Optimal timing and outcomes among COVID-19 patients undergoing tracheostomy.

BACKGROUND: 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? METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Practice Patterns of Transesophageal Echocardiography Use Among Trauma Patients: A Multi-Institutional Retrospective Study.

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.

Clinical epigenetics and multidrug-resistant bacterial infections: host remodelling in critical illness.

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 transcriptional programmes 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 ß-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.

The Effect of Modified Ultrafiltration on Serum Vancomycin Levels During Cardiopulmonary Bypass in Cardiac Surgery.

OBJECTIVE: 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. DESIGN: Prospective study. SETTING: Single tertiary cardiac center. PARTICIPANTS: Twenty-six elective adult patients undergoing cardiac surgery with cardiopulmonary bypass from April 2014 to April 2015. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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 (P < 0.0001) 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. CONCLUSIONS: 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.

Postoperative ICU management of vascular surgery patients.

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.

Transesophageal echocardiography guidance for stent-graft repair of a thoracic aneurysm is facilitated by the ability of partial stent deployment.

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.

Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice.

AIMS: The role of hydrogen sulfide (H(2)S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H(2)S 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 H(2)S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H(2)S breathing attenuated LPS-induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H(2)S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H(2)S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-γ-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice. INNOVATION: By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H(2)S breathing during endotoxemia. CONCLUSION: These observations suggest that H(2)S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice.

Antioxidants increase number of progenitor endothelial cells through multiple gene expression pathways.

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.

Beneficial effects of low doses of red wine consumption on perturbed shear stress-induced atherogenesis.

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.

Therapeutic targeting of the stem cell niche in experimental hindlimb ischemia.

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.

Effect of L-arginine on circulating endothelial progenitor cells and VEGF after moderate physical training in mice.

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<0.001) and VEGF serum levels (P<0.001). Our report highlights the beneficial effect of l-arginine in the modulation of EPC levels and VEGF secretion.

Effect of red wine antioxidants and minor polyphenolic constituents on endothelial progenitor cells after physical training in mice.

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<0.05) in mice after short-term supplementation with RW. VEGF serum concentration was significantly increased by physical training in the presence or absence of RW supplementation (P<0.001). These in vivo observations support previous in vitro observation of the beneficial effect of RW in the modulation of EPC levels.

Functional impairment of hematopoietic progenitor cells in patients with coronary heart disease.

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.

Therapeutic effects of autologous bone marrow cells and metabolic intervention in the ischemic hindlimb of spontaneously hypertensive rats involve reduced cell senescence and CXCR4/Akt/eNOS pathways.

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.

Ischemia and reperfusion increases susceptibility to ventilator-induced lung injury in rats.

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.

Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress.

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.

The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial.

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.