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Patients who require mechanical ventilation secondary to severe COVID-19 infection have poor survival. It is unknown if the benefit of tracheostomy extends to COVID-19 patients. If so, what is the optimal timing?Retrospective cohort study within a large hospital system in the United States. The population included patients with COVID-19 from January 1, 2020 to September 30, 2020. In total, 93,918 cases were identified. They were excluded if no intubation or tracheostomy, underwent tracheostomy before intubation,18 years old, hospice patients before admission, and bacterial pneumonia. In total, 5,911 patients met the criteria. Outcomes between patients who underwent endotracheal intubation only versus tracheostomy were compared. The primary outcome was inpatient mortality. All patients who underwent tracheostomy versus intubation only were compared. Three cohort analysis compared early (10 days) versus late (10 days) tracheostomy versus control. Eight cohort analysis compared days 0-2, days 3-6, days 7-10, days 11-14, days 15-18, days 19-22, and days 23+ to tracheostomy versus control.There was an overall inpatient mortality rate of 37.5% in the tracheostomy cohort compared to 54.4% in the control group (P.0001). There was an early tracheostomy group inpatient mortality rate of 44.7% (adjusted odds ratio 0.73, 95% confidence interval 0.52-1.01) compared to 33.1% (adjusted odds ratio 0.44, 95% confidence interval 0.34-0.58) in the late tracheostomy group.COVID-19 patients with tracheostomy had a significantly lower mortality rate compared to intubated only. Optimal timing for tracheostomy placement for COVID-19 patients is 11 days or later. Future studies should focus on early tracheostomy patients.

Knowledge of respiratory mechanics is fundamental for correct use of mechanical ventilation and full understanding of the impact of lung disease during anesthetic administration. The role of the respiratory system is to deliver oxygen to cells so that respiration can occur. To accomplish this task, the respiratory system during spontaneous breathing generates negative pressure differentials able to overcome airway and tissue resistance, allowing inspiration. In contrast, mechanical ventilation uses positive pressure differentials between the mouth and the alveoli to inflate the lungs and allow for inspiration. The work of breathing, which is responsible for the energy consumption required for respiration, should be kept to a minimum. Increases in work of breathing can lead to fatigue and respiratory failure.

Biphasic positive airway pressure (BiPAP), airway pressure release ventilation (APRV), and prone ventilation are used as rescue therapies for refractory hypoxemia in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). BiPAP and its variant, APRV, allow the patient to breathe spontaneously at two levels of continuous positive airway pressure (CPAP). BiPAP uses conventional I:E ratios, while APRV is an inverse ratio ventilation. The significant advantages of these two modes of ventilation are the preservation of spontaneous breathing, improved ventilation-perfusion matching, use of lower peak pressure, and better oxygenation. Ventilation in the prone position determines a rapid and sustained improvement in oxygenation in patients with ALI/ARDS. Mechanisms that can explain its beneficial effects include a reduced pleural pressure gradient with more uniform lung inflation and improved lung recruitment, an increase in functional residual capacity, redistribution of regional lung perfusion, variations in diaphragm movement, and better clearance of secretions.

Cardiac output is the amount of blood ejected from the ventricles with each cardiac cycle. The pulmonary artery catheter has been the mainstay in assessing cardiac output for decades. Its routine use carries potential risks of right ventricular perforation, pulmonary artery rupture, and/or embolization. Echocardiography, esophageal Doppler, transpulmonary thermodilution, and pulse wave analysis are alternative methods to assess cardiac output. To properly assess the cardiac output in surgical and critically ill patients, it is of great importance to become familiar with the chosen technique and its pitfalls. Nevertheless, estimating the cardiac output in patients is important for anesthesiologists and intensivists in order to ensure adequate oxygen delivery and tissue perfusion.

Mixed venous oxygen saturation (SvO2) is the percentage of oxygenated hemoglobin in the blood returning to the right side of the heart. SvO2 reflects the balance between oxygen delivery and oxygen consumed by tissues. Normally, SvO2 is 65%–75%. SvO2 can be measured with intermittent blood samples from the pulmonary artery or continuously with the use of oximetric catheters. Determinants of SvO2 are cardiac output, hemoglobin concentration, arterial oxygen saturation, and oxygen consumption. A decrease in oxygen delivery (e.g., cardiogenic shock, anemia, hypoxemia) or increase in oxygen demand (e.g., hyperthermia, shivering, malignant hyperthermia) causes a drop in SvO2. An increase in oxygen delivery (e.g., increased cardiac output, hyperoxia) and decrease in oxygen demand (e.g., hypothermia, anesthesia) cause high SvO2 values. SvO2 in combination with other clinical information can help to identify global tissue hypoxia during the perioperative period and in critically ill patients.

Mechanical ventilation provides an artificial lung support that completely or partially supports the work carried by respiratory muscles. It is indicated in patients with inadequate respiratory drive, hypoxia, and failure to maintain adequate ventilation. Delivery of air into the lung under positive pressure via an artificial airway (endotracheal tube/tracheostomy tube) is referred to as invasive ventilation. Noninvasive ventilation uses a different interface (mask) and provides support without invasive artificial airway. The mode of mechanical ventilation defines the relationship between the type of breath (spontaneous, assisted, or mandatory) and a group of control variables (volume, pressure) and phase variables (trigger, limit, cycle) that regulate the pattern of breath delivery. Modes of ventilation include assist control, SIMV (synchronized intermittent mandatory ventilation), pressure support, pressure controlled and inverse ratio, APRV (airway pressure release ventilation), and high-frequency ventilation.

Familial dysautonomia is a rare autosomal recessive neurodegenerative disease affecting cells of the autonomic nervous system. Patients with this disease are insensitive to pain but their autonomic nervous system is still activated with noxious stimuli. This report details a case of a patient with familial dysautonomia who underwent right ankle open reduction and internal fixation for a bimalleolar right ankle fracture. The patients preoperative and intraoperative course were uneventful but shortly after handoff to the intensive care unit, the patient experienced an autonomic crisis. Management of these patients is complex, requiring maintenance of physiologic homeostasis as well as preventing hemodynamic instability caused by noxious stimuli. Any deviations from baseline may cause an autonomic crisis, as happened in our patient. Herein, we detail the perioperative management of a patient with familial dysautonomia in further detail.

Transesophageal echocardiography (TEE) can be utilized for hemodynamic monitoring and resuscitation. In order to study the pattern of TEE use in trauma patients, a multi-institutional retrospective cohort study was performed comparing adult trauma patients who underwent TEE or those who underwent traditional invasive hemodynamic monitoring (TIHM). TIHM was defined as the use of arterial line, central venous line, or pulmonary artery catheter without TEE. Mortality rates were obtained and multivariable logistic regression was used to risk adjust for age, gender, race, insurance status, Glasgow coma scale (GCS), ICD Injury severity score (ICISS). Compared to TIHM group, more patients in TEE group had a history of congestive heart failure (CHF) or chronic pulmonary disease (CPD). Mortality rate was lower in the TEE group 7 versus 23% ( P-value < .0001). After adjusting for GCS and ICISS in multivariable analysis, inpatient mortality was significantly lower in the TEE cohort.

Summary The emergence of highly pathogenic strains of influenza virus and coronavirus (CoV) has been responsible for large epidemic and pandemic outbreaks characterised by severe pulmonary illness associated with high morbidity and mortality. One major challenge for critical care is to stratify and minimise the risk of multi-organ failure during the stay in the intensive care unit (ICU). Epigenetic-sensitive mechanisms, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) methylation, histone modifications, and non-coding RNAs may lead to perturbations of the host immune-related transcriptional programmes by regulating chromatin structure and gene expression patterns. Viruses causing severe pulmonary illness can use epigenetic-regulated mechanisms during host–pathogen interaction to interfere with innate and adaptive immunity, adequacy of inflammatory response, and overall outcome of viral infections. For example, Middle East respiratory syndrome-CoV and H5N1 can affect host antigen presentation through DNA methylation and histone modifications. The same mechanisms would presumably occur in patients with coronavirus disease 2019, in which tocilizumab may epigenetically reduce microvascular damage. Targeting epigenetic pathways by immune modulators (e.g. tocilizumab) or repurposed drugs (e.g. statins) may provide novel therapeutic opportunities to control viral–host interaction during critical illness. In this article, we provide an update on epigenetic-sensitive mechanisms and repurposed drugs interfering with epigenetic pathways which may be clinically suitable for risk stratification and beneficial for treatment of patients affected by severe viral respiratory infections.

The inappropriate use of antibiotics in man is driving to insurgence of pathogenic bacteria resistant to multiple drugs (MDR) representing a challenge in critical illness. The interaction of MDR bacteria with host cells can guide molecular perturbations of host transcriptionalprogrammes involving epigenetic-sensitive mechanisms, mainly DNA methylation, histone modifications, and non-coding RNAs leading to pathogen survival. Clinical evidence of epigenetic manipulation from MDR bacteria mainly arises from Mycobacterium tuberculosis as well as Helicobacter pylori, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Legionella pneumophila infection suggesting possible biomarkers of disease. For example, DNA hypermethylation of E-cadherin (CDH1), upstream transcription factor 1/2 (USF1/2), WW domain containing oxidoreductase (WWOX), and mutL homolog 1 (MLH1) genes in gastric mucosa is correlated with malignancy suggesting useful biomarkers of early disease state. Moreover, upregulated circulating miR-361-5p, miR-889, miR-576-3p may be useful biomarkers to discriminate tuberculosis patients. Moreover, Listeria monocytogenes can indirectly induce H3 hyperacetylation leading to inflammation in human endothelial cells whereas Pseudomonas aeruginosa excretes QS 2-AA to directly induce H3 deacetylation leading to bacterial persistence in human monocytes. Remarkably, epigenetic-sensitive drugs may aid to counteract MDR in clinical setting. Trichostatin A, a histone deacetyltransferase inhibitor (HDACi), leads to AMP β-defensin 2 (HBD2) gene up-regulation in human epithelial cells suggesting a useful ‘epi-therapy’ for Escherichia coli-induced intestinal diseases. We update on the most current clinical studies focusing on epigenetic changes involved in bacterial-host interactions and their putative role as biomarkers or drug targets to improve precision medicine and personalized therapy in critical illness and transplantation setting.

Background The objective of the study was to assess the cerebrospinal fluid (CSF) findings in COVID-19 patients. Aims This was an observational retrospective cohort from electronic medical records of hospitalized patients (n = 2655) with confirmed COVID-19 between February 15, 2020, and April 15, 2020, in 182 hospitals from a large health system in the USA. The review of data yielded to a total of 79 patients in 20 hospitals who had CSF analysis. Methods Outcomes during hospitalization, including hospital length of stay, disease severity, ventilator time, and in-hospital death were recorded. Independent variables collected included patient demographics, diagnoses, laboratory values, and procedures. Results A total of 79 patients underwent CSF analysis. Of these, antigen testing was performed in 73 patients. Ten patients had CSF analysis for general markers such as total protein, cell count, glucose, clarity, and color. Seven of the 10 cases (70%) had normal total cell count and normal white blood cell count in CSF. Sixty-three percent (5/8) had elevated total protein. Two patients had normal levels of lactate dehydrogenase (LDH) and 1 patient had significantly elevated (fourfold) neuron-specific enolase (NSE) level in CSF. Conclusion Unlike bacterial infections, viral infections are less likely to cause remarkable changes in CSF glucose, cell count, or protein. Our observations showed no pleocytosis, but mild increase in protein in the CSF of the COVID-19 patients. The fourfold elevation of NSE may have diagnostic/prognostic value as a biomarker in CSF for COVID-19 patients who have altered mental status. Graphical abstract

Epigenetic mechanisms including deoxyribonucleic acid (DNA) methylation, histone modifications (eg, histone acetylation), and microribonucleic acids (miRNAs) have gained much scientific interest in the last decade as regulators of genes expression and cellular function. Epigenetic control is involved in the modulation of inflammation and immunity, and its dysregulation can contribute to cell damage and organ dysfunction. There is growing evidence that epigenetic changes can contribute to the development of multiorgan dysfunction syndrome (MODS), a leading cause of mortality in the intensive care unit (ICU). DNA hypermethylation, histone deacetylation, and miRNA dysregulation can influence cytokine and immune cell expression and promote endothelial dysfunction, apoptosis, and end-organ injury, contributing to the development of MODS after a critical injury. Epigenetics processes, particularly miRNAs, are emerging as potential biomarkers of severity of disease, organ damage, and prognostic factors in critical illness. Targeting epigenetics modifications can represent a novel therapeutic approach in critical care. Inhibitors of histone deacetylases (HDCAIs) with anti-inflammatory and antiapoptotic activities represent the first class of drugs that reverse epigenetics modifications with human application. Further studies are required to acquire a complete knowledge of epigenetics processes, full understanding of their individual variability, to expand their use as accurate and reliable biomarkers and as safe target to prevent or attenuate MODS in critical disease.

The aim of this study was to investigate whether the use of modified ultrafiltration at the end of cardiopulmonary bypass for cardiac surgical procedures significantly changes vancomycin serum concentrations.Prospective study.Single tertiary cardiac center.Twenty-six elective adult patients undergoing cardiac surgery with cardiopulmonary bypass from April 2014 to April 2015.Serum vancomycin concentrations were measured just before cardiopulmonary bypass; during cardiopulmonary bypass at 5, 30, 60 minutes and then every 60 minutes; after completion of cardiopulmonary bypass before initiation of modified ultrafiltration; and at the end of modified ultrafiltration.Seventeen patients received modified ultrafiltration at the end of cardiopulmonary bypass. Serum vancomycin concentrations prior to cardiopulmonary bypass (45.9 ± 17.3 μg/mL) were significantly higher (P0.0001) than each time point following cardiopulmonary bypass (5 min 20.4 ± 6.4 μg/mL, 30 min 18.8 ± 5.4 μg/mL, 60 min 16.6 ± 4.9 μg/mL, and 120 min 14.3 ± 4.7 μg/mL). In the modified ultrafiltration group, serum vancomycin concentrations were 14.7 ± 4.6 μg/mL prior to modified ultrafiltration and 13.9 ± 4.3 μg/mL after ultrafiltration; this difference was statistically significant (P = 0.0288). The mean modified ultrafiltration volume was 465 ± 158 mL.Using modified ultrafiltration at the end of cardiopulmonary bypass significantly decreases serum vancomycin levels, but not by a clinically relevant amount. The decrease is to a concentration that is still significantly higher than the minimum inhibitory concentration for Staphylococcus epidermidis and Staphylococcus aureus; thus additional vancomycin administration is not recommended.

Critical care management of vascular surgical patients poses significant challenges owing to patients' comorbidities and the magnitude of the surgical procedures. The primary goals of the anesthesiologist and intensivist are reestablishing preoperative homeostasis, optimizing hemodynamics until return of normal organ function, and managing postoperative complications promptly and effectively. Postoperative critical care management demands a detailed knowledge of the various vascular surgical procedures and the potential postoperative complications. In this review, the authors describe the postoperative complications related to the major specific vascular surgical procedures and their perioperative management.

Background Circulating endothelial progenitors cells (EPCs) play a critical role in neovascularization and endothelial repair. There is a growing evidence that hyperglycemia related to Diabetes Mellitus (DM) decreases EPC number and function so promoting vascular complications. Aim of the Study This study investigated whether an intensive glycemic control regimen in Type 2 DM can increase the number of EPCs and restores their function. Methods Sixty-two patients with Type 2 DM were studied. Patients were tested at baseline and after 3 months of an intensive regimen of glycemic control. The Type 2 DM group was compared to control group of subjects without diabetes. Patients with Type 2 DM (mean age 58.2±5.4 years, 25.6% women, disease duration of 15.4±6.3 years) had a baseline HgA1c of 8.7±0.5% and lower EPC levels (CD34+/KDR+) in comparison to healthy controls (p

Aims: The role of hydrogen sulfide (H2S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H2S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice. Results: Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H2S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p

Aim. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. Objectives. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostanes). Material and methods. In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosisrelated diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostane levels were measured. Results. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P b .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. Conclusion. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure–lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients. (Am Heart J 2008;156:1154.e1-1154.e8.)

The endothelium represents the largest functional organ in the human body playing an active role in vasoregulation, coagulation, inflammation, and microvascular permeability. Endothelium contributes to maintain vascular integrity, intravascular volume, and tissue oxygenation promoting inflammatory network response for local defense and repair. Acid-basis homeostasis is an important physiologic parameter that controls cell function, and changes in pH can influence vascular tone by regulating endothelium and vascular smooth muscle cells. This review presents a current perspective of the effects of intracellular acidosis on the function and the basic regulatory mechanisms of endothelial cells.

Nitric oxide (NO) exerts a plethora of vascular beneficial effects. The NO-releasing beta-blocker nebivolol is a racemic mixture of D/L-enantiomers that displays negative inotropic as well as direct vasodilating activity. The in vivo antiatherogenic activity of therapeutic doses of the beta-blocker with antioxidant properties carvedilol (12.5mg/day) or nebivolol (5mg/day) was tested in cholesterol-fed rabbits. Animals received a 1% cholesterol-rich diet alone (controls) or mixed with drugs (treated animals) for 8 weeks. While it did not affect hyperlipidemia, nebivolol inhibited the development of atherosclerosis, expressed as computer-assisted imaging analysis of aortic area covered by lesions (23.3+/-4.1% in treated vs 38.2+/-6.4% in control animals, p0.01). Differently, in our experimental condition of therapeutic drug doses, this antiatherogenic effect did not reach statistical significance in rabbits treated with carvedilol (32.5+/-5.1% aortic area covered by lesions, p=NS vs controls). Plasma nitrates increased in rabbits treated with nebivolol while both beta-blockers reduced LDL oxidation. Moreover, nebivolol induced a consistent increase of endothelial reactivity and aortic eNOS expression compared with control animals (p0.05) and those receiving carvedilol (p0.05). Since NO may exert beneficial effects in atherosclerosis, a NO-dependent mechanism could explain this data. These observations suggest that the NO-releasing beta-blocker, nebivolol, might represent an effective pharmacological approach for preventing atherosclerotic lesion progression.

Background The custom microenvironment ‘vascular niche’ is a potential therapeutic target for several pathophysiological conditions. Osteoblasts regulate the hematopoietic stem cell niche, and activation of the parathyroid hormone (PTH) receptor can increase the number of cells mobilized into the bloodstream. Methods C57Bl/6 mice were randomly assigned treatment with granulocyte-colony stimulating factor (G-CSF), PTH, G-CSF plus PTH or saline. All mice underwent hindlimb ischemia. Blood flow was measured by laser Doppler imaging. Indices of capillary activity were determined by electron microscopy in muscle tissue. CD34+ and Ki67+ cells were detected and evaluated by immunofluorescence, apoptosis by TUNEL, surface antigen and endothelial progenitor cells by fluorescence-activated cell sorting analysis, and vascular endothelial growth factor-164 and angiopoietin-1 expression by reverse-transcriptase polymerase chain reaction. Frozen bone marrow sections were stained for antigen-specific B cells and fibronectin and analyzed by confocal laser scanning microscopy. Results Following mobilization induced by G-CSF treatment, mice also treated with PTH showed increases in blood flow, capillary density, nitrite/nitrate release, angiogenic factors and circulating progenitor cells, as well as reduced apoptosis, fibrosis, oxidative stress and inflammation in ischemic muscles. Furthermore, hematopoietic antigen-specific B cells in the bone marrow were also increased by G-CSF alone and in combination with PTH. Conclusions PTH might increase the efficiency of hematopoietic stem-cell-based therapy in a recognized model of peripheral ischemia. Our translational experimental therapeutic targeting of the vascular niche points to novel clinical targets for the hematopoietic stem-cell treatment of ischemic vascular diseases.

The circulating form of endothelial progenitors cells (EPCs) are derived from bone marrow (BM)-derived hematopoietic stem cells (HSCs). Enhanced mobilization of EPCs was shown to be linked to cardiac diseases. This study investigated whether reduced EPC levels in advanced coronary heart disease (CHD) are secondary to a functional exhaustion of HSCs in the BM or to reduced mobilization. Number and functional properties of EPCs were assessed in 15 healthy controls, and 40 patients with CHD. The colony-forming unit (CFU) capacity of BM-derived mononuclear cells and the CD34+ HSC number were examined in four healthy volunteers, and 15 CHD patients. EPC number was reduced in CHD patients (P < 0.01 vs. controls). Moreover, the migratory capacity was significantly impaired in EPCs of CHD patients (P < 0.05 vs. controls). On multivariate analysis, CHD was an independent predictor of functional EPC impairment. CFUs were reduced in CHD patients (59.6 +/- 21.2 vs. 75.4 +/- 25.8 in controls, P < 0.05). CHD was also predictor of impaired CFU capacity. In this small clinical study, CHD is associated with selective impairment of HSC function in the BM and in the peripheral blood, which may contribute to impairment of cardiac function.

To date, there is no report on the effect of antioxidants on endothelial progenitor cells (EPCs). This study shows that in vitro incubation of EPCs with vitamin C and E reverted the already well documented lowering effect of TNF-alpha on EPC number and increased p-p38 expression levels. In order to document major changes of gene expression levels and gain insight into signalling pathways, microarray analysis was performed and a significant variation of the expression of 5389 genes in EPCs following antioxidant treatment was detected. Also in vivo evidence is provided about the positive effect of antioxidant vitamins on EPCs, since vitamin C and E supplementation potentiated the physical training-induced increase of EPC number and VEGF levels. Together, these data indicate that antioxidant treatment ameliorates EPC number and causes major changes of gene expression within these cells in vitro. Furthermore, concomitant antioxidant supplementation and physical training in vivo raised the levels of circulating EPCs and serum VEGF more than physical training alone.

Peripheral arterial disease (PAD) is a major health problem, especially when associated with severe hypertension. Administration of autologous bone marrow cells (BMCs) is emerging as a novel intervention to induce neoangiogenesis in ischemic limb models and in patients with PAD. This study evaluates the neovascularization capacity of BMCs alone or in combination with metabolic cotreatment (0.8% vitamin E, 0.05% vitamin C, and 5% of L-arginine) in a rat model of ischemic hindlimbs of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Molecular mechanisms were investigated in bone marrow-derived endothelial progenitor cells (BM-EPC) derived from rats. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and it decreased interstitial fibrosis. These effects were amplified by metabolic cotreatment, an intervention that induces vascular protection at least partly through the nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) pathway, reduction of systemic oxidative stress, and macrophage activation. In addition, BMC therapy alone and, more consistently, in combination with metabolic treatment, ameliorated BM-EPC functional activity via decreased cellular senescence and improved homing capacity by increasing CXCR4-expression levels. These data suggest potential therapeutic effects of autologous BMCs and metabolic treatment in hypertensive PAD patients.

Purpose of review Acute critical illness increases the risk of malnutrition, are more obese, and have multiple comorbidities and frequent pre-existing nutritional deficits. There is a vast amount of research and literature being written on nutritional practices in the critically ill. We review and discuss herein the important nutrition literature over the past 12 months. Recent findings Sarcopenia, defined as loss of skeletal mass and strength, is associated with increased mortality and morbidity, particularly in elderly patients with trauma. Ultrasound is emerging as a noninvasive and promising method of measuring muscularity. Measuring gastric residuals and postpyloric feeding may not decrease rates of pneumonia in critically ill patients. Trophic and full feeding lead to similar long-term functional and cognitive outcomes in patients with acute respiratory distress syndrome. Summary Nutrition and metabolic support of critically ill patients is a complex and diverse topic. Nutritional measurements, requirements, and modes and routes of delivery are currently being studied to determine the best way to treat these complicated patients. We present just a few of the current controversial topics in this fascinating arena.

We show that human osteosarcoma cells (Saos-2) have downregulation of alpha3beta1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha3 gene was silenced in Saos-2 cells causing a low expression of alpha3beta1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the alpha3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha3beta1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.

OBJECTIVES: Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome. Hypothesis: HSR exacerbates mechanical stress-induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury. METHODS: Rats were subjected to HSR, and were randomized into an HSR + high tidal volume and zero positive end-expiratory pressure (PEEP) or a HSR + low tidal volume with 5 cm H(2)O PEEP. A sham-operated rat + high tidal volume and zero PEEP served as a control. RESULTS: HSR increased susceptibility to ventilator-induced lung injury as evidenced by an increase in lung elastance and the wet/dry ratio and a reduction in Pa(O(2)) as compared with the other groups. The lung injury observed in the HSR + high tidal volume group was associated with a higher level of interleukin 6 in the lung and blood, increased epithelial cell apoptosis in the kidney and small intestine villi, and a tendency toward high levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatinine in plasma. CONCLUSIONS: HSR priming renders the lung and kidney more susceptible to mechanical ventilation-induced organ injury.

Massive increase in radical species can lead to oxidative stress, promoting cell injury and death. This review focuses on experimental evidence of oxidative stress in critical illnesses, sepsis and multisystem organ dysfunction. Oxidative stress could negatively affect organ injury and thus overall survival of experimental models. Based on this experimental evidence, we could improve the rationale of supplementation of antioxidants alone or in combination with standard therapies aimed to reduce oxidative stress as novel adjunct treatment in critical care.

Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p -JUN) in the endothelium. Evidence suggests that polyphenolic antioxidants contained in the juice derived from the pomegranate can contribute to the reduction of oxidative stress and atherogenesis. The aim of the present study was to evaluate the effects of intervention with pomegranate juice (PJ) on oxidation-sensitive genes and endothelial NO synthase (eNOS) expression induced by high shear stress in vitro and in vivo . Cultured human coronary artery endothelial cells (EC) exposed to high shear stress in vitro and hypercholesterolemic mice were used in this study. PJ concentrate reduced the activation of redox-sensitive genes (ELK-1 and p -JUN) and increased eNOS expression (which was decreased by perturbed shear stress) in cultured EC and in atherosclerosis-prone areas of hypercholesterolemic mice. Moreover, oral administration of PJ to hypercholesterolemic mice at various stages of disease reduced significantly the progression of atherosclerosis. This experimental study indicates that the proatherogenic effects induced by perturbed shear stress can be reversed by chronic administration of PJ. This approach may have implications for the prevention or treatment of atherosclerosis and its clinical manifestations.

We investigated whether intervention with antioxidant vitamins C and E in enteral feeding influenced oxidative stress and clinical outcome in critically ill patients. Two-hundred-sixteen patients expected to require at least 10 days of enteral feeding completed the study. One-hundred-five patients received enteral feeding supplemented with antioxidants, and 111 control patients received an isocaloric formula. Plasma lipoperoxidation (by thiobarbituric acid reactive substances [TBARS] and prostaglandin F(2alpha) isoprostane levels), low-density lipoprotein (LDL) oxidizability, and LDL tocopherol content were determined at baseline and at the end of the 10-day period. The clinical 28-day outcome was also assessed. Plasma TBARS and isoprostanes were 5.33 +/- 1.26 nM/mL and 312 +/- 68 pg/mL, respectively, before treatment and 2.42 +/- 0.61 nM/mL and 198 +/- 42 pg/mL after intervention (P < 0.01 for both comparisons). Antioxidants improved LDL resistance to oxidative stress by approximately 30% (the lag time before treatment was 87 +/- 23 min and was 118 +/- 20 min after treatment; P < 0.04). There was a significantly reduced 28-day mortality after antioxidant intervention (45.7% in the antioxidant group and 67.5% in the regular-feeding group; P < 0.05). Isoprostanes may provide a sensitive biochemical marker for dose selection in studies involving antioxidants.

Endothelial integrity is mandatory for physiologic organ function; however, endothelium dysfunction can be caused by systemic inflammation, occurring during sepsis or organ rejection after transplantation. This article will address our current understanding of endothelial involvement in organ transplantation and rejection. Overall, more detailed studies focusing on the endothelial modulation after organ transplantation would be necessary to investigate the role of endothelium activation during organ rejection.

Publisher Summary Nitric oxide (NO), a gaseous free radical produced by a wide variety of cell types, has emerged as a significant signaling molecule involved in many physiological systems. Synthesized by a family of enzymes known as NO synthases (NOS), NO exerts its effects primarily by cyclic guanosine-monophosphate (cGMP)-dependent mechanisms, involving activation of soluble guanylate cyclase (sGC). Critical illness is associated with oxidative stress that could exacerbate organ injury and thus overall outcome. The small amounts of nitric oxide (NO) produced physiologically have beneficial effects contributing to the maintenance of normal homeostasis. Increased and persistent production of NO, as observed in critical illnesses, can lead to an overwhelming inflammatory response and tissue injury, promoting cell injury and death. Microcirculatory dysfunction, as a result of an imbalance between NO availability and reactive oxygen species, plays an important role in the pathogenesis of critical illnesses. The most important physiologic factor for NO synthesis is shear stress; that is, a tangential distortion of the endothelial cells produced by blood flow. NO is also released in response to pharmacological agonists such as acetylcholine. NO has been recognized as an important mediator in liver I/R, occurring during transplantation, surgery, hemorrhagic shock, and late sepsis. While eNOS can exert a protective effect on the liver, the excessive NO production from iNOS with associated peroxynitrite formation is generally considered to mediate hepatic injury. The enhanced production of NO contributes to myocardial dysfunction, mediating the depressant effects of proinflammatory cytokines. NO can reduce myocardial contractility by reducing the calcium affinity of contractile apparatus and cause direct myocyte damage by peroxynitrite production.

Clinical consequences of heart failure are fatigue, dyspnea, and progressive impairment of exercise tolerance. Regular exercise training is associated with health-improving effects. In patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and quality of life, as well as reduce hospitalization and, to some extent, risk of mortality. Progressive exercise training is associated with pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that increase oxygen delivery and energy production. This Review focuses on current knowledge of mechanisms by which progressive and moderate exercise training can have sustained beneficial effects on patients with heart failure.

Acute lung injury can result from distinct insults, such as sepsis, ischemia-reperfusion, and ventilator-induced lung injury. Physiologic and morphologic manifestations of disparate forms of injury are often indistinguishable. We sought to demonstrate that acute lung injury resulting from distinct insults may lead to different gene expression profiles.Microarray analysis was used to examine early molecular events in lungs from three rat models of acute lung injury: lipopolysaccharide, hemorrhage shock/resuscitation, and high-volume ventilation.University laboratory.Male Sprague-Dawley rats (body weight, 300-350 g).Rats were subjected to hemorrhagic shock or lipopolysaccharide followed by resuscitation or were subjected to sham operation. First hit was followed by ventilation with either low (6 mL/kg) or high (12 mL/kg) tidal volume for 4 hrs.Physiologic and morphologic variables were assessed. Total RNA was hybridized to Affymetrix chips. Bioconductor was used to identify significantly altered genes. Functional enrichment predictions were performed in Gene Ontology Tree Machine. Confirmation studies included real-time polymerase chain reaction, Western blots, and immunohistochemistry. Physiologic and morphologic variables were noncontributory in determining the cause of acute lung injury. In contrast, molecular analysis revealed unique gene expression patterns that characterized exposure to lipopolysaccharide and high-volume ventilation. We used hypergeometric probability to demonstrate that specific functional enrichment groups were regulated by biochemical vs. biophysical factors. Genes stimulated by lipopolysaccharide were involved in metabolism, defense response, immune cell proliferation, differentiation and migration, and cell death. In contrast, high-volume ventilation led to the regulation of genes involved primarily in organogenesis, morphogenesis, cell cycle, proliferation, and differentiation.These results demonstrate the application of functional genomics to the molecular "fingerprinting" of acute lung injury and the potential for decoupling biophysical from biochemical injury.

Since its introduction into clinical practice as life-sustaining therapy in the polio epidemic, mechanical ventilation has proved to be an important tool for the treatment of the respiratory failure. One of the main reasons for a patient's admission into the intensive care unit (ICU) is to receive ventilator support [1]. According to a recent review by Esteban and co-workers [2], 66% of patients who require mechanical ventilation suffer from acute respiratory failure, including acute respiratory distress syndrome (ARDS), heart failure, pneumonia, sepsis, complications of surgery and trauma. The remaining indications include coma (15%), acute exacerbation of chronic obstructive pulmonary disease (13%) and neuromuscular disorders (5%). The aims of mechanical ventilation are primarily to decrease the work of breathing and to reverse life-threatening hypoxaemia or acute progressive respiratory acidosis. However, over the last two decades, research in a number of animal models has shown that mechanical ventilation itself can produce acute lung injury (ALI) [3]. The classical form of iatrogenic lung injury, recognised clinically for many decades, is the well-known barotrauma, defined as radiological evidence of extra-alveolar air [4]. The extraalveolar accumulation of air has several manifestations, of which the most threatening is tension pneumothorax. © 2008 Springer-Verlag Italia.

Circulating endothelial progenitor cells (EPCs) play a significant role in regeneration of damaged blood vessels. Levels and functional activities of EPCs are noticeable altered by risk factors for coronary heart disease (CHD) and compounds that can prevent or ameliorate EPC dysfunction are currently of special clinical interest. Here, we evaluate the effects of red wine (RW) on EPCs in C57BL/6J mice subjected to physical exercise. FACS computed counting showed a significant increase of EPC number (P

Alteration of levels and functional activities of circulating endothelial progenitor cells (EPCs) induced by risk factors for coronary heart disease (CHD) profoundly influence their role in the regeneration of tissue ischemia and angiogenesis. Among antioxidant nutrients in the prevention of CHD, L-arginine is particularly effective in enhancing the protection afforded by moderate physical exercise. Here, we aimed to evaluate the effects of L-arginine on EPC levels in C57BL/6J mice subjected to moderate physical exercise. Results showed that supplementation with L-arginine potentiates the effects of moderate physical exercise by increasing significantly EPCs (P

Moderate wine intake is associated with a reduced risk of morbidity and mortality from cardiovascular disease. Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases also the endothelial expression of oxidation-sensitive responsive genes (such as ELK-1 and p-JUN). This study evaluates the effects of chronic consumption of red wine on perturbed shear stress-induced atherogenesis. Results indicated that chronic treatment with red wine significantly attenuated the activation of redox-sensitive genes (ELK-1 and p-JUN) and increased endothelial nitric oxide synthase (eNOS) expression (which was decreased by perturbed shear stress) in cultured human coronary endothelial cells (EC) and in atherosclerosis-prone areas of hypercholesterolemic mice. Oral administration of red wine to hypercholesterolemic mice reduced significantly the progression of atherosclerosis. Moreover, short-term supplementation with red wine to C57BL/6J mice significantly increased upregulation of aortic eNOS and SIRT1 expression induced by physical training. These findings establish that administration of low doses of red wine can attenuate the proatherogenic effects induced by perturbed shear stress in vitro and in vivo. This evidence may have implications for the prevention of atherosclerotic lesion progression and its clinical manifestations.

Moderate physical exercise (PE) combined with metabolic treatment (MT) (antioxidants and l -arginine) are well known to reduce atherosclerotic lesion formation in hypercholesterolemic mice. However, the long-term beneficial effects on unstable atheroma remain poorly understood. We started early PE training in large groups of 6-week-old hypercholesterolemic mice (by graduated swimming) alone or in combination with nutritional supplementation (1.0% vitamin E added to the chow and 0.05% vitamin C and 6% l -arginine added to the drinking water). Inactive controls did not receive PE. The spontaneous development of atherosclerotic plaque rupture (associated with advanced atherosclerosis) and survival rates were evaluated. Moderate PE elicited an increase in plasma levels of nitric oxide. Early combined treatment with PE and MT in the hypercholesterolemic mice significantly reduced lesions (also detected noninvasively at 10 months) and spontaneous atherosclerotic plaque rupture and prolonged survival more effectively than each intervention alone. Thus, early concerted actions of MT and PE improve the natural history of atherosclerotic lesions and reduce the plaque instability in hypercholesterolemic mice.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of non-cardiogenic pulmonary oedema associated with bilateral pulmonary infiltrates, stiff lungs and refractory hypoxaemia. ARDS is characterized by an explosive acute inflammatory response in the lung parenchyma, leading to alveolar oedema, decreased lung compliance and, ultimately, hypoxaemia. Although our understanding of the causes and pathophysiology of ARDS has increased, the mortality rate remains in the range of 30-50%. No major advances in pharmacological therapy have been achieved. Mechanical ventilation is the main therapeutic intervention in the management of ARDS. The only approach that has been shown to reduce the inflammatory response and mortality is the use of lung-protective ventilatory strategy with a low tidal volume and high positive-end expiratory pressure. This chapter will review the current state of the literature on the pathogenesis of ARDS and ventilatory and pharmacotherapy approaches to its management.

The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo ( n = 10), 30 mg/kg/day NO-aspirin ( n = 10), or 18 mg/kg/day of regular aspirin ( n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 ± 12.3% compared with that of the placebo ( P < 0.001). Regular aspirin did not reduce significantly aortic lesions (−5.1 ± 2.3%) compared with the placebo [ P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content ( P < 0.001) as well as by the prolongation of lag-time ( P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 ( P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages–derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.

Transesophageal echocardiography (TEE) is routinely used in our Institution for monitoring correct positioning of thoracic aortic stent grafts. We present a case of successful endovascular repair of three discrete thoracic aortic aneurysms with Zenith TX2 endovascular stent grafts in an 82-year-old female patient. Our focus is on the increased value of TEE guidance because of the ability of partial stent deployment and manipulation during insertion.

Introduction Although inhalation of 80 parts per million (ppm) of hydrogen sulfide (H2S) reduces metabolism in mice, doses higher than 200 ppm of H2S were required to depress metabolism in rats. We therefore hypothesized that higher concentrations of H2S are required to reduce metabolism in larger mammals and humans. To avoid the potential pulmonary toxicity of H2S inhalation at high concentrations, we investigated whether administering H2S via ventilation of an extracorporeal membrane lung (ECML) would provide means to manipulate the metabolic rate in sheep. Methods A partial venoarterial cardiopulmonary bypass was established in anesthetized, ventilated (fraction of inspired oxygen = 0.5) sheep. The ECML was alternately ventilated with air or air containing 100, 200, or 300 ppm H2S for intervals of 1 hour. Metabolic rate was estimated on the basis of total CO2 production (V˙CO2) and O2 consumption (V˙O2). Continuous hemodynamic monitoring was performed via indwelling femoral and pulmonary artery catheters. Results V˙CO2, V˙O2, and cardiac output ranged within normal physiological limits when the ECML was ventilated with air and did not change after administration of up to 300 ppm H2S. Administration of 100, 200 and 300 ppm H2S increased pulmonary vascular resistance by 46, 52 and 141 dyn·s/cm5, respectively (all P ≤ 0.05 for air vs. 100, 200 and 300 ppm H2S, respectively), and mean pulmonary artery pressure by 4 mmHg (P ≤ 0.05), 3 mmHg (n.s.) and 11 mmHg (P ≤ 0.05), respectively, without changing pulmonary capillary wedge pressure or cardiac output. Exposure to 300 ppm H2S decreased systemic vascular resistance from 1,561 ± 553 to 870 ± 138 dyn·s/cm5 (P ≤ 0.05) and mean arterial pressure from 121 ± 15 mmHg to 66 ± 11 mmHg (P ≤ 0.05). In addition, exposure to 300 ppm H2S impaired arterial oxygenation (PaO2 114 ± 36 mmHg with air vs. 83 ± 23 mmHg with H2S; P ≤ 0.05). Conclusions Administration of up to 300 ppm H2S via ventilation of an extracorporeal membrane lung does not reduce V˙CO2 and V˙O2, but causes dose-dependent pulmonary vasoconstriction and systemic vasodilation. These results suggest that administration of high concentrations of H2S in venoarterial cardiopulmonary bypass circulation does not reduce metabolism in anesthetized sheep but confers systemic and pulmonary vasomotor effects.