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.

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.

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.

Scintigraphic detection of experimental myocardial infarction with 99mTc-heparin in the dog.

Experimental infarctions were produced in 12 dogs by ligation of the Ramus interventricularis anterior of the left coronary artery, and their uptake of 99mTc-heparin was measured 7, 24 and 48 h as well as 7 days thereafter by recording an in vivo chest scintigram 4 h after intravenous injection of the compound. The dogs were subsequently killed, the heart removed and an in vitro scintigram obtained. Finally, the uptake of the compound was measured in tissue samples. The results indicate that 99mTc-heparin is accumulated in lesions which are not older than 24 h. At the other points in time uptake is low but even 24-h old lesions cannot be demonstrated reliably. The results are impaired by the high blood activity on the cardiac chambers and by the background activity of the lungs. In general, 99mTc-heparin has less useful properties than the more frequently employed 99mTc-pyrophosphate so that a change of procedure is not to be recommended.

Scintigraphic myocardial imaging with 99mTC-labelled pyrophosphate of experimentally produced cardiomyopathy in dogs.

Scintigraphic examination of the myocardium using 99mTc-labelled pyrophosphate was carried out in 10 dogs with experimentally produced cardiomyopathy. This was brought about by intravenous administration of high doses of adrenalin and theophylline. The scan was positive in 8 out of 10 dogs. "Hot" foci were very extensive. The degree of accumulation was however low (2+). Histological examination of the myocardium using the light microscope showed only scarcely distinguishable damage to the tissue without the presence of necrosis. ECG examinations were normal in all cases. By means of 99mTc-labelled pyrophosphate even very small myocardial disorders can thus be detected. This fact may be of clinical importance for an early diagnosis of heart lesions.

Pyrophosphate scan of the temporarily ischemized dog myocardium.

In 9 dogs a transient myocardial ischemia was provoked using complete occlusion of the ramus interventricularis anterior of the left coronary artery. The occlusion was removed after 5, 10 or 15 min. Four hrs after removal of the occlusion a scan of the myocardium was carried out using 99mTc-labelled pyrophosphate. In 7 out of 9 dogs under study the scan was markedly positive, in 2 dogs negative. ECG demonstrated ischemic changes practically in all dogs; the changes became normal after removal of the occlusion, namely in 5 to 35 min. The histological examination of the tissue demonstrated in all 9 dogs only a slight impairment of the myocardium.

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.

[Scintigraphic diagnosis of experimentally induced pericarditis in dogs using 99mTc-labelled pyrophosphate (author's transl)]. / Szintigraphische Diagnostik der experimentellen Perikarditis des Hundes mittels 99mTc-Pyrophosphat.

In the present paper the possibilities of scintigraphic diagnosis of experimental pericarditis are discussed. Pericarditis was induced by either talc or formaldehyde intrapericardially. In all animals the administration of talc as well as formaldehyde produced inflammatory changes which were more serious after formaldehyde. The scan of the talc pericarditis was carried out on the 7th day after operation and of the formaldehyde pericarditis on the 3rd, 7th or 14th days. No positive scintigraphic finding was made in any of the experimental animals, apart from a massive incorporation in the operation scars. The counting of radioactive impulses after the exstirpation of the tissue samples confirmed the scintigraphic findings. Statistical evaluation did not reveal any essential difference between the accumulation of the radiopharmaceutical into the pericarditis as well as into the pericardial bag in comparison with the control animals. Although our model does not exactly reflect the situation of patients suffering from pericarditis it may be assumed that pyrophosphate scintigraphy is not suitable for the diagnosis of acute pericarditis in clinical practice.

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.

Scintigraphic detection of experimental myocardial infarction with 99mTc-2,3-dimercaptosuccinic acid.

Acute myocardial infarctions were produced by ligature of the left frontal descending coronary artery in 9 dogs. The possibility of scintigraphic imaging with 99mTc-DMSA 4 hrs after intravenous administration was studied. The infarctions were 4, 24 and 48 hrs old. The in vivo scan was positive in only one dog with a 4-hr old infarction. The in vivo scans were confirmed by the analysis of the radioactivity in tissue samples. The accumulation of the radiopharmaceutical increased slightly in 48-hr old lesions; however, this increase was not sufficient for a positive scintigraphic finding. Thus, we do not recommend 99mTc-DMSA for clinical use in acute lesions.

The pyrophosphate heart scintigram in children with progressive muscular dystrophy.

A pyrophosphate heart scintigram was obtained in 16 boys with progressive muscular dystrophy Duchenne. All of them showed pathological ECG findings and high plasma levels of CK, AST, ALT and LD. In 4 patients the scintigram was distinctly positive and in further 3 it reached borderline values. The remaining 9 boys had normal scintigraphic findings. Those with a positive heart scintigram had very high plasma levels of the enzymes under study which was suggestive of current progression of the disease. There was, however, no relation between heart scintigraphy and the affliction of the skeletal muscles expressed by means of an index.

Scintigraphic myocardial imaging with 99mTc-labelled gluconate of experimentally produced cardiomyopathy in dogs.

In 10 dogs experimental cardiomyopathy was produced using high intravenous doses of adrenaline and theophylline. The possibility of scintigraphic detection of this non-ischaemic damage was tested by means of 99mTc-gluconate. In 5 dogs the scintigraphic examination was carried out 4 hrs following the production of the damage. In all 5 cases a marked positivity of the heart scan was observed. The finding was confirmed by the radioactivity of tissue samples from all sections of the heart. In 3 out of 5 dogs the histological examination of the myocardium (PAS and HBFP staining) was positive. In the remaining 5 dogs the scan was performed 24 hrs following the development of the damage. A positive scintigraphic finding was observed in 4 cases, the degree of accumulation being lower than at 4 hrs. The radioactivities of tissue samples were also significantly lower as compared with the 4-hr values. In contrast, the histological findings were markedly positive in all 5 dogs. It follows that 99mTc-gluconate is capable of detecting in addition to infarctions non-ischaemic damages to the myocardium, too. The normalization of the finding is very quick. This experimental finding appears to be of importance in clinical practice.

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.

[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.

[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.