The association of prior paracetamol intake with outcome of very old intensive care patients with COVID-19: results from an international prospective multicentre trial.

BACKGROUND: In the early COVID-19 pandemic concerns about the correct choice of analgesics in patients with COVID-19 were raised. Little data was available on potential usefulness or harmfulness of prescription free analgesics, such as paracetamol. This international multicentre study addresses that lack of evidence regarding the usefulness or potential harm of paracetamol intake prior to ICU admission in a setting of COVID-19 disease within a large, prospectively enrolled cohort of critically ill and frail intensive care unit (ICU) patients. METHODS: This prospective international observation study (The COVIP study) recruited ICU patients ≥ 70 years admitted with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, prior paracetamol intake within 10 days before admission, ICU therapy, limitations of care and survival during the ICU stay, at 30 days, and 3 months. Paracetamol intake was analysed for associations with ICU-, 30-day- and 3-month-mortality using Kaplan Meier analysis. Furthermore, sensitivity analyses were used to stratify 30-day-mortality in subgroups for patient-specific characteristics using logistic regression. RESULTS: 44% of the 2,646 patients with data recorded regarding paracetamol intake within 10 days prior to ICU admission took paracetamol. There was no difference in age between patients with and without paracetamol intake. Patients taking paracetamol suffered from more co-morbidities, namely diabetes mellitus (43% versus 34%, p < 0.001), arterial hypertension (70% versus 65%, p = 0.006) and had a higher score on Clinical Frailty Scale (CFS; IQR 2-5 versus IQR 2-4, p < 0.001). Patients under prior paracetamol treatment were less often subjected to intubation and vasopressor use, compared to patients without paracetamol intake (65 versus 71%, p < 0.001; 63 versus 69%, p = 0.007). Paracetamol intake was not associated with ICU-, 30-day- and 3-month-mortality, remaining true after multivariate adjusted analysis. CONCLUSION: Paracetamol intake prior to ICU admission was not associated with short-term and 3-month mortality in old, critically ill intensive care patients suffering from COVID-19. TRIAL REGISTRATION: This prospective international multicentre study was registered on ClinicalTrials.gov with the identifier "NCT04321265" on March 25, 2020.

Real-world experience with the cusp-overlap deployment technique in transcatheter aortic valve replacement: A propensity-matched analysis.

Background: The implantation depth (ID) is a critical condition for optimal hemodynamic and clinical outcomes in transcatheter aortic valve replacement (TAVR). The recently recommended cusp-overlap technique (COT) offers optimized fluoroscopic projections facilitating a precise ID. This single-center observational study aimed to investigate short-term clinical performance, safety, and efficacy outcomes in patients undergoing TAVR with self-expandable prostheses and application of COT in a real-world setting. Materials and methods: From September 2020 to April 2021, a total of 170 patients underwent TAVR with self-expandable devices and the application of COT, while 589 patients were treated from January 2016 to August 2020 with a conventional three-cusp coplanar view approach. The final ID and 30-day outcomes were compared after 1:1 propensity score matching, resulting in 150 patients in both cohorts. Results: The mean ID was significantly reduced in the COT cohort (-4.2 ± 2.7 vs. -4.9 ± 2.3 mm; p = 0.007) with an improvement of ID symmetry of less than 2 mm difference below the annular plane (47.3 vs. 57.3%; p = 0.083). The rate of new permanent pacemaker implantation (PPI) following TAVR was effectively reduced (8.0 vs. 16.8%; p = 0.028). While the fluoroscopy time decreased (18.4 ± 7.6 vs. 19.8 ± 7.6 min; p = 0.023), the dose area product increased in the COT group (4951 ± 3662 vs. 3875 ± 2775 Gy × cm2; p = 0.005). Patients implanted with COT had a shorter length of in-hospital stay (8.4 ± 4.0 vs. 10.3 ± 6.7 days; p = 0.007). Conclusion: Transcatheter aortic valve replacement using the cusp-overlap deployment technique is associated with an optimized implantation depth, leading to fewer permanent conduction disturbances. However, our in-depth analysis showed for the first time an increase of radiation dose due to extreme angulations of the gantry to obtain the cusp-overlap view.

Structured Allocation of Transcatheter Aortic Valve Replacement Patients during Coronavirus Disease 2019 Pandemic: Impact on Patient Selection and Clinical Results.

Due to shortages of medical resources during the Coronavirus Disease 2019 (COVID-19) pandemic, an allocation algorithm for Transcatheter Aortic Valve Replacement (TAVR) was established. We investigated the impact on patient selection and procedural results. In total, 456 TAVR patients before (pre-COVID-19 group) and 456 TAVR patients after (COVID-19 group) the implementation of our allocation algorithm were compared. Concerning patient characteristics, the COVID-19 group revealed a higher rate of cardiac decompensations/cardiogenic shocks (10.5% vs. 1.3%; p < 0.001), severe angina pectoris (Canadian Cardiovascular Society (CCS) II, III and IV: 18.7% vs. 11.8%; p = 0.004), troponin elevation (>14 ng/L: 84.9% vs. 77%; p = 0.003) and reduced left ventricular ejection fraction (LVEF) (<45%: 18.9% vs. 12%; p = 0.006). Referring to procedural characteristics, more predilatations (46.3% vs. 35.1%; p = 0.001) and a longer procedural time (80.2 min (+/−29.4) vs. 66.9 min (+/−17.5); p < 0.001) were observed. The success rate was evenly high; no differences in safety parameters were reported. Examining the utilization of hospital resources, the COVID-19 group showed a shorter in-hospital stay (8.4 days (+/−5.9) vs. 9.5 days (+/−9.33); p = 0.041) and fewer TAVR patients were treated per month (39 (+/−4.55) vs. 46.11 (+/−7.57); p = 0.03). Our allocation algorithm supported prioritization of sicker patients with similar efficient and safe TAVR procedures. In-hospital stay could be shortened.

Bioprosthetic valve dysfunction and failure after TAVI in bicuspid aortic valve stenosis during one-year follow-up according to VARC-3.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) in bicuspid aortic valve (BAV) stenosis has become more frequent in the last years. This may pose challenges for long-time valve durability. Therefore, we aimed to evaluate the prevalence of bioprosthetic valve dysfunction (BVD) with the newest-generation devices in BAV stenosis up to one-year follow-up (FU). METHODS: The primary endpoint was defined as the prevalence of BVD during the first procedural year according to Valve Academic Research Consortium (VARC)-3 criteria. Secondary endpoints were defined as failure in device success and clinical endpoints according to VARC-3. RESULTS: A total of 107 patients were included. Of these, 34 subjects (31.8%) met the criteria for BVD during a mean FU of 263 ± 180 days, of which 20.2% were already documented after thirty days. Device success after one year was lower in the + BVD cohort (57.6% vs. 98.7%, p < 0.0001*). The rates of structural valve deterioration were 6.5%, non-structural valve deterioration (NSVD) 17.8%, subclinical leaflet thickening 10.3%, and endocarditis 0.9%. NSVD was foremost triggered by patient prosthesis mismatch in balloon-expandable valves. Hemodynamic valve deterioration stage 1 and 2 was confirmed in 16.8% of + BVD patients, while stage 1 and 3 bioprosthetic valve failure occurred in 1.9%. There was no impact of BVD on mortality. CONCLUSION: There is critical evidence of early BVD after TAVI in BAV during one-year FU in one-third of patients, also lowering device success. The most frequently observed bioprosthetic valve dysfunction was NSVD due to patient prosthesis mismatch following TAVI with a balloon-expandable valve.

Lactate is associated with mortality in very old intensive care patients suffering from COVID-19: results from an international observational study of 2860 patients.

PURPOSE: Lactate is an established prognosticator in critical care. However, there still is insufficient evidence about its role in predicting outcome in COVID-19. This is of particular concern in older patients who have been mostly affected during the initial surge in 2020. METHODS: This prospective international observation study (The COVIP study) recruited patients aged 70 years or older (ClinicalTrials.gov ID: NCT04321265) admitted to an intensive care unit (ICU) with COVID-19 disease from March 2020 to February 2021. In addition to serial lactate values (arterial blood gas analysis), we recorded several parameters, including SOFA score, ICU procedures, limitation of care, ICU- and 3-month mortality. A lactate concentration ≥ 2.0 mmol/L on the day of ICU admission (baseline) was defined as abnormal. The primary outcome was ICU-mortality. The secondary outcomes 30-day and 3-month mortality. RESULTS: In total, data from 2860 patients were analyzed. In most patients (68%), serum lactate was lower than 2 mmol/L. Elevated baseline serum lactate was associated with significantly higher ICU- and 3-month mortality (53% vs. 43%, and 71% vs. 57%, respectively, p < 0.001). In the multivariable analysis, the maximum lactate concentration on day 1 was independently associated with ICU mortality (aOR 1.06 95% CI 1.02-1.11; p = 0.007), 30-day mortality (aOR 1.07 95% CI 1.02-1.13; p = 0.005) and 3-month mortality (aOR 1.15 95% CI 1.08-1.24; p < 0.001) after adjustment for age, gender, SOFA score, and frailty. In 826 patients with baseline lactate ≥ 2 mmol/L sufficient data to calculate the difference between maximal levels on days 1 and 2 (∆ serum lactate) were available. A decreasing lactate concentration over time was inversely associated with ICU mortality after multivariate adjustment for SOFA score, age, Clinical Frailty Scale, and gender (aOR 0.60 95% CI 0.42-0.85; p = 0.004). CONCLUSION: In critically ill old intensive care patients suffering from COVID-19, lactate and its kinetics are valuable tools for outcome prediction. TRIAL REGISTRATION NUMBER: NCT04321265.

ICU-Mortality in Old and Very Old Patients Suffering From Sepsis and Septic Shock.

Purpose: Old (>64 years) and very old (>79 years) intensive care patients with sepsis have a high mortality. In the very old, the value of critical care has been questioned. We aimed to compare the mortality, rates of organ support, and the length of stay in old vs. very old patients with sepsis and septic shock in intensive care. Methods: This analysis included 9,385 patients, from the multi-center eICU Collaborative Research Database, with sepsis; 6184 were old (aged 65-79 years), and 3,201 were very old patients (aged 80 years and older). A multi-level logistic regression analysis was used to fit three sequential regression models for the binary primary outcome of ICU mortality. A sensitivity analysis in septic shock patients (n = 1054) was also conducted. Results: In the very old patients, the median length of stay was shorter (50 ± 67 vs. 56 ± 72 h; p < 0.001), and the rate of a prolonged ICU stay was lower (>168 h; 9 vs. 12%; p < 0.001) than the old patients. The mortality from sepsis was higher in very old patients (13 vs. 11%; p = 0.005), and after multi-variable adjustment being very old was associated with higher odds for ICU mortality (aOR 1.32, 95% CI 1.09-1.59; p = 0.004). In patients with septic shock, mortality was also higher in the very old patients (38 vs. 36%; aOR 1.50, 95% CI 1.10-2.06; p = 0.01). Conclusion: Very old ICU-patients suffer from a slightly higher ICU mortality compared with old ICU-patients. However, despite the statistically significant differences in mortality, the clinical relevance of such minor differences seems to be negligible.

Provision of critical care for the elderly in Europe: a retrospective comparison of national healthcare frameworks in intensive care units.

OBJECTIVES: In Europe, there is a distinction between two different healthcare organisation systems, the tax-based healthcare system (THS) and the social health insurance system (SHI). Our aim was to investigate whether the characteristics, treatment and mortality of older, critically ill patients in the intensive care unit (ICU) differed between THS and SHI. SETTING: ICUs in 16 European countries. PARTICIPANTS: In total, 7817 critically ill older (≥80 years) patients were included in this study, 4941 in THS and 2876 in the SHI systems. PRIMARY AND SECONDARY OUTCOMES MEASURES: We chose generalised estimation equations with robust standard errors to produce population average adjusted OR (aOR). We adjusted for patient-specific variables, health economic data, including gross domestic product (GDP) and human development index (HDI), and treatment strategies. RESULTS: In SHI systems, there were higher rates of frail patients (Clinical Frailty Scale>4; 46% vs 41%; p<0.001), longer length of ICU stays (90±162 vs 72±134 hours; p<0.001) and increased levels of organ support. The ICU mortality (aOR 1.50, 95% CI 1.09 to 2.06; p=0.01) was consistently higher in the SHI; however, the 30-day mortality (aOR 0.89, 95% CI 0.66 to 1.21; p=0.47) was similar between THS and SHI. In a sensitivity analysis stratifying for the health economic data, the 30-day mortality was higher in SHI, in low GDP per capita (aOR 2.17, 95% CI 1.42 to 3.58) and low HDI (aOR 1.22, 95% CI 1.64 to 2.20) settings. CONCLUSIONS: The 30-day mortality was similar in both systems. Patients in SHI were older, sicker and frailer at baseline, which could be interpreted as a sign for a more liberal admission policy in SHI. We believe that the observed trend towards ICU excess mortality in SHI results mainly from a more liberal admission policy and an increase in treatment limitations. TRIAL REGISTRATION NUMBERS: NCT03134807 and NCT03370692.

Factors associated with a high or low implantation of self-expanding devices in TAVR.

OBJECTIVES: Optimizing valve implantation depth (ID) plays a crucial role in minimizing conduction disturbances and achieving optimal functional integrity. Until now, the impact of intraprocedural fast (FP) or rapid ventricular pacing (RP) on the implantation depth has not been investigated. Therefore, we aimed to (1) evaluate the impact of different pacing maneuvers on ID, and (2) identify the independent predictors of deep ID. METHODS: 473 TAVR patients with newer-generation self-expanding devices were retrospectively enrolled and one-to-one propensity-score-matching was performed, resulting in a matching of 189 FP and RP patients in each cohort. The final ID was analyzed, and the underlying functional, anatomical, and procedural conditions were evaluated by univariate and multivariate analysis. RESULTS: The highest ID was reached under RP in severe aortic valve calcification and valve size 26 mm. Multivariate analysis identified left ventricular outflow (LVOT) calcification [OR 0.50 (0.31-0.81) p = 0.005*], a "flare" aortic root [OR 0.42 (0.25-0.71), p = 0.001*], and RP (OR 0.49 [0.30-0.79], p = 0.004*) as independent highly preventable predictors of a deep ID. In a model of protective factors, ID was significantly reduced with the number of protective criteria (0-2 criteria: - 5.7 mm ± 2.6 vs. 3-4 criteria - 4.3 mm ± 2.0; p < 0.0001*). CONCLUSION: Data from this retrospective analysis indicate that RP is an independent predictor to reach a higher implantation depth using self-expanding devices. Randomized studies should prove for validation compared to fast and non-pacing maneuvers during valve delivery and their impact on implantation depth. TRAIL REGISTRATION: Clinical Trial registration: NCT01805739. STUDY DESIGN: Evaluation of the impact of different pacing maneuvers (fast ventricular pacing-FP vs. rapid ventricular pacing-RP) on implantation depth (ID). After one-to-one-propensity-score-matching, independent protective and risk factors for a very deep ID beneath 6 mm toward the LVOT (< - 6 mm) were identified. Stent frame pictures as a courtesy by Medtronic®. AVC aortic valve calcification.

Impella versus extracorporal life support in cardiogenic shock: a propensity score adjusted analysis.

AIMS: The mortality in cardiogenic shock (CS) is high. The role of specific mechanical circulatory support (MCS) systems is unclear. We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS. METHODS AND RESULTS: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 2.5 or ECLS from two European registries. The decision for device implementation was made at the discretion of the treating physician. The primary endpoint of this study was all-cause mortality at 30 days. A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR). In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS. The feasibility of device implantation was high (87%) and similar (aOR: 3.14; 95% CI: 0.18-56.50; P = 0.41) with both systems. The rates of vascular injuries (aOR: 0.95; 95% CI: 0.10-3.50; P = 0.56) and bleedings requiring transfusions (aOR: 0.44; 95% CI: 0.09-2.10; P = 0.29) were similar in ECLS patients and Impella patients. The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 4.19; 95% CI: 0.53-33.25; P = 0.17), after correction for propensity score and baseline lactate level. Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 1.29; 95% CI: 1.14-1.45; P < 0.001). CONCLUSIONS: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar. The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies. In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors.

Usefulness of Serum Free Thyroxine Concentration to Predict Ventricular Arrhythmia Risk in Euthyroid Patients With Structural Heart Disease.

The aim of the present study was to determine whether free thyroxine (FT4) and calculated thyroid parameters predict the incidence of ventricular arrhythmias in euthyroid heart failure patients with implantable cardioverter-defibrillators (ICD). In this open-label prospective cohort study, 115 consecutive euthyroid patients (mean age 62.9 ± 1.3 years; 87% male; ischemic cardiomyopathy 63%) scheduled for primary prevention ICD implantation or exchange were enrolled. Serum concentrations of thyrotropin (thyroid-stimulating hormone) and FT4 were measured 1 day before device operation. Primary and secondary end points were defined as occurrence of appropriate ICD therapy (AIT) and cardiovascular death, respectively. During a mean follow-up of 1,191 ± 35 days, 24 patients (21%) experienced AIT, and cardiovascular death was observed in 10 patients (9%). Patients with AIT had higher FT4 concentrations compared with those without AIT (18.9 ± 0.48 vs 16.2 ± 0.22 pmol/L, p <0.001). FT4 was an independent predictor of AIT in an adjusted Cox regression (hazard ratio = 1.47, p <0.001). Kaplan-Meier analysis demonstrated that Jostel's thyroid-stimulating hormone index, reflecting the central component of the hypothalamus-pituitary-thyroid loop, and SPINA-GT as surrogate markers for thyroid's secretory capacity predicted AIT incidences. None of the indices predicted cardiovascular death. In conclusion, FT4 concentration predicts an increased incidence of ventricular arrhythmias in euthyroid patients receiving ICDs for primary prevention. Our data suggest that both impending primary hyperthyroidism and an increased thyroid homeostasis set point may increase the rate of AIT in this patient population.

The effects of different aerobic exercise intensities on serum serotonin concentrations and their association with Stroop task performance: a randomized controlled trial.

PURPOSE: Acute exercise improves selective aspects of cognition such as executive functioning. Animal studies suggest that some effects are based on exercise-induced alterations in serotonin (5-HT) secretion. This study evaluates the impact of different aerobic exercise intensities on 5-HT serum levels as well as on executive functioning considering 5-HT as a potential mediator. METHODS: 121 young adults (23.8 ± 3.6 years) were examined in a randomized controlled trial including three exercise intervention (35 min) groups (low intensity, 45 % of the maximal heart rate (HRmax); moderate intensity, 65 % HRmax; high intensity, 85 % HRmax) and one control group. 5-HT levels and response inhibition (measured by a computerized Stroop test) were assessed pre- and post-intervention. RESULTS: There was a significant (p = 0.022) difference between groups regarding serum Δ5-HT levels. Post hoc tests indicated significant (p = 0.013) higher 5-HT serum levels for the high-intensity group compared to the control group while other groups did not differ significantly from each other. Serum Δ5-HT levels and exercise intensity were shown to be linearly associated through polynomial contrast analysis (p = 0.003). Furthermore, ANOVA revealed a significant difference for Stroop parameter reading (p = 0.030) and a tendency for reverse Stroop effect (p = 0.061). Correlation analysis showed that augmented 5-HT levels were associated with improved results in response inhibition. CONCLUSIONS: This study indicates that intensive acute exercise increases serum 5-HT levels compared to a control group. These findings might be relevant for many other related research fields in exercise science, since 5-HT receptors are expressed on many different cell types including endothelia and immune cells.

Exhaustive Exercise Alters Thinking Times in a Tower of London Task in a Time-Dependent Manner.

Purpose: In contrast to other aspects of executive functions, acute exercise-induced alterations in planning are poorly investigated. While only few studies report improved planning performances after exercise, even less is known about their time course after exhaustive exercise. Methods: One hundred and nineteen healthy adults performed the Tower of London (ToL) task at baseline, followed by a graded exercise test (GXT). Participants were subsequently randomized into one of four groups (immediately, 30, 60, and 90 min after the GXT) to repeat the ToL. Main outcomes of the ToL were planning (number of tasks completed in the minimum number of moves), solutions (correct responses independent of the given number of moves) as well as thinking times (time between presentation of each problem and first action) for tasks with varying difficulty (four-, five,- and six-move problems). Blood lactate levels were analyzed as a potential mediator. Results: No effect of exercise on planning could be detected. In contrast to complex problem conditions, median thinking times deteriorated significantly in the immediately after GXT tested group in less challenging problem conditions (four-move problems: p = 0.001, F = 5.933, df = 3; five-move problems: p = 0.005, F = 4.548, df = 3). Decreased lactate elimination rates were associated with impaired median thinking times across all groups ΔMTT4-6 (p = 0.001, r = -0.309), ΔMTT4 (p < 0.001, r = -0.367), and ΔMTT5 (p = 0.001, r = -0.290). Conclusion: These results suggest that planning does not improve within 90 min after exhaustive exercise. In line with previous research, revealing a negative impact of exhaustive exercise on memory and attention, our study extends this knowledge of exercise-induced alterations in cognitive functioning as thinking times as subcomponents of planning are negatively affected immediately after exercise. This is further associated with peripheral lactate levels.