SARS-CoV-2 viral load is linked to remdesivir efficacy in severe Covid-19 admitted to intensive care.

Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity.

Echocardiography predictors of sustained sinus rhythm after cardioversion of supraventricular arrhythmia in patients with septic shock.

PURPOSE: The echocardiography parameters may predict the maintenance of sinus rhythm after cardioversion of a supraventricular arrhythmia (SVA). MATERIALS AND METHODS: Patients in septic shock with onset of an SVA, normal to moderately reduced LV systolic function (EF_LV˃̳35%) and on a continuous noradrenaline of <1.0 µg/kg.min were included. Echocardiography was performed at the arrhythmia onset, 1 h and 4 h post cardioversion on an infusion of propafenone or amiodarone. RESULTS: Cardioversion was achieved in 96% of the 209 patients within a median time of 6(1.8-15.6)h, 134(64.1%) patients experienced at least one SVA recurrence after cardioversion. At 4 h the left atrial emptying fraction (LA_EF, cut-off 38.4%, AUC 0.69,p˂0.001), and transmitral A wave velocity-time-integral (Avti, cut-off 6.8 cm, AUC 0.65,p = 0.001) showed as limited predictors of a single arrhythmia recurrence. The LA_EF 44(36,49)%, (p = 0.005) and the Avti 8.65(7.13,9.50)cm, (p < 0.001) were associated with sustained sinus rhythm and decreased proportionally to increasing numbers of arrhythmia recurrences (p < 0.001 and p = 0.007, respectively). The enlarged left atrial end-systolic diameter at the arrhythmia onset (p = 0.04) and elevated systolic pulmonary artery pressure at 4 h (p = 0.007) were weak predictors of multiple(˃3) recurrences. CONCLUSION: The LA_EF and Avti are related to arrhythmia recurrences post-cardioversion suggesting potential guidance to the choice between rhythm and rate control strategies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03029169, registered on 24th of January 2017.

Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients.

BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.

Is the process of withdrawal of life-sustaining measures in the intensive care unit different for deceased organ donors compared with other dying patients? A secondary analysis of prospectively collected data.

OBJECTIVE: To investigate whether observable differences exist between patterns of withdrawal of life-sustaining measures (WLSM) for patients eligible for donation after circulatory death (DCD) in whom donation was attempted compared with those patients in whom no donation attempts were made. SETTING: Adult intensive care units from 20 centres in Canada, the Czech Republic and the Netherlands. DESIGN: Secondary analysis of quantitative data collected as part of a large, prospective, cohort study (the Death Prediction and Physiology after Removal of Therapy study). PARTICIPANTS: Patients ≥18 years of age who died after a controlled WLSM in an intensive care unit. Patients were classified as not DCD eligible, DCD eligible with DCD attempted or DCD eligible but DCD was not attempted. PRIMARY AND SECONDARY OUTCOME MEASURES: The process of WLSM (timing and type and, if applicable, dosages of measures withdrawn, dosages of analgesics/sedatives) was compared between groups. RESULTS: Of the 635 patients analysed, 85% had either cardiovascular support stopped or were extubated immediately on WLSM. Of the DCD eligible patients, more were immediately extubated at the initiation of WLSM when DCD was attempted compared with when DCD was not attempted (95% vs 61%, p<0.0001). Initiation of WLSM with the immediate cessation of cardiovascular measures or early extubation was associated with earlier time to death, even after adjusting for confounders (OR 2.94, 95% CI 1.39 to 6.23, at 30 min). Other than in a few patients who received propofol, analgesic and sedative dosing after WLSM between DCD attempted and DCD eligible but not attempted patients was not significantly different. All patients died. CONCLUSIONS: Patients in whom DCD is attempted may receive a different process of WLSM. This highlights the need for a standardised and transparent process for end-of-life care across the spectrum of critically ill patients and potential organ donors.

Changes of cortical perfusion in the early phase of subarachnoid bleeding in a rat model and the role of intracranial hypertension.

Brain perfusion is reduced early after subarachnoid hemorrhage (SAH) due to intracranial hypertension and early vasospasm. The contribution of these two mechanisms is unknown. By performing a prophylactic decompressive craniectomy (DC) in a rat model of SAH we aimed to study brain perfusion after the component of intracranial hypertension has been eliminated. We used 2x2 factorial design, where rats received either decompressive craniectomy or sham operation followed by injection of 250 microl of blood or normal saline into prechiasmatic cistern. The cortical perfusion has been continually measured by laser speckle-contrast analysis for 30 min. Injection of blood caused a sudden increase of intracranial pressure (ICP) and drop of cerebral perfusion, which returned to baseline within 6 min. DC effectively prevented the rise of ICP, but brain perfusion after SAH was significantly lower and took longer to normalize compared to non-DC animals due to increased cerebral vascular resistance, which lasted throughout 30 min experimental period. Our findings suggest that intracranial hypertension plays dominant role in the very early hypoperfusion after SAH whilst the role of early vasospasm is only minor. Prophylactic DC effectively maintained cerebral perfusion pressure, but worsened cerebral perfusion by increased vascular resistance.

Apoptosis as an early event in the development of multiple organ failure?

We have recently developed a simple method of plasma free DNA detection, which enables us to distinguish between apoptotic and genomic (necrotic) DNA. After applying this method to the critically ill, we revealed apoptotic DNA on the day of admission to be higher than later when multiple-organ failure developed. Moreover, apoptotic DNA contributed to total plasma DNA much more than DNA from necrotic cells and its increase predicted future development of multiple-organ failure and death.

[Diabetic diet and reduction diet are worthy of a basic discussion of their paradigms]. / Diabetická i redukcní dieta zasluhují základní diskusi o svých paradigmatech.

Present knowledge of etiopathogenesis of various types of diabetes postulate substantial differences between type I and type II diabetes. Whereas type I diabetes results from autoimmune destruction of pancreatic B-cells and subsequent absolute lack of insulin, type II diabetes is connected with insulin resistance and frequently with rather relative lack of sometimes absolutely elevated plasmatic insulin. From the viewpoint of the diet therapy an access to both types of diabetes fairly differs. Whilst in type I diabetes it is necessary to find out relationship among preprandial insulin dose, received carbohydrates, and expected physical activity soon after meal, treatment of type II diabetes is based in an effort to influence insulin resistance and the whole metabolic syndrome. Therefore, on one side carbohydrates with low glycemic index and plenty of fibers are administered in a diet and on the other side monoenic and polyenic fatty acids are preferred to saturated fatty acids and trans fatty acids are continuously reduced in a diet. Of course, diets for patients with overweight and for obese patients are low energy. From the viewpoint of the current structure of the diabetic diets it is suitable to differentiate diets for patients with type I and type II diabetes. Instead of the use of a fix proportion of nutrients we have to discuss diets with regard to a qualitative composition of fatty acids in fats, glycemic index of saccharides, and an amount of fibers in the diet.

[Hexakis, (t-butylisonitryl/technetium, 99mTc-TBI), a cold-focal cardiac radiopharmaceutic agent and its distribution in the body]. / Studenoloziskové srdecní radiofarmakon Hexakis (t-Butylisonitryl/Technetium (99mTc-TBI) a jeho distribuce v organismu.

The distribution of coldfocal cardiopharmacological substance 99mTc-TBI has been studied on a total of 14 dogs in relation to the healthy heart tissue. The quality heart scan resulted from the use of 99mTc-TBI. It may be performed 30 min after the administration of mentioned substance, when its blood activity is smaller than 10% activity of myocardium From the other organs, the myocardium scan may be influenced negatively with only liver which achieves 200% activity of left heart ventricle what is evidently consequential in worse imaging of "lower" ischemic lesions. These results justify us to conclude that the 99mTc-TBI is a substance suitable for scintigraphical imaging of myocardium.

[A 5-year study of cardiac involvement in polymyositis/dermatomyositis]. / Petiletá studie postizení srdce u polymyositidy/dermatomyositidy.

Improvement of the diagnosis and new therapeutic opportunities revealed a number of organ affections also in patients with polymyositis and dermatomyositis. One of the prognostically important organ manifestations is affection of the heart. The prospective investigation comprises 15 patients with a confirmed diagnosis of polymyositis (10) or dermatomyositis (5). The investigation, using a number of non-invasive method (ECG, echocardiography, systolic time intervals, 99mTc pyrophosphate scan of the heart muscle), proved in the course of the 60-month investigation an increase of pathological findings from 40% at the onset (6/15) to 6 from 11 surviving patients (three died), i.e. a total of 64.3% of the group. Investigation of the fate of patients with signs of myocardial damage during the active stage of the disease (positive myocardial scan) indicates that in these patients also other signs of cardiac damage develop more frequently and that the general prognosis is more unfavourable. The authors consider therefore cardiac damage in the active stage of the disease a reason for intensive treatment.

[Scintigraphic imaging of the heart in dogs damaged by irradiation]. / Scintigrafické zobrazení srdce psu poskozeného zárením.

The paper verified literature data assuming that the heart damage caused by irradiation of thorax may be scintigraphically detected by means of 99mTc-pyrophosphate. Three dogs underwent a single irradiation of thorax with a gamma cobalt source by the Dose 40 Gy. The myocardium scan was performed 24 hours, 20 days, 50 days, 80 days and 93 days after the irradiation. The scintigraphic examination proved to be negative at all the intervals observed. A comparison of the scan with morphological findings and with radioactivity of tissue samples after the dogs were sacrificed 93 days after the irradiation proved that the negativity of the pyrophosphate scintigraphy was caused by a minimum damage of the myocardium and not by an inability of 99mTc-pyrophosphate to be incorporated into radiation lesions. The data in literature on myocardium damage by irradiation appear to be considerably exaggerated.

[The pathophysiologic basis for the incorporation of 99mTc-pyrophosphate into myocardial infarct]. / Príspevek k patofyziologické podstate inkorporace 99mTc-pyrofosfátu do srdecního infarktu.

The investigation studied the relation of 99mTc-pyrophosphate incorporation (99mTc-PYP) into experimental, 48-hours old myocardial infarction in dogs to tissue vascular supply and to the extent of necrotic tissue. The experimental myocardial infarction was induced in five animals during an operation by the ligation RIVA. The myocardial blood supply was measured in tissue samples, taken from transverse sections of the infarction by means of 86Rb captation. The extent of myocytolysis was measured by depletion of tissue creatine kinase (CK). In the subendocardial layer of the infarction it became obvious that 99mTc-PYP incorporation was proportional to the decrease of tissue blood supply. No relation between the extent of necrosis and the incorporation of the radioactive chemical was demonstrated. The accumulation of 99mTc-PYP requires the necrosis to be present, but its extent apparently does not influence the intensity of incorporation. In the subepicardial infarction layer there was neither a relation of the radioactive chemical cumulation to the blood flow, nor to the extent of the necrosis proved.

99mTc-aminohexylidendiphosphonate and 99mTc-pyrophosphate in the scintigraphic diagnosis of experimental myocardial infarction in dogs.

99mTc-aminohexylidendiphosphonate (99mTc-AHDP) is a new Czechoslovak pharmaceutical of the phosphonate line which contains the amino group NH2 in its molecule. This substance was tested in 5 dogs with experimentally provoked 48-h old myocardial infarction. The in-vivo scan and the radioactivity of tissue samples demonstrated that 99mTc-AHDP is as suitable for imaging acute myocardial infarction as is the commonly used 99mTc-pyrophosphate.

99mTc-aminohexylidendiphosphonate and 99mTc-pyrophosphate in the scintigraphic diagnosis of experimental cardiomyopathy in dogs.

Experimental cardiomyopathy was provoked in 24 dogs with high intravenous doses of adrenaline and theophylline. These lesions were studied by means of the new agent 99mTc-AHDP and 99mTc-PYP in comparison. Cardiomyopathy could be imaged as early as 4 h after the onset of involvement but not later than 7 days. A maximum accumulation occurred in lesions 24 h old. 99mTc uptake in the myocardium was graded scintigraphically. 99mTc-AHDP was accumulated in the altered myocardium to a greater extent than 99mTc-PYP. Scintigraphic findings were in good agreement with plasma levels of creatine-kinase. A comparison with histology demonstrated that the maximum accumulation of radiopharmaceuticals occurred at the time when the development of myocardium involvement reached the stage of myocytolysis.

Pyrophosphate scintigraphy and other non-invasive methods in the detection of cardiac involvement in some systemic connective tissue diseases.

Thirteen patients with systemic lupus erythematosus, 8 patients with polymyositis, and 6 patients with spondylitis ankylopoetica (Bechterew's disease) underwent clinical cardiologic examination and scintigraphy of the myocardium (99mTc-pyrophosphate), ECG, echocardiography, polygraphy, and their blood pressure was taken. The aim of the study was to ascertain how such a combination of non-invasive examinations can help in recognizing a cardiac involvement. In systemic lupus erythematosus cases one or more positive findings were revealed in 9 patients (69%), in 4 patients all examinations were negative (31%). Four patients (50%) with polymyositis had positive findings. In patients with spondylitis ankylopoetica positive findings occurred in 2 cases (33%). The study has shown that a combination of non-invasive cardiologic methods increases the probability of detecting cardiac involvement in systemic connective tissue diseases.