Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery-A Randomized, Controlled Clinical Trial.

OBJECTIVES: Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: The University Medical Center Ljubljana, Slovenia. PARTICIPANTS: Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each). INTERVENTIONS: Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB. MEASUREMENTS AND MAIN RESULTS: The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration. CONCLUSIONS: Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.

Pulmonary hypertension at admission predicts ICU mortality in elderly critically ill with severe COVID-19 pneumonia: retrospective cohort study.

BACKGROUND: Point-of-care ultrasound (POCUS) is a useful diagnostic tool for non-invasive assessment of critically ill patients. Mortality of elderly patients with COVID-19 pneumonia is high and there is still scarcity of definitive predictors. Aim of our study was to assess the prediction value of combined lung and heart POCUS data on mortality of elderly critically ill patients with severe COVID-19 pneumonia. METHODS: This was a retrospective observational study. Data of patients older than 70 years, with severe COVID-19 pneumonia admitted to mixed 25-bed, level 3, intensive care unit (ICU) was analyzed retrospectively. POCUS was performed at admission; our parameters of interest were pulmonary artery systolic pressure (PASP) and presence of diffuse B-line pattern (B-pattern) on lung ultrasound. RESULTS: Between October 2020 and March 2021, 117 patients aged 70 years or more (average age 77 ± 5 years) were included. Average length of ICU stay was 10.7 ± 8.9 days. High-flow oxygenation, non-invasive ventilation and invasive mechanical ventilation were at some point used to support 36/117 (31%), 39/117 (33%) and 75/117 (64%) patients respectively. ICU mortality was 50.9%. ICU stay was shorter in survivors (8.8 ± 8.3 vs 12.6 ± 9.3 days, p = 0.02). PASP was lower in ICU survivors (32.5 ± 9.8 vs. 40.4 ± 14.3 mmHg, p = 0.024). B-pattern was more often detected in non-survivors (35/59 (59%) vs. 19/58 (33%), p = 0.005). PASP and B-pattern at admission, and also mechanical ventilation and development of VAP, were univariate predictors of mortality. PASP at admission was an independent predictor of ICU (OR 1.061, 95%CI 1.003-1.124, p = 0.039) and hospital (OR 1.073, 95%CI 1.003-1.146, p = 0.039) mortality. CONCLUSIONS: Pulmonary artery systolic pressure at admission is an independent predictor of ICU and hospital mortality of elderly patients with severe COVID-19 pneumonia.

Red Blood Cell Transfusion in the Intensive Care Unit.

Importance: Red blood cell (RBC) transfusion is common among patients admitted to the intensive care unit (ICU). Despite multiple randomized clinical trials of hemoglobin (Hb) thresholds for transfusion, little is known about how these thresholds are incorporated into current practice. Objective: To evaluate and describe ICU RBC transfusion practices worldwide. Design, Setting, and Participants: International, prospective, cohort study that involved 3643 adult patients from 233 ICUs in 30 countries on 6 continents from March 2019 to October 2022 with data collection in prespecified weeks. Exposure: ICU stay. Main Outcomes and Measures: The primary outcome was the occurrence of RBC transfusion during ICU stay. Additional outcomes included the indication(s) for RBC transfusion (consisting of clinical reasons and physiological triggers), the stated Hb threshold and actual measured Hb values before and after an RBC transfusion, and the number of units transfused. Results: Among 3908 potentially eligible patients, 3643 were included across 233 ICUs (median of 11 patients per ICU [IQR, 5-20]) in 30 countries on 6 continents. Among the participants, the mean (SD) age was 61 (16) years, 62% were male (2267/3643), and the median Sequential Organ Failure Assessment score was 3.2 (IQR, 1.5-6.0). A total of 894 patients (25%) received 1 or more RBC transfusions during their ICU stay, with a median total of 2 units per patient (IQR, 1-4). The proportion of patients who received a transfusion ranged from 0% to 100% across centers, from 0% to 80% across countries, and from 19% to 45% across continents. Among the patients who received a transfusion, a total of 1727 RBC transfusions were administered, wherein the most common clinical indications were low Hb value (n = 1412 [81.8%]; mean [SD] lowest Hb before transfusion, 7.4 [1.2] g/dL), active bleeding (n = 479; 27.7%), and hemodynamic instability (n = 406 [23.5%]). Among the events with a stated physiological trigger, the most frequently stated triggers were hypotension (n = 728 [42.2%]), tachycardia (n = 474 [27.4%]), and increased lactate levels (n = 308 [17.8%]). The median lowest Hb level on days with an RBC transfusion ranged from 5.2 g/dL to 13.1 g/dL across centers, from 5.3 g/dL to 9.1 g/dL across countries, and from 7.2 g/dL to 8.7 g/dL across continents. Approximately 84% of ICUs administered transfusions to patients at a median Hb level greater than 7 g/dL. Conclusions and Relevance: RBC transfusion was common in patients admitted to ICUs worldwide between 2019 and 2022, with high variability across centers in transfusion practices.

A Motorcycle Paramedic Increases the Survival Rate of Patients after OHCA.

Background and Objectives: Despite advancements in modern medicine, the survival rate of patients after out-of-hospital cardiac arrest (OHCA) remains low. The proportion of OHCA patients who could be saved under ideal circumstances is unknown. A significant portion of patients experience cardiac arrest due to irreversible conditions. The survival of patients with reversible causes depends on the prompt initiation of basic life support (BLS) and early defibrillation. In order to increase the chances of survival, the motorcycle paramedic (MP) project was implemented in Ljubljana in 2003. The MP is equipped with an AED. In the case of OHCA with a shockable rhythm, he performs defibrillation before the arrival of the emergency medical team (EMT). The aim of this study was to evaluate whether the MP, by reducing response times to OHCA patients, increases the survival and outcome of these patients compared to the EMT. Materials and Methods: A retrospective analysis of OHCA cases within the area covered by Ljubljana Emergency Medical Service (EMS) was conducted for the period from January 2003 to December 2022. Instances where the MP arrived at the scene before the EMT were considered MP interventions and classified as the MP group; all other interventions were classified as the EMT group. Results: Between January 2003 and December 2022, the EMT performed resuscitation on 3352 patients. In 316 cases, the MP was simultaneously activated and arrived at the scene before the EMT. The response time in the MP group was shorter compared to the EMT group (7.7 ± 4.1 min vs. 9.9 ± 6.5 min, p < 0.001). In 16 patients, return of spontaneous circulation (ROSC) was achieved before the arrival of the EMT. The MP group had a higher ROSC rate, a larger proportion of patients were discharged from the hospital and there were more patients with a good neurological outcome compared to the EMT group (44.3% vs. 36.9%, p = 0.009; 18.7% vs. 13.0%, p = 0.005; 15.9% vs. 10.6%, p = 0.004, respectively). Conclusion: This study has demonstrated that the implementation of the MP into the EMS in Ljubljana has resulted in shorter response times, an increased survival rate and improved neurological outcome for OHCA patients.

Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α.

Inhibition of pyruvate dehydrogenase kinase (PDK) emerged as a potential strategy for treatment of cancer and metabolic disorders. Dichloroacetate (DCA), a prototypical PDK inhibitor, reduces the abundance of some PDK isoenzymes. However, the underlying mechanisms are not fully characterized and may differ across cell types. We determined that DCA reduced the abundance of PDK1 in breast (MDA-MB-231) and prostate (PC-3) cancer cells, while it suppressed both PDK1 and PDK2 in skeletal muscle cells (L6 myotubes). The DCA-induced PDK1 suppression was partially dependent on hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator of PDK1, in cancer cells but not in L6 myotubes. However, the DCA-induced alterations in the mRNA and the protein levels of PDK1 and/or PDK2 did not always occur in parallel, implicating a role for post-transcriptional mechanisms. DCA did not inhibit the mTOR signaling, while inhibitors of the proteasome or gene silencing of mitochondrial proteases CLPP and AFG3L2 did not prevent the DCA-induced reduction of the PDK1 protein levels. Collectively, our results suggest that DCA reduces the abundance of PDK in an isoform-dependent manner via transcriptional and post-transcriptional mechanisms. Differential response of PDK isoenzymes to DCA might be important for its pharmacological effects in different types of cells.

Effectiveness of wound infusion of 0.2% ropivacaine by patient control analgesia pump after minithoracotomy aortic valve replacement: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Local anesthetic wound infusion has become an invaluable technique in multimodal analgesia. The effectiveness of wound infusion of 0.2% ropivacaine delivered by patient controlled analgesia (PCA) pump has not been evaluated in minimally invasive cardiac surgery. We tested the hypothesis that 0.2% ropivacaine wound infusion by PCA pump reduces the cumulative dose of opioid needed in the first 48 h after minithoracothomy aortic valve replacement (AVR). METHODS: In this prospective, randomized, double-blind, placebo-controlled study, 70 adult patients (31 female and 39 male) were analyzed. Patients were randomized to receive 0.2% ropivacaine or 0.9% saline wound infusion by PCA pump for 48 h postoperatively. PCA pump was programmed at 5 ml h- 1 continuously and 5 ml of bolus with 60 min lockout. Pain levels were assessed and recorded hourly by Numeric Rating Scale (NRS). If NRS score was higher than three the patient was administered 3 mg of opioid piritramide repeated and titrated as needed until pain relief was achieved. The primary outcome was the cumulative dose of the opioid piritramide in the first 48 h after surgery. Secondary outcomes were frequency of NRS scores higher than three, patient's satisfaction with pain relief, hospital length of stay, side effects related to the local anesthetic and complications related to the wound catheter. RESULTS: The cumulative dose of the opioid piritramide in the first 48 h after minithoracotomy AVR was significantly lower (p < 0.001) in the ropivacaine (R) group median 3 mg (IQR 6 mg) vs. 9 mg (IQR 9 mg). The number of episodes of pain where NRS score was greater than three median 2 (IQR 2), vs 3 (IQR 3), (p = 0.002) in the first 48 h after surgery were significantly lower in the ropivacaine group, compared to control. Patient satisfaction with pain relief in our study was high. There were no wound infections and no side-effects from the local anesthetic. CONCLUSIONS: Wound infusion of local anesthetic by PCA pump significantly reduced opioid dose needed and improves pain control postoperatively. We have also shown that it is a feasible method of analgesia and it should be considered in the multimodal pain control strategy following minimally invasive cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03079830 , date of registration: March 15, 2017. Retrospecitvely registered.

Near-infrared spectroscopy for assessing microcirculation during laparoscopic gynaecological surgery under combined spinal-general anaesthesia or general anaesthesia alone: a randomised controlled trial.

While pneumoperitoneum causes negative macrohaemodynamic effects, much less is known about microcirculatory effects of different anaesthetic techniques and laparoscopy. Therefore, we aimed to explore microcirculatory effects of combined spinal-general anaesthesia and laparoscopy, as measured by near-infrared spectroscopy over forearm and calf muscles utilising a 3-min ischemic challenge. Patients (n = 102) undergoing elective laparoscopic gynaecological surgery were randomised to receive general anaesthesia alone or in combination with high-dose or low-dose spinal analgesia (levobupivacaine 7.5 mg or 3.75 mg, respectively, plus sufentanil 2.5 µg). Primary outcomes were near-infrared spectroscopy derived parameters before general anaesthesia induction, 5 min after tracheal intubation, and 15 min after pneumoperitoneum commencement. General anaesthesia resulted in impaired post-ischaemic recovery rate in the forearm (p < 0.001, within all groups), which improved during laparoscopy. For the calf, before general anaesthesia induction, high and low dose spinal analgesia significantly slowed the post-ischaemic recovery compared to control (34 ± 16% min-1 and 36 ± 13% min-1 vs. 52 ± 27% min-1, respectively; p = 0.002 and p = 0.006). General anaesthesia abolished differences between the groups (24 ± 14% min-1 and 25 ± 12% min-1 vs. 27 ± 18% min-1), while during laparoscopy high-dose spinal analgesia further reduced the post-ischaemic recovery compared to low-dose spinal and control groups (p = 0.023 and p = 0.040, respectively). During gynaecological laparoscopy patients show impaired calf but maintain forearm microcirculatory function, regardless of the anaesthetic technique. Reduction in post-ischaemic recovery with high-dose spinal analgesia is explained by its sympatholytic effects: number of perfused capillaries is increased, leading to a haemodynamically more favourable state. Blood pressure is positively correlated with the post-ischaemic recovery rate in vascular beds not affected by spinal analgesia.

Neurotoxicity of intraneural injection of bupivacaine liposome injectable suspension versus bupivacaine hydrochloride in a porcine model.

OBJECTIVE: To test whether neurotoxic effects of a bupivacaine liposome injectable suspension differ from those of a standard formulation of bupivacaine hydrochloride (HCl) after intraneural injection into the sciatic nerves in pigs. STUDY DESIGN: Prospective, randomized study. ANIMALS: Fifteen pigs, hybrids of Landrace and Large White. METHODS: After the National Ethics Committee approval, 15 pigs were randomly allocated to three groups (n = 5/group) to receive intraneural injections of 4 mL of 1.33% bupivacaine liposome injectable suspension, 0.5% bupivacaine HCl or normal saline. Serial neurologic examinations were conducted to detect sensory and motor response to noxious stimuli using a modified Thalhammer's scale at 2 hour intervals for the first 12 hours after injection and daily thereafter for 2 weeks. Fiber characteristics (density) of the harvested sciatic nerves were measured during histomorphometric analysis. Inflammatory response was studied using immunohistochemical analysis. Data were tested using analyses of variance; p values for paired comparisons were Bonferroni adjusted. RESULTS: Compared with bupivacaine HCl, bupivacaine liposome injectable suspension provided longer sensory (11.2 ± 1.8 hours versus 3.2 ± 1.1 hours, respectively, p < 0.0001) and motor (10.0 ± 2.0 hours versus 4.0 ± 1.4 hours respectively, p < 0.0001) blockade. Histomorphometric parameters were similar among the groups. No changes in axonal density or myelin structure indicative of injury to the sciatic nerves were observed in any of the groups. Number of immunopositive cells did not differ between the bupivacaine liposome injectable suspension (23 ± 6 cells per mm2) and the bupivacaine HCl groups (21 ± 4 cells per mm2), p > 0.90. CONCLUSIONS AND CLINICAL RELEVANCE: Intraneural injections of bupivacaine liposome injectable suspension or bupivacaine HCl in our porcine model did not result in evidence of neurotoxicity.

Glucose Metabolism in Cancer and Ischemia: Possible Therapeutic Consequences of the Warburg Effect.

The Warburg effect states that the main source of energy for cancer cells is not aerobic respiration, but glycolysis-even in normoxia. The shift from one to the other is governed by mutually counteracting enzymes: pyruvate dehydrogenase and pyruvate dehydrogenase kinase (PDK). Anaerobic metabolism of cancer cells promotes cell proliferation, local tissue immunosuppression, resistance to hypoxic conditions, and metastatic processes. By switching glucose back to oxidative metabolism, these effects might be reversed. This can be achieved using PDK inhibitors, such as dichloroacetate. Patients suffering from ischemic conditions might benefit from this effect. On the other hand, the ß-blockers (adrenergic ß-antagonists) often used in these patients appear to improve cancer-specific survival, and nonselective ß-blockers have been shown to promote glucose oxidation. Might there be a link?

Measurement of breath ammonia for detection of patients with chronic kidney disease.

BACKGROUND: In a healthy individual, ammonia is converted to urea in the liver. Urea is then transported through the bloodstream and then excreted into the urine by the kidneys. In patients with chronic kidney disease (CKD), the accumulated urea is degraded by salivary urease into ammonia, which is then excreted by breathing. Breath ammonia can therefore be used for detecting the increased nitrogen-bearing wastes. In our pilot study, an electrochemical sensor was used to measure and analyze breath ammonia in healthy volunteers and patients with CKD. PATIENTS AND METHODS: In our study, 8 patients with CKD (stages 4 and 5) and 6 healthy volunteers were enrolled. All participants were nonsmokers and without pulmonary or liver disease. One controlled breath sample was collected from each participant. Immediately after the sample was collected, a gas analyzer was used for measuring breath ammonia in our participants. RESULTS: Mean creatinine value of CKD patients was 455.2 ± 294.1 µmol/L and 62.1 ± 7.5 µmol/L for healthy volunteers. Breath ammonia levels (3.32 ± 2.19 ppm vs. 0.49 ± 0.08 ppm; p = 0.003) and measured electric current (4.33 ± 0.25 mA vs. 4.01 ± 0.01 mA; p = 0.003) were significantly higher in the CKD group. CONCLUSIONS: The results of our pilot study show that breath monitoring of ammonia can be a simple, useful, fast, and noninvasive tool for detection of advanced kidney impairment.
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Red blood cell transfusion and skeletal muscle tissue oxygenation in anaemic haematologic outpatients.

BACKGROUND: Stored red blood cells (RBCs) accumulate biochemical and biophysical changes, known as storage lesion. The aim of this study was to re-challenge current data that anaemia in chronically anaemic haematology patients is not associated with low skeletal muscle tissue oxygen (StO2), and that RBC storage age does not influence the tissue response after ischaemic provocation, using near-infrared spectroscopy. PATIENTS AND METHODS: Twenty-four chronic anaemic haematology patients were included. Thenar skeletal muscle StO2 was measured at rest (basal StO2), with vascular occlusion testing (upslope StO2, maximum StO2) before and after transfusion. RESULTS: Basal StO2 was low (53% ± 7%). Average RBC storage time was 10.5 ± 3.9 days. Effects of RBC transfusions were as follows: basal StO2 and upslope StO2 did not change significantly; maximum StO2 increased compared to baseline (64 ± 14% vs. 59 ± 10%, p = 0.049). Change of basal StO2, upslope StO2 and maximum StO2 was negatively related to age of RBCs. The decrease of maximum StO2 was predicted (sensitivity 70%, specificity 100%), after receiving RBCs ≥ 10days old. DISCUSSION: Resting skeletal muscle StO2 in chronic anaemic patients is low. RBC storage time affects skeletal muscle StO2 in the resting period and after ischaemic provocation.

Cytokine response of cultured skeletal muscle cells stimulated with proinflammatory factors depends on differentiation stage.

Myoblast proliferation and myotube formation are critical early events in skeletal muscle regeneration. The attending inflammation and cytokine signaling are involved in regulation of skeletal muscle cell proliferation and differentiation. Secretion of muscle-derived cytokines upon exposure to inflammatory factors may depend on the differentiation stage of regenerating muscle cells. Cultured human myoblasts and myotubes were exposed to 24-hour treatment with tumor necrosis factor (TNF)- α or lipopolysaccharide (LPS). Secretion of interleukin 6 (IL-6), a major muscle-derived cytokine, and interleukin 1 (IL-1), an important regulator of inflammatory response, was measured 24 hours after termination of TNF- α or LPS treatment. Myoblasts pretreated with TNF- α or LPS displayed robustly increased IL-6 secretion during the 24-hour period after removal of treatments, while IL-1 secretion remained unaltered. IL-6 secretion was also increased in myotubes, but the response was less pronounced compared with myoblasts. In contrast to myoblasts, IL-1 secretion was markedly stimulated in LPS-pretreated myotubes. We demonstrate that preceding exposure to inflammatory factors stimulates a prolonged upregulation of muscle-derived IL-6 and/or IL-1 in cultured skeletal muscle cells. Our findings also indicate that cytokine response to inflammatory factors in regenerating skeletal muscle partially depends on the differentiation stage of myogenic cells.

Skeletal muscle oxygenation during cardiopulmonary resuscitation as a predictor of return of spontaneous circulation: a pilot study.

BACKGROUND: Near-infrared spectroscopy (NIRS) provides regional tissue oxygenation (rSO2) even in pulseless states, such as out-of-hospital cardiac arrest (OHCA). Brain rSO2 seems to be important predictor of return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). Aim of our study was to explore feasibility for monitoring and detecting changes of skeletal muscle rSO2 during resuscitation. METHODS: Skeletal muscle and brain rSO2 were measured by NIRS (SenSmart Model X-100, Nonin, USA) during CPR in adult patient with OHCA. Start (basal) rSO2, maximal during CPR (maximal) and difference between maximal-minimal rSO2 (delta-rSO2), were recorded. Patients were divided into ROSC and NO-ROSC group. RESULTS: 20 patients [age: 66.0ys (60.5-79.5), 65% male] with OHCA [50% witnessed, 70% BLS, time to ALS 13.5 min (11.0-19.0)] were finally analyzed. ROSC was confirmed in 5 (25%) patients. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group [49.0% (39.7-53.7) vs. 15.0% (12.0-25.2), P = 0.006; 76.0% (52.7-80.5) vs. 34.0% (18.0-49.5), P = 0.005, respectively]. There was non-linear cubic relationship between time of collapse and basal skeletal muscle rSO2 in witnessed OHCA and without BLS (F-ratio = 9.7713, P = 0.0261). There was correlation between maximal skeletal muscle and brain rSO2 (n = 18, rho: 0.578, P = 0.0121). CONCLUSIONS: Recording of skeletal muscle rSO2 during CPR in patients with OHCA is feasible. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group. Clinical trial registration number ClinicalTrials.gov, NCT04058925, registered on: 16th August 2019. URL of trial registry record: https://www. CLINICALTRIALS: gov/ct2/show/NCT04058925?titles=Tissue+Oxygenation+During+Cardiopulmonary+Resuscitation+as+a+Predictor+of+Return+of+Spontaneous+Circulation&draw=2&rank=1 .

Neurovascular coupling in severe aortic valve stenosis.

OBJECTIVES: Aortic stenosis (AS) is characterized by obstruction of blood outflow from the left ventricle, which can impair target organ perfusion such as the brain. We hypothesized that hemodynamic changes in AS may lead to dysfunction of cerebral blood flow regulatory mechanisms. The aim of our study was to evaluate neurovascular coupling in patients with AS by Transcranial Doppler ultrasonography. METHODS: Neurovascular coupling was assessed using visually evoked cerebral blood flow velocity responses (VEFR) calculated as relative blood flow velocity changes in the posterior cerebral artery upon visual stimulation. We analyzed peak systolic, mean and end diastolic VEFR in 54 patients with severe AS and 43 controls in 10 consecutive cycles of visual stimulation. Repeated-measures ANOVA test was used to compare cerebral hemodynamic data by group. RESULTS: Patients with AS had significantly higher peak systolic (12.9% ± 5.6% and 10.5% ± 4.5%; p = .009) and mean VEFR (14.4% ± 5.8% and 12.2% ± 4.9%; p = .021) compared to controls, whereas only a tendency for higher end diastolic VEFR was observed (16.7% ± 6.9% and 14.4% ± 6.2%; p = .061). CONCLUSION: We have shown for the first time that patients with severe AS exhibit higher VEFR than controls indicating dysregulation of neurovascular coupling, which can be one of the factors contributing to development of cognitive decline.

Total plasma sulfide in congestive heart failure.

BACKGROUND: Hydrogen sulfide (H(2)S) has emerged as a third gaseous transmitter in mammals. In animal models of heart failure, treatment with an H(2)S donor can protect the heart against adverse remodeling and attenuate cardiac dysfunction. The aim was to determine total plasma sulfide in patients with congestive heart failure. METHODS AND RESULTS: Total plasma sulfide was determined in 57 patients on admission to an outpatient clinic or cardiology department. Total plasma sulfide concentrations in these patients was lower compared with a control group (5.32 [2.22, 8.00] µM vs. 8.5 [6.00, 14.00] µM; P = .05). Total plasma sulfide decreased significantly across the New York Heart Association (NYHA) functional classes (II, 5.84 [4.33, 8.00] µM vs. III, 4.67 [4.00, 7.17] µM vs. IV, 2.67 [2.22, 4.31] µM; P = .001). The total plasma sulfide negatively correlated with pro-BNP (R(2) cubic, 0.692; P = .001) and pulmonary artery systolic pressure (R(2) cubic, 0.569; P = .001). The receiver operating characteristic analysis of the area under the curve for total plasma sulfide as a predictor of mortality was 0.904 (95% CI, 0.822-0.987; P = .001), and of rehospitalization was 0.779 (95% CI, 0.650-0.908; P = .001). Total plasma sulfide was a univariate predictor of mortality (odds ratio, 0.245; 95% CI, 0.108-0.555; P = .001). CONCLUSION: Total plasma sulfide is negatively related to severity of congestive heart failure: it is lowest in NYHA Class IV and in patients with high pro-BNP and high pulmonary artery pressure. Low total plasma sulfide predicts a higher mortality rate.

SepsEast Registry indicates high mortality associated with COVID-19 caused acute respiratory failure in Central-Eastern European intensive care units.

The coronavirus disease (COVID-19) pandemic caused unprecedented research activity all around the world but publications from Central-Eastern European countries remain scarce. Therefore, our aim was to characterise the features of the pandemic in the intensive care units (ICUs) among members of the SepsEast (Central-Eastern European Sepsis Forum) initiative. We conducted a retrospective, international, multicentre study between March 2020 and February 2021. All adult patients admitted to the ICU with pneumonia caused by COVID-19 were enrolled. Data on baseline and treatment characteristics, organ support and mortality were collected. Eleven centres from six countries provided data from 2139 patients. Patient characteristics were: median 68, [IQR 60-75] years of age; males: 67%; body mass index: 30.1 [27.0-34.7]; and 88% comorbidities. Overall mortality was 55%, which increased from 2020 to 2021 (p = 0.004). The major causes of death were respiratory (37%), cardiovascular (26%) and sepsis with multiorgan failure (21%). 1061 patients received invasive mechanical ventilation (mortality: 66%) without extracorporeal membrane oxygenation (n = 54). The rest of the patients received non-invasive ventilation (n = 129), high flow nasal oxygen (n = 317), conventional oxygen therapy (n = 122), as the highest level of ventilatory support, with mortality of 50%, 39% and 22%, respectively. This is the largest COVID-19 dataset from Central-Eastern European ICUs to date. The high mortality observed especially in those receiving invasive mechanical ventilation renders the need of establishing national-international ICU registries and audits in the region that could provide high quality, transparent data, not only during the pandemic, but also on a regular basis.

Cerebral blood flow impairment and cognitive decline in heart failure.

BACKGROUND AND PURPOSE: Cognitive decline is an important contributor to disability in patients with chronic heart failure, affecting 25%-50% of patients. The aim of this review is to stress the importance of understanding pathophysiological mechanisms of heart failure involved in cognitive decline. METHODS: An extensive PubMed search was conducted for the literature on the basic mechanisms of cerebral blood flow regulation, the effect of cardiac dysfunction on cerebral blood flow, and possible mechanisms underlying the association between cardiac dysfunction and cognitive decline. RESULTS: Published literature supports the thesis that cardiac dysfunction leads to cerebral blood flow impairment and predisposes to cognitive decline. One of the postulated mechanisms underlying cognitive decline in chronic heart failure is chronic regional hypoperfusion of critical brain areas. Cognitive function may be further compromised by microvascular damage due to cardiovascular risk factors. Furthermore, it is implied that cerebral blood flow assessment could enable early recognition of patients at risk and help guide appropriate therapeutic strategies. CONCLUSION: Interdisciplinary knowledge in the fields of neurology and cardiology is essential to clarify heart and brain interconnections in chronic heart failure. Understanding and identifying the basic neuropathophysiological changes in chronic heart failure could help with developing methods for early recognition of patients at risk, followed by institution of therapeutic actions to prevent or decrease cognitive decline.

Cerebral microemboli in mini-sternotomy compared to mini- thoracotomy for aortic valve replacement: a cross sectional cohort study.

BACKGROUND: Recently adopted mini-thoracotomy approach for surgical aortic valve replacement has shown benefits such as reduced pain and shorter recovery, compared to more conventional mini-sternotomy access. However, whether limited exposure of the heart and ascending aorta resulting from an incision in the second intercostal space may lead to increased intraoperative cerebral embolization and more prominent postoperative neurologic decline, remains inconclusive. The aim of our study was to assess potential neurological complications after two different minimal invasive surgical techniques for aortic valve replacement by measuring cerebral microembolic signal during surgery and by follow-up cognitive evaluation. METHODS: Trans-cranial Doppler was used for microembolic signal detection during aortic valve replacement performed via mini-sternotomy and mini-thoracotomy. Patients were evaluated using Addenbrooke's Cognitive Examination Revised Test before and 30 days after surgical procedure. RESULTS: A total of 60 patients were recruited in the study. In 52 patients, transcranial Doppler was feasible. Of those, 25 underwent mini-sternotomy and 27 had mini-thoracotomy. There were no differences between groups with respect to sex, NYHA class distribution, Euroscore II or aortic valve area. Patients in mini-sternotomy group were younger (60.8 ± 14.4 vs.72 ± 5.84, p = 0.003), heavier (85.2 ± 12.4 vs.72.5 ± 12.9, p = 0.002) and had higher body surface area (1.98 ± 0.167 vs. 1.83 ± 0.178, p = 0.006). Surgery duration was longer in mini-sternotomy group compared to mini-thoracotomy (158 ± 24 vs. 134 ± 30 min, p < 0.001, respectively). There were no differences between groups in microembolic load, length of ICU or total hospital stay. Total microembolic signals count was correlated with cardiopulmonary bypass duration (5.64, 95%CI 0.677-10.60, p = 0.027). Addenbrooke's Cognitive Examination Revised Test score decreased equivalently in both groups (p = 0.630) (MS: 85.2 ± 9.6 vs. 82.9 ± 11.4, p = 0.012; MT: 85.2 ± 9.6 vs. 81.3 ± 8.8, p = 0.001). CONCLUSION: There is no difference in microembolic load between the groups. Total intraoperative microembolic signals count was associated with cardiopulmonary bypass duration. Age, but not micorembolic signals load, was associated with postoperative neurologic decline. TRIAL REGISTRY NUMBER: clinicaltrials.gov , NCT02697786 14.

Near-infrared spectroscopy during stagnant ischemia estimates central venous oxygen saturation and mixed venous oxygen saturation discrepancy in patients with severe left heart failure and additional sepsis/septic shock.

INTRODUCTION: Discrepancies of 5-24% between superior vena cava oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2) have been reported in patients with severe heart failure. Thenar muscle tissue oxygenation (StO2) measured with near-infrared spectroscopy (NIRS) during arterial occlusion testing decreases slower in sepsis/septic shock patients (lower StO2 deoxygenation rate). The StO2 deoxygenation rate is influenced by dobutamine. The aim of this study was to determine the relationship between the StO2 deoxygenation rate and the ScvO2-SvO2 discrepancy in patients with severe left heart failure and additional sepsis/septic shock treated with or without dobutamine. METHODS: Fifty-two patients with severe left heart failure due to primary heart disease with additional severe sepsis/septic shock were included. SvO2 and ScvO2 were compared to the thenar muscle StO2 before and during arterial occlusion. RESULTS: SvO2 correlated significantly with ScvO2 (Pearson correlation 0.659, P = 0.001), however, Bland Altman analysis showed a clinically important difference between both variables (ScvO2-SvO2 mean 72 +/- 8%, ScvO2-SvO2 difference 9.4 +/- 7.5%). The ScvO2-SvO2 difference correlated with plasma lactate (Pearson correlation 0.400, P = 0.003) and the StO2 deoxygenation rate (Pearson correlation 0.651, P = 0.001). In the group of patients treated with dobutamine, the ScvO2-SvO2 difference correlated with plasma lactate (Pearson correlation 0.389, P = 0.011) and the StO2 deoxygenation rate (Pearson correlation 0.777, P = 0.0001). CONCLUSIONS: In patients with severe heart failure with additional severe sepsis/septic shock the ScvO2-SvO2 discrepancy presents a clinical problem. In these patients the skeletal muscle StO2 deoxygenation rate is inversely proportional to the difference between ScvO2 and SvO2; dobutamine does not influence this relationship. When using ScvO2 as a treatment goal, the NIRS measurement may prove to be a useful non-invasive diagnostic test to uncover patients with a normal ScvO2 but potentially an abnormally low SvO2. TRIAL REGISTRATION: NCT00384644 ClinicalTrials.Gov.