In Nordic countries 30-day mortality rate is half that estimated with EuroSCORE II in high-risk adult patients given aprotinin and undergoing mainly complex cardiac procedures.

Objectives. To describe current on- (isolated coronary arterty bypass grafting, iCABG) and off-label (non-iCABG) use of aprotinin and associated safety endpoints in adult patients undergoing high-risk cardiac surgery in Nordic countries. Design. Data come from 10 cardiac surgery centres in Finland, Norway and Sweden participating in the European Nordic aprotinin patient registry (NAPaR). Results. 486 patients were given aprotinin between 2016 and 2020. 59 patients (12.1%) underwent iCABG and 427 (87.9%) non-iCABG, including surgery for aortic dissection (16.7%) and endocarditis (36.0%). 89.9% were administered a full aprotinin dosage and 37.0% were re-sternotomies. Dual antiplatelet treatment affected 72.9% of iCABG and 7.0% of non-iCABG patients. 0.6% of patients had anaphylactic reactions associated with aprotinin. 6.4% (95 CI% 4.2%-8.6%) of patients were reoperated for bleeding. Rate of postoperative thromboembolic events, day 1 rise in creatinine >44µmol/L and new dialysis for any reason was 4.7% (95%CI 2.8%-6.6%), 16.7% (95%CI 13.4%-20.0%) and 14.0% (95%CI 10.9%-17.1%), respectively. In-hospital mortality and 30-day mortality was 4.9% (95%CI 2.8%-6.9%) and 6.3% (95%CI 3.7%-7.8%) in all patients versus mean EuroSCORE II 11.4% (95%CI 8.4%-14.0%, p < .01). 30-day mortality in patients undergoing surgery for aortic dissection and endocarditis was 6.2% (95%CI 0.9%-11.4%) and 6.3% (95%CI 2.7%-9.9%) versus mean EuroSCORE II 13.2% (95%CI 6.1%-21.0%, p = .11) and 14.5% (95%CI 12.1%-16.8%, p = .01), respectively. Conclusions. NAPaR data from Nordic countries suggest a favourable safety profile of aprotinin in adult cardiac surgery.

Evaluation of Quatsome Morphology, Composition, and Stability for Pseudomonas aeruginosa Biofilm Eradication.

Biofilm infections are a major cause of food poisoning and hospital-acquired infections. Quaternary ammonium compounds are a group of effective disinfectants widely used in industry and households, yet their efficacy is lessened when used as antibiofilm agents compared to that against planktonic bacteria. It is therefore necessary to identify alternative formulations of quaternary ammonium compounds to achieve an effective biofilm dispersal. Quaternary ammonium amphiphiles can form vesicular structures termed "quatsomes" in the presence of cholesterol. In addition to their intrinsic antimicrobial properties, quatsomes can also be used for the delivery of other types of antibiotics or biomarkers. In this study, quatsomes were prepared from binary mixtures of cholesterol and mono- or dialkyl-quaternary ammonium compounds; then, the integrity and stability of their vesicular structure were assessed and related to monomer chain number and chain length. The quatsomes were used to treat Pseudomonas aeruginosa biofilms, showing effective antibiofilm abilities comparable to those of their monomers. A systematic liquid chromatography-mass spectrometry method for quantifying quatsome vesicle components was also developed and used to establish the significance of cholesterol in the quatsome self-assembly processes.

Cardiorespiratory fitness and the incidence of surgery for aortic valve stenosis-the HUNT study.

OBJECTIVES: Aortic valve stenosis (AVS) shares many risk factors with coronary disease, the latter being strongly and inversely associated with physical activity (PA) and cardiorespiratory fitness (CRF). However, the relationship between PA, CRF and AVS needs to be established. We explored whether PA habits and estimated CRF affect the risk of developing AVS demanding aortic valve replacement (AVR) and how these factors affect postoperative mortality. METHODS: Participants from the second and third waves of Trøndelag Health Study were cross-linked with a local heart surgery registry and the Norwegian Cause of Death Registry. Estimated CRF was calculated through a developed algorithm based on clinical and self-reported data. Fine-Gray competing risk analyses were used to investigate how PA habits and estimated CRF were associated with the risk of AVR across CRF quintiles, PA groups and per 1-metabolic equivalent task (MET) (3.5 ml/min/kg). RESULTS: In a study population of 57 214 participants, we found a 15% [95% confidence interval (CI) 1-27] reduced risk of AVR per 1-MET estimated CRF increment. Those in the highest CRF quintile had a 56% (95% CI 14-77) lower risk of surgery compared to the lowest quintile. Analyses on PA groups did not show significant results. Finally, we found a 37% (95% CI 17-53) lower risk of postoperative mortality per 1-MET increased estimated CRF. CONCLUSIONS: Our findings indicate a strong and inverse relationship between estimated CRF and incidence of AVR due to AVS. Higher estimated CRF was associated with lower mortality after surgery.

Is a hyperosmolar pump prime for cardiopulmonary bypass a risk factor for postoperative delirium? A double blinded randomised controlled trial.

Objective: Postoperative delirium (POD) is common after cardiac surgery. We have previously identified plasma sodium concentration and the volume of infused fluids during surgery as possible risk factors. Both are linked to the selection and composition of the pump prime used for cardiopulmonary bypass (CPB). Present study aims to examine whether hyperosmolality increases the risk for POD. Design: Patients ≥65 years (n = 195) scheduled for cardiac surgery were prospectively enrolled into this double blinded randomised clinical trial. Study group received a pump prime containing mannitol and ringer-acetate (966 mOsmol) (n = 98) vs. ringer-acetate (388 mOsmol) (n = 97) in the control group. Postoperative delirium was defined according to DSM-5 criteria based on a test-battery pre- and postoperatively (days 1-3). Plasma osmolality was measured on five occasions and coordinated with the POD assessments. The primary outcome was the POD incidence related to hyperosmolality as the secondary outcome. Results: The incidence of POD was 36% in the study group and 34% in the control group, without intergroup difference (p=.59). The plasma osmolality was significantly higher in the study group, both on days 1 and 3 and after CPB (p<.001). Post hoc analysis indicated that high osmolality levels increased the risk for delirium on day 1 by 9% (odds ratio (OR) 1.09, 95% CI 1.03-1.15) and by 10% on day 3 (OR 1.10, 95% CI 1.04-1.16). Conclusions: Use of a prime solution with high osmolality did not increase the incidence of POD. However, the influence of hyperosmolality as a risk factor for POD warrants further investigation.

2021 MiECTiS focused update on the 2016 position paper for the use of minimal invasive extracorporeal circulation in cardiac surgery.

The landmark 2016 Minimal Invasive Extracorporeal Technologies International Society (MiECTiS) position paper promoted the creation of a common language between cardiac surgeons, anesthesiologists and perfusionists which led to the development of a stable framework that paved the way for the advancement of minimal invasive perfusion and related technologies. The current expert consensus document offers an update in areas for which new evidence has emerged. In the light of published literature, modular minimal invasive extracorporeal circulation (MiECC) has been established as a safe and effective perfusion technique that increases biocompatibility and ultimately ensures perfusion safety in all adult cardiac surgical procedures, including re-operations, aortic arch and emergency surgery. Moreover, it was recognized that incorporation of MiECC strategies advances minimal invasive cardiac surgery (MICS) by combining reduced surgical trauma with minimal physiologic derangements. Minimal Invasive Extracorporeal Technologies International Society considers MiECC as a physiologically-based multidisciplinary strategy for performing cardiac surgery that is associated with significant evidence-based clinical benefit that has accrued over the years. Widespread adoption of this technology is thus strongly advocated to obtain additional healthcare benefit while advancing patient care.

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050.

Complete embolization of a mechanical aortic valve during trail running-a case report with a lucky ending.

Background: Complete embolization of a prosthetic heart valve is extremely rare and dangerous. This case reports a total embolization of a mechanical aortic valve and contributes to the literature regarding the diagnostic challenges related to infective endocarditis and follow-up after valvular surgery. Case summary: A 28-year-old male 11.5 years status-post a mechanical aortic valve replacement presented with acute onset of chest pain and dyspnoea while jogging. The patient lost consciousness and went into cardiopulmonary arrest with acute pulmonary oedema and circulatory shock. An echocardiogram revealed an empty aortic annulus, and a chest radiograph showed an embolized valve in the aortic arch. The patient underwent emergent removal of the embolized valve and replacement with a new mechanical aortic valve. The patient survived with minimal sequelae. At a 3-month follow-up, he had resumed work, and the only sequelae were mild left ventricular dysfunction and minor vision loss. Although he experienced no warning signs or symptoms, the most likely aetiology for embolization of the valvular prosthesis was infective endocarditis, which was revealed by re-evaluation of an echocardiogram recorded 1 month before the presentation which demonstrated a subtle motion abnormality of the valve. Conclusions: We present a case of a late complete embolization of a mechanical aortic valve most likely caused by asymptomatic infective endocarditis. The case illustrates the challenges in follow-up after valvular surgery and highlights the ultimate benefit of a well-functioning pre-hospital to hospital chain.

Cardiorespiratory fitness and the incidence of coronary surgery and postoperative mortality: the HUNT study.

OBJECTIVES: Low physical activity and cardiorespiratory fitness are known risk factors for coronary artery disease, but how they affect the risk of undergoing coronary artery bypass graft surgery is not established. We explored how physical activity and estimated cardiorespiratory fitness affect the risk of coronary surgery and postoperative outcome. METHODS: Participants with no history of coronary disease from the second wave of the Trøndelag Health Study (HUNT2) were cross-linked with the local heart surgery register and the Norwegian Cause of Death Registry. Cardiorespiratory fitness was estimated by a previously developed algorithm using clinical and self-reported information. Fine-Gray competing risk analyses were used to calculate the risk of undergoing isolated coronary surgery across physical activity groups and estimated cardiorespiratory fitness (mL/kg/min) as quintiles and per 1 metabolic equivalent of task (MET) (3.5 mL/kg/min). RESULTS: We included 45,491 participants. The mean population age was 46.0 [standard deviation (SD) 15.8] years, and the mean estimated fitness was 41.3 (SD 8.9) mL/kg/min. A total of 672 (1.5%) participants underwent coronary surgery during the follow-up period. The risk of undergoing isolated coronary surgery was 26% [95% confidence interval (CI) 3-44] lower for those classified as highly active compared to those classified as least active. Further, an 11% (95% CI 6-15) lower risk per 1-MET (3.5 mL/kg/min) of higher fitness. Finally, we observed a 15% (95% CI 5-23) lower mortality risk after surgery per 1-MET of higher fitness among those undergoing surgery. CONCLUSIONS: High levels of physical activity and high estimated fitness levels were inversely associated with the risk of developing coronary disease requiring surgery and overall mortality after surgery.

Serotonin-A Driver of Progressive Heart Valve Disease.

It is well known that some serotoninergic drugs and neuroendocrine tumors producing serotonin (5-HT) may induce valvular heart disease by stimulation of proliferation of valvular cells via interaction with a 5-HT receptor type 2B. Serotonin could play a role in the pathogenesis of progressive valvular disease for example as a complication of rheumatic fever, in patients with congenital bicuspid aortic valves or in degenerative aortic valve stenosis. The initial inflammation in acute rheumatic fever seems to affect both right and the left-side cardiac valves. Some patients develop chronic right-sided valve disease, particularly in connection with septum defects, though left-sided valves typically are predominantly affected, indicating that high flow velocity and systemic pressure close to the valves may be central in the pathogenesis. Serotonin is transported in granules in blood platelets. Changes in platelet number and concentrations of substances released from platelets in patients with valvular disease indicate that serotonin is released locally by shear stress when passing through an abnormal valve. Accordingly, any functional changes (like bicuspid aortic valves and changes secondary to degeneration) in the valves may progress due to locally released serotonin. Unfortunately, due to serotonin release by sampling and preparation of plasma, local serotonin assessment is not possible. Nevertheless, we suggest that serotonin may play a role in valvular disease in general and that patients may benefit from treatment reducing the effect of serotonin on the heart.

Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors.

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

Long-term follow-up after surgery for atrial fibrillation with concomitant open heart surgery. / Langtidsoppfølging etter atrieflimmeroperasjon og samtidig åpen hjertekirurgi.

BACKGROUND: Patients with atrial fibrillation and atrial flutter scheduled to undergo open heart surgery can receive ablation treatment of arrhythmogenic foci during the same intervention. Sinus rhythm is restored in the majority in the short term, but the long-term results are more uncertain. This study, which is part of the international CURE-AF trial, evaluates results after Cox-Maze IV surgery for atrial fibrillation in Norway at six-year follow-up. MATERIAL AND METHOD: Nineteen patients were included in this prospective cohort study. Atrial fibrillation had persisted for 40 months in the group with long-standing persistent atrial fibrillation (n = 12) and 6 months in the group with persistent atrial fibrillation (n = 7). Surgery for atrial fibrillation was performed according to the Cox-Maze IV procedure in the CURE-AF protocol. Follow-up in the first 12 months was strictly according to the CURE-AF protocol, thereafter conducted by the primary health service. RESULTS: Sinus rhythm was restored in 11 patients at the time of discharge and in 14 patients six months postoperatively. After 5-6 years of follow-up, all patients with long-standing persistent atrial fibrillation had experienced recurrence. Two achieved sinus rhythm after electroconversion. Six of the seven in the group with persistent atrial fibrillation had sinus rhythm after 5-6 years. INTERPRETATION: The results were good initially, with restoration of sinus rhythm in more than two thirds of the patients after 6-9 months. Five years later, a high recurrence rate was found in patients with long-standing persistent atrial fibrillation. Several recurrences had not been detected by the public health service or treatment had not been attempted.

Relative impact of red blood cell transfusion and anaemia on 5-year mortality in cardiac surgery.

OBJECTIVES: The aim was to compare the relative effects of red blood cell (RBC) transfusion and preoperative anaemia on 5-year mortality following open-heart cardiac surgery using structural equation modelling. We hypothesized that patient risk factors associated with RBC transfusion are of larger importance than transfusion itself. METHODS: This prospective cohort study, part of the Cardiac Surgery Outcome Study at St. Olavs University Hospital, Trondheim, Norway, included open-heart on-pump cardiac surgery patients operated on from 2000 through 2017 (n = 9315). Structural equation modelling, which allows for intervariable correlations, was used to analyse pathway diagrams between known risk factors and observed mortality between 30 days and 5 years postoperatively. Observation times between 30 days and 1 year, and 1-5 years postoperatively were also compared with the main analysis. RESULTS: In a simplified model, preoperative anaemia had a larger effect on 5-year mortality than RBC transfusion (standardized coefficients: 0.17 vs 0.09). The complete model including multiple risk factors showed that patient risk factors such as age (0.15), anaemia (0.10), pulmonary disease (0.11) and higher creatinine level (0.12) had larger effects than transfusion (0.03). Results from several sensitivity analyses supported the main findings. The models showed good fit. CONCLUSIONS: Preoperative anaemia had a larger impact on 5-year mortality than RBC transfusion. Differences in 5-year mortality were mainly associated with patient risk factors.

Long-term results after aortic valve replacement for bicuspid or tricuspid valve morphology in a Swedish population.

OBJECTIVES: Our goal was to study long-term observed and relative survival after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass surgery with reference to valve morphology (i.e. bicuspid vs tricuspid). METHODS: Consecutive patients (n = 5086) from 3 Swedish hospitals, operated on between 1 January 2005 and 31 December 2016, were included. The 30-day mortality (n = 116, 2.3%) was excluded from the analysis of long-term observed and relative survival (n = 4970). Observed survival was analysed using Cox regression. Relative survival was calculated as the ratio between observed and expected survival based on data from the general Swedish population, matched for age, sex and calendar year. Risk factors for death were explored using multivariable analysis. RESULTS: During the follow-up (median 4.7 years) period, 1157 (23%) patients died. Observed survival excluding 30-day mortality was 96.6%, 82.7% and 57.6% after 1, 5 and 10 years. Compared with the general Swedish population, the relative 1-, 5- and 10-year survival rates were 99.0%, 97.5% and 89.0%. Bicuspid morphology was independently associated with higher observed and relative long-term survival. Renal dysfunction, diabetes, chronic obstructive pulmonary disease, heart failure, smoking and atrial fibrillation were associated with higher long-term mortality. Combined surgery was not associated with higher observed or relative mortality. CONCLUSIONS: Patients with a bicuspid morphology had better prognosis, matching that of the general population. With increased age, long-term relative survival compared favourably with survival in the general Swedish population. Adding coronary artery bypass surgery to an aortic valve replacement procedure did not affect long-term outcome.

Limited effect of red blood cell transfusion on long-term mortality among anaemic cardiac surgery patients.

OBJECTIVES: Our goal was to investigate long-term mortality associated with red blood cell (RBC) transfusion among patients with anaemia undergoing cardiac surgery when adjusting for known risk factors. METHODS: Adults with preoperative anaemia as defined by World Health Organization criteria undergoing open-heart surgery from 2000 through 2017 were included. Cox regression was performed for long-term mortality (30 days-5 years), comparing patients who received ≥1 unit of RBC with those who did not. Unadjusted and multivariable analyses adjusted for risk factors were performed. RESULTS: The study included 1859 patients, 1525 (82%) of whom received RBC transfusion. A total of 370 (19.9%) deaths were registered between 30 days and 5 years; 88 patients (23.8%) died between 30 days and 1 year. The unadjusted hazard ratio (HR) associated with RBC transfusion was 2.09 (1.49-2.93, P < 0.001) from 30 days to 5 years postoperatively. The HR for RBC transfusion were 4.70 (1.72-12.81, P = 0.002) and 1.77 (1.23-2.55, P = 0.002) for 30 days-1 year and 1-5 years, respectively. Adjusting for perioperative risk factors, which included postoperative complications, the HR decreased to 1.16 (0.80-1.68, P = 0.43), 1.79 (0.63-5.12, P = 0.28) and 1.11 (0.75-1.65, P = 0.61) for observation time from 30 days to 5 years, 30 days to 1 year and 1 to 5 years, respectively. Results were similar when postoperative complications were excluded from the adjustment variables. CONCLUSIONS: No statistically significant association between RBC transfusion and long-term mortality was found when we adjusted for known risk factors. This study suggests that the observed difference in mortality in this patient group is largely due to patient-related risk factors.