, and Heart Rate in Comatose Patients After Out-of-Hospital Cardiac Arrest.

OBJECTIVES: To investigate the effects of the glucagon-like peptide-1 analog exenatide on blood glucose, lactate clearance, and hemodynamic variables in comatose, resuscitated out-of-hospital cardiac arrest patients. DESIGN: Predefined post hoc analyzes from a double-blind, randomized clinical trial. SETTING: The ICU of a tertiary heart center. PATIENTS: Consecutive sample of adult, comatose patients undergoing targeted temperature management after out-of-hospital cardiac arrest from a presumed cardiac cause, irrespective of the initial cardiac rhythm. INTERVENTIONS: Patients were randomized 1:1 to receive 6 hours and 15 minutes of infusion of either 17.4 µg of the glucagon-like peptide-1 analog exenatide (Byetta; Lilly) or placebo within 4 hours from sustained return of spontaneous circulation. The effects of exenatide were examined on the following prespecified covariates within the first 6 hours from study drug initiation: lactate level, blood glucose level, heart rate, mean arterial pressure, and combined dosage of norepinephrine and dopamine. MEASUREMENTS AND MAIN RESULTS: The population consisted of 106 patients receiving either exenatide or placebo. During the first 6 hours from study drug initiation, the levels of blood glucose and lactate decreased 17% (95% CI, 8.9-25%; p = 0.0004) and 21% (95% CI, 6.0-33%; p = 0.02) faster in patients receiving exenatide versus placebo, respectively. Exenatide increased heart rate by approximately 10 beats per minute compared to placebo (p < 0.0001). There was no effect of exenatide on other hemodynamic variables. CONCLUSIONS: In comatose out-of-hospital cardiac arrest patients, infusion with exenatide lowered blood glucose and resulted in increased clearance of lactate as well as increased heart rate. The clinical importance of these physiologic effects remains to be investigated.

Importance of comorbidities in comatose survivors of shockable and non-shockable out-of-hospital cardiac arrest treated with target temperature management.

OBJECTIVE: Comorbidity prior to out-of-hospital cardiac arrest (OHCA) and primary rhythm in relation to survival is not well established. We aimed to assess the prognostic importance of comorbidity in relation to primary rhythm in OHCA-patients treated with Target Temperature Management (TTM). DESIGN: Consecutive comatose survivors of OHCA treated with TTM in hospitals in the Copenhagen area between 2002-2011 were included. Utstein-based pre- and in-hospital data collection was performed. Data on comorbidity was obtained from The Danish National Patient Register and patient charts, assessed by the Charlson Comorbidity Index (CCI). RESULTS: A total of 666 patients were included. A third (n = 233, 35%) presented with non-shockable rhythm, and they were less often male (64% vs. 82%, p < .001), and OHCA in public, witnessed OHCA, and bystander cardiopulmonary resuscitation (CPR) were less common compared to patients with a shockable primary rhythm (public: 27% vs. 48%, p < .001, witnessed: 79% vs. 90%, p < .001, bystander CPR: 47% vs. 63%, p < .001). 30-day mortality was 62% compared to 28% in patients with non-shockable and shockable rhythm, respectively. By Cox-regression analyses, any comorbidity (CCI ≥1) was the only factor independently associated with 30-day mortality in patients with non-shockable rhythm (HR =1.9 (95% CI: 1.2-2.9), p < .01), whereas in patients with shockable rhythm comorbidity was not associated with outcome after adjustment for prognostic factors (HR = 0.82 (0.55-1.2), p = .34). No significant interaction between primary rhythm and comorbidity in terms of mortality was present. CONCLUSION: A higher comorbidity burden was independently associated with a higher 30-day mortality rate in patients presenting with non-shockable primary rhythm but not in patients with shockable rhythm.

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial.

BACKGROUND: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. METHODS: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 µg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. RESULTS: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. CONCLUSIONS: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

Atrial Fibrillation Following Out-of-Hospital Cardiac Arrest and Targeted Temperature Management-Are We Giving It the Attention it Deserves?

OBJECTIVES: Atrial fibrillation has been associated with increased mortality in the general population and mixed populations of critical ill. Atrial fibrillation can also affect patients during post-cardiac arrest care. We sought to assess the prognostic implications of atrial fibrillation following out-of-hospital cardiac arrest, including relation to the level of targeted temperature management. DESIGN: A post hoc analysis of a prospective randomized trial. SETTING: Thirty-six ICUs. PATIENTS: We included 897 (96%) of the 939 comatose out-of-hospital cardiac arrest survivors from the targeted temperature management trial (year, 2010-2013) with data on heart rhythm on day 2. INTERVENTIONS: Targeted temperature management at 33°C or 36°C. MEASUREMENTS AND MAIN RESULTS: Endpoints included cumulative proportion of atrial fibrillation following out-of-hospital cardiac arrest and 180-day all-cause mortality and specific death causes stratified by atrial fibrillation. Atrial fibrillation on day 2 was used as primary endpoint analyses to exclude effects of short-term atrial fibrillation related to resuscitation and initial management. The cumulative proportions of atrial fibrillation were 15% and 11% on days 1 and 2, respectively. Forty-three percent of patients with initial atrial fibrillation the first day were reported with sinus rhythm on day 2. No difference was found between the groups treated with targeted temperature management at 33°C and 36°C. Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; plogrank < 0.0001 and unadjusted hazard ratio, 1.75 [1.35-2.30]; p < 0.0001). The association between atrial fibrillation and higher mortality remained significant (adjusted hazard ratio, 1.34 [1.01-1.79]; p < 0.05) adjusted for potential confounders. Atrial fibrillation was independently associated with increased risk of cardiovascular death and multiple-organ failure (adjusted hazard ratio, 2.07 [1.39-3.09]; p < 0.001), whereas no association with higher risk of death from cerebral causes was found. CONCLUSIONS: Atrial fibrillation was independently associated with higher mortality, primarily driven by cardiovascular causes and multiple-organ failure, and may thus identify a vulnerable subpopulation. Whether treatment to prevent atrial fibrillation is associated with an improved prognosis remains to be established.

Bradycardia During Targeted Temperature Management: An Early Marker of Lower Mortality and Favorable Neurologic Outcome in Comatose Out-of-Hospital Cardiac Arrest Patients.

OBJECTIVES: Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C. DESIGN: Post hoc analysis of a prospective randomized study. SETTING: Thirty-six ICUs in 10 countries. PATIENTS: We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013. INTERVENTIONS: Targeted temperature management at 33°C and 36°C. MEASUREMENTS AND MAIN RESULTS: Endpoints were 180-day mortality and unfavorable neurologic function (cerebral performance category 3-5). Patients were stratified by target temperature and minimum heart rate during targeted temperature management (< 50, 50-59, and ≥ 60 beats/min [reference]) at 12, 20, and 28 hours after randomization. Heart rates less than 50 beats/min and 50-59 beats/min were recorded in 132 (30%) and 131 (29%) of the 33°C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (< 50 beats/min = 32%, 50-59 beats/min = 43%, and ≥ 60 beats/min = 60%; p(log-rank) < 0.0001). Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratio(adjusted) = 0.50 [0.34-0.74; p < 0.001]) and lower odds of unfavorable neurologic outcome (odds ratio(adjusted) = 0.38 [ 0.21-0.68; p < 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation, and lactate at admission. Similar, albeit less strong, independent associations of lower heart rates and favorable outcome were found in patients treated with targeted temperature management at 36°C. CONCLUSIONS: This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia during targeted temperature management at 33°C may thus be a novel, early marker of favorable outcome.

Comorbidity burden is not associated with higher mortality after out-of-hospital cardiac arrest.

OBJECTIVES: We investigated whether comorbidity burden of comatose survivors of out-of-hospital cardiac arrest (OHCA) affects outcome and if comorbidity modifies the effect of target temperature management (TTM) on final outcome. DESIGN: The TTM trial randomized 939 patients to 24 h of TTM at either 33 or 36 °C with no difference regarding mortality and neurological outcome. This post-hoc study of the TTM-trial formed a modified comorbidity index (mCI), based on available comorbidities from the Charlson comorbidity index (CCI). RESULTS: Bystander cardiopulmonary resuscitation (CPR) decreased with higher comorbidity group, p = 0.01. Comorbidity groups were univariately associated with higher mortality compared to mCI0 (HRmCI1: 1.55, CI: 1.25-1.93, p < 0.001, HRmCI2: 2.01, CI: 1.55-2.62, p < 0.001, HRmCI ≥ 3: 2.16, CI: 1.57-2.97, p < 0.001). When adjusting for confounders there was a consistent, nonsignificant association between level of comorbidity and mortality (HRmC11: 1.17, CI: 0.92-1.48, p = 0.21, HRmCI2: 1.28, CI: 0.96-1.71, p = 0.10, HRmCI ≥ 3: 1.37, CI: 0.97-1.95, p = 0.08). There was no interaction between comorbidity burden and level of TTM on outcome, p = 0.61. CONCLUSION: Comorbidity burden was associated with higher mortality following OHCA, but when adjusting for confounders, the influence was no longer significant. The association between mCI and mortality was not modified by TTM. Comorbidity burden is associated with lower rates of bystander cardiopulmonary resuscitation after OHCA.

Factors Associated With Successful Resuscitation After Out-of-Hospital Cardiac Arrest and Temporal Trends in Survival and Comorbidity.

STUDY OBJECTIVE: Out-of-hospital cardiac arrest has an overall poor prognosis. We sought to identify what temporal trends and influencing factors existed for this condition in one region. METHODS: We studied consecutive out-of-hospital cardiac arrest patients from 2007 to 2011 with attempted resuscitation in Copenhagen. From an Utstein database, we assessed survival to admission and comorbidity with the Charlson comorbidity index from the National Patient Registry and employment status from the Danish Rational Economic Agents Model database. We used logistic regression analyses to identify factors associated with outcome. RESULTS: Of a total of 2,527 attempted resuscitations in out-of-hospital cardiac arrest patients, 40% (n=1,015) were successfully resuscitated and admitted to the hospital. The strongest independent factors associated with successful resuscitation were shockable primary rhythm (multivariate odds ratio [OR]=3.9; 95% confidence interval [CI] 3.1 to 5.0), witnessed arrest (multivariate OR=3.5; 95% CI 2.7 to 4.6), and out-of-hospital cardiac arrest in a public area (multivariate OR=2.1; 95% CI 1.6 to 2.8), whereas no comorbidity (multivariate OR=1.1; 95% CI 0.8 to 1.45), sex (multivariate OR=1.14; 95% CI 0.91 to 1.44), and employment status (multivariate OR=1.17; 95% CI 0.89 to 1.56) were not independently associated with outcome. The number of patients with a high comorbidity burden (Charlson comorbidity index ≥3) increased during the study period (P trend <.001), from 18% to 31% (P trend <.001), whereas the percentage of out-of-hospital cardiac arrest patients with successful resuscitation to hospital admission increased by 3% per year during the study period, from 37% in 2007 to 43% in 2011 (P trend <.001). CONCLUSION: Our observations confirm the importance of key features that influence out-of-hospital cardiac arrest survival to hospital admission but are not highly influenced by public health actions. Despite increased illness burden, this short term outcome from cardiac arrest improved as care system efforts matured.

Exploring death scenes and circumstances in fatal opioid poisonings: Insights for preventive strategies using forensic autopsy cases in Western Denmark.

INTRODUCTION: Fatal opioid poisoning is a growing global issue. This study aims to describe circumstances surrounding fatal opioid poisonings by examining death scenes, demographics, and information from bystanders with the goal of informing prevention efforts. METHODS: We extracted data from the autopsy reports of 327 forensic autopsy cases with fatal poisoning involving methadone and/or morphine from 2013-2020. RESULTS: Fatal opioid poisonings occurred in both rural and urban areas. Death scene was the decedent's own home and a relative's or friend's home in 62% and 21%, respectively. The decedent died alone in 64% of the cases while other people were staying at the same address while death occurred in 30%. Decedents aged 15-34 years were more likely to die with other people staying at the same address than persons aged > 44 years (OR±SD: 2.3 ± 0.9, p = 0.005), and had lower postmortem blood methadone concentrations compared to persons > 34 years (Median [interquartile range]: 0.36 [0.23-0.62] vs 0.63 [0.28-1.2] mg/kg, p = 0.002). Female sex was more prevalent, and persons using illegal drugs were less prevalent in decedents aged > 44 years compared to those with age 15-44 years (29% vs 20%, p = 0.05% and 67% vs 89%, p < 0.001, respectively). Other psychoactive drugs were detected in 97% of decedents, mainly benzodiazepines (80%). CONCLUSIONS: Preventive strategies based on our findings include the need for harm reduction initiatives in both urban and rural areas, recognizing symptoms of fatal poisoning, and awareness of low tolerance among younger age groups. Urgent attention should be given to avoiding opioid use alone, particularly among older individuals, including women using prescribed opioids. Conveying the risks of polydrug use to all age groups is essential, especially co-use of sedative drugs.

Thoracentesis to alleviate pleural effusion in acute heart failure: study protocol for the multicentre, open-label, randomised controlled TAP-IT trial.

INTRODUCTION: Pleural effusion is present in half of the patients hospitalised with acute heart failure. The condition is treated with diuretics and/or therapeutic thoracentesis for larger effusions. No evidence from randomised trials or guidelines supports thoracentesis to alleviate pleural effusion due to acute heart failure. The Thoracentesis to Alleviate cardiac Pleural effusion Interventional Trial (TAP-IT) will investigate if a strategy of referring patients with acute heart failure and pleural effusion to up-front thoracentesis by pleural pigtail catheter insertion in addition to pharmacological therapy compared with pharmacological therapy alone can increase the number of days the participants are alive and not hospitalised during the 90 days following randomisation. METHODS AND ANALYSIS: TAP-IT is a pragmatic, multicentre, open-label, randomised controlled trial aiming to include 126 adult patients with left ventricular ejection fraction ≤45% and a non-negligible pleural effusion due to heart failure. Participants will be randomised 1:1, stratified according to site and anticoagulant treatment, and assigned to referral to up-front ultrasound-guided pleural pigtail catheter thoracentesis in addition to standard pharmacological therapy or to standard pharmacological therapy only. Thoracentesis is performed according to local guidelines and can be performed in participants in the pharmacological treatment arm if their condition deteriorates or if no significant improvement is observed within 5 days. The primary endpoint is how many days participants are alive and not hospitalised within 90 days from randomisation and will be analysed in the intention-to-treat population. Key secondary outcomes include 90-day mortality, complications, readmissions, and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region of Denmark Scientific Ethical Committee (H-20060817) and Knowledge Center for Data Reviews (P-2021-149). All participants will sign an informed consent form. Enrolment began in August 2021. Regardless of the nature, results will be published in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05017753.

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.

Disparities in cardiovascular disease and treatment in the Nordic countries.

The Nordic countries, including Denmark, Finland, Iceland, Norway, and Sweden have seen a steep decline in cardiovascular mortality in recent decades. They are among the most egalitarian countries by several measures, and all have universal, publicly funded welfare systems providing healthcare for all citizens. However, despite these seemingly ideal conditions, disparities in access to cardiovascular care and outcomes persist. To address this challenge, The Lancet Region Health-Europe convened experts from a broad range of countries to summarize the current state of knowledge on cardiovascular disease disparities across Europe. This Series Paper presents the main challenges in Nordic countries based on evidence from high-quality nationwide registries. Focusing on major cardiovascular health determinants, areas in need of improvement were identified. There is a need for addressing structural causes underlying these disparities, such as poverty and discrimination, but also to improve access to healthcare in deprived neighborhoods and to address underlying social determinants of health that may mitigate disparities in cardiovascular outcomes. Overall, while the Nordic countries have made great strides in promoting egalitarianism and providing universal healthcare, there is still much work to be done to ensure equitable access to care and improved cardiovascular outcomes for all members of society.

Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury.

AIM: To investigate how the inflammatory response after out-of-hospital cardiac arrest (OHCA) is modulated by blocking IL-6-mediated signalling with tocilizumab, and to relate induced changes to clinical status, myocardial- and brain injury. METHODS: This is a preplanned substudy of the IMICA trial (ClinicalTrials.gov, NCT03863015). Upon admission 80 comatose OHCA patients were randomized to infusion of tocilizumab or placebo. Inflammation was characterized by a cytokine assay, CRP, and leukocyte differential count; myocardial injury by TnT and NT-proBNP; brain injury by neuron-specific enolase (NSE) and Neurofilament Light chain (NFL), while sequential organ assessment (SOFA) score and Vasoactive-Inotropic Score (VIS) represented overall clinical status. RESULTS: Responses for IL-5, IL-6, IL-17, neutrophil as well as monocyte counts, and VIS were affected by tocilizumab treatment (all p < 0.05), while there was no effect on levels of NFL. IL-5 and IL-6 were substantially increased by tocilizumab, while IL-17 was lowered. Neutrophils and monocytes were lower at 24 and 48 hours, and VIS was lower at 24 hours, for the tocilizumab group compared to placebo. Multiple correlations were identified for markers of organ injury and clinical status versus inflammatory markers; this included correlations of neutrophils and monocytes with TnT, NSE, NFL, SOFA- and VIS score for the tocilizumab but not the placebo group. NT-proBNP, NFL and SOFA score correlated with CRP in both groups. CONCLUSIONS: Treatment with tocilizumab after OHCA modulated the inflammatory response with notable increases for IL-5, IL-6, and decreases for neutrophils and monocytes, as well as reduced vasopressor and inotropy requirements.

Repolarization and ventricular arrhythmia during targeted temperature management post cardiac arrest.

BACKGROUND: Targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) prolongs the QT-interval but our knowledge of different temperatures and risk of arrhythmia is incomplete. OBJECTIVE: To assess whether the QTc, QT-peak (QTp) and T-peak to T-end interval (TpTe) may be useful markers of ventricular arrhythmia in contemporary post cardiac arrest treatment. METHODS: An ECG-substudy of the TTM-trial (TTM at 33 °C vs. 36 °C) with serial ECGs from 680 (94%) patients. Bazett's (B) and Fridericia's (F) formula were used for heart rate correction of the QT, QTp and TpTe. Ventricular arrhythmia (VT/VF) were registered during the first three days of post cardiac arrest care. RESULTS: The QT, QTc and QTp intervals were prolonged more at 33 °C compared to 36 °C and restored to similar and lower levels after rewarming. The TpTe-interval remained between 92-100 ms throughout TTM in both groups. The QTc intervals were associated with ventricular arrhythmia, but not after adjustment for cardiac arrest characteristics. The QTp-interval was not associated with risk of ventricular arrhythmia. Heart rate corrected TpTe-intervals were associated with higher risk of arrhythmia (Odds ratio (OR): TpTe(B): 1.12 (1.02-1.23, p = 0.01 TpTe(F): 1.12 (1.02-1.23, p = 0.02) per 20 ms). Further a prolonged TpTe-interval ≥ 90 ms was consistently associated with higher risk (ORadjusted: TpTe(B): 2.05 (1.25-3.37), p < 0.01, TpTe(F): 2.14 (1.32-3.49), p < 0.01). CONCLUSIONS: TTM prolongs the QT-interval by prolongation of the QTp-interval without association to increased risk. The TpTe-interval is not significantly affected by core temperature, but heart rate corrected TpTe intervals are robustly associated with risk of ventricular arrhythmia. TRIAL REGISTRATION: The TTM-trial is registered and accessible at ClinicalTrials.gov (Identifier: NCT01020916).

Cardiac output, heart rate and stroke volume during targeted temperature management after out-of-hospital cardiac arrest: Association with mortality and cause of death.

AIM: Myocardial dysfunction and low cardiac index are common after out-of-hospital cardiac arrest (OHCA) as part of the post-cardiac arrest syndrome. This study investigates the association of cardiac index during targeted temperature management (TTM) with mortality. METHODS: In the TTM-trial, which randomly allocated patients to TTM of 33 °C or 36 °C for 24 h, we prospectively and consecutively monitored 151 patients with protocolized measurements from pulmonary artery catheters (PAC) as a single site substudy. Cardiac index, heart rate and stroke volume were measured at 3 time-points during the 24 h TTM period and averaged. Uni- and multivariate Cox regression was used to assess association with mortality. RESULTS: Of 151 patients, 50 (33%) were deceased after 180 days. Cardiac index during TTM was not significantly associated with mortality in univariate (HR: 0.84 [0.54-1.31], p = 0.59) or multivariate analyses (HRadjusted: 1.03 [0.57-1.83], p = 0.93). Cardiac index during TTM was also not significantly associated with non-neurological death (HRadjusted: 1.25 [0.43-3.59], p = 0.68). Higher heart rate (p = 0.03) and lower stroke volume (p = 0.04) were associated with increased mortality in univariate, but not multivariate analyses. No hemodynamic variables were associated with cerebral death, however, increasing lactate during TTM (HRadjusted: 2.15 [1.19-3.85], p = 0.01) and lower mean arterial pressure during TTM (HRadjusted: 0.89 [0.81-0.97], p = 0.008) were independently associated with non-neurological death. CONCLUSION: Cardiac index during TTM after resuscitation from OHCA is not associated with mortality. Future studies should investigate whether certain subgroups of patients could benefit from targeting higher goals for cardiac index.

Cardiac output during targeted temperature management and renal function after out-of-hospital cardiac arrest.

PURPOSE: After resuscitation from out-of-hospital cardiac arrest (OHCA), renal injury and hemodynamic instability are common. We aimed to assess the association between low cardiac output during targeted temperature management (TTM) and acute kidney injury (AKI) after OHCA. MATERIALS AND METHODS: Single-center substudy of 171 patients included in the prospective, randomized TTM-trial. Hemodynamic evaluation was performed with serial measurements by pulmonary artery catheter. AKI was the primary endpoint and was defined according to the KDIGO-criteria. RESULTS: Of 152 patients with available hemodynamic data, 49 (32%) had AKI and 21 (14%) had AKI with need for renal replacement therapy (RRT) in the first three days. During targeted temperature management, patients with AKI had higher heart rate (11 beats/min, pgroup < 0.0001), higher mean arterial pressure (MAP) (4 mmHg, pgroup = 0.001) and higher lactate (1 mmol/L, pgroup < 0.0001) compared to patients without AKI. However, there was no difference in cardiac index (pgroup = 0.25). In a multivariate logistic regression model, adjusting for potential confounders, MAP (p = .03), heart rate (p = .01) and lactate (p = .006), but not cardiac output, were independently associated with AKI. CONCLUSIONS: Blood pressure, heart rate and lactate, but not cardiac output, during 24 h of TTM were associated with AKI in comatose OHCA-patients.

Mean arterial pressure during targeted temperature management and renal function after out-of-hospital cardiac arrest.

PURPOSE: This study investigates the association between mean arterial pressure (MAP) and renal function after out-of-hospital cardiac arrest (OHCA). MATERIALS AND METHODS: Post-hoc analysis of 851 comatose OHCA-patients surviving >48 h included in the targeted temperature management (TTM)-trial. RESULTS: Patients were stratified by mean MAP during TTM in the following groups; <70 mmHg (22%), 70-80 mmHg (43%), and > 80 mmHg (35%). Median (interquartile range) eGFR (ml/min/1.73 m2) 48 h after OHCA was inversely associated with MAP-group (70 (47-102), 84 (56-113), 94 (61-124), p < .001, for the <70-group, 70-80-group and > 80-group respectively). After adjusting for potential confounders, in a mixed model including eGFR after 1, 2 and 3 days this association remained significant (pgroup_adjusted = 0.0002). Higher mean MAP was independently associated with lower odds of renal replacement therapy (odds ratioadjusted = 0.77 [95% confidence interval, 0.65-0.91] per 5 mmHg increase; p = .002]). CONCLUSIONS: Low mean MAP during TTM was independently associated with decreased renal function and need of renal replacement therapy in a large cohort of comatose OHCA-patients. Increasing MAP above the recommended 65 mmHg could potentially be renal-protective. This hypothesis should be investigated in prospective trials.

Lactate is a Prognostic Factor in Patients Admitted With Suspected ST-Elevation Myocardial Infarction.

AIMS: The diagnosis of cardiogenic shock depends on clinical signs of poor perfusion and low blood pressure. Lactate concentration will increase with poor tissue perfusion, and it has prognostic value in cardiogenic shock patients. We sought to assess the prognostic value of lactate concentration in subjects admitted with suspected ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: In 2,094 (93%) out of 2,247 consecutive suspected STEMI-subjects, lactate concentration was measured on admission. The prognostic value of lactate concentration on 30-day mortality was assessed in addition to clinical signs of peripheral hypoperfusion, systolic blood pressure (sBP), and left ventricular ejection fraction (LVEF) in multivariable models.Lactate concentration added prognostic information beyond signs of peripheral hypoperfusion, sBP, and LVEF, and was independently associated with 30-day mortality (hazard ratio [95% confidence interval] 1.11 [1.07-1.14], P < 0.0001). Lactate also provided predictive information on 30-day mortality to the combination of signs of peripheral hypoperfusion, sBP, and LVEF (area under the receiver-operating characteristics curve = 0.88 vs. 0.83, P < 0.0001). CONCLUSIONS: In conclusion, admission lactate concentration in suspected STEMI-subjects contains prognostic information on 30-day mortality when added to variables used in cardiogenic shock-definition. We recommend lactate measurement in STEMI-subjects, especially when signs of compromised hemodynamics are present.