Correlation between antifungal clinical practices and a new clinical decision support system ANTIFON-CLIC® for the treatment of invasive candidiasis: a retrospective multicentre study.

BACKGROUND: Invasive candidiasis is still recognized as a major cause of morbidity and mortality. To support clinicians in the optimal use of antifungals for the treatment of invasive candidiasis, a computerized decision support system (CDSS) was developed based on institutional guidelines. OBJECTIVES: To evaluate the correlation of this newly developed CDSS with clinical practices, we set-up a retrospective multicentre cohort study with the aim of providing the concordance rate between the CDSS recommendation and the medical prescription (NCT05656157). PATIENTS AND METHODS: Adult patients who received caspofungin or fluconazole for the treatment of an invasive candidiasis were included. The analysis of factors associated with concordance was performed using mixed logistic regression models with department as a random effect. RESULTS: From March to November 2022, 190 patients were included from three centres and eight departments: 70 patients from centre A, 84 from centre B and 36 from centre C. Overall, 100 patients received caspofungin and 90 received fluconazole, mostly (59%; 112/190) for empirical/pre-emptive treatment. The overall percentage of concordance between the CDSS and medical prescriptions was 91% (173/190) (confidence interval 95%: 82%-96%). No significant difference in concordance was observed considering the centres (P > 0.99), the department of inclusion (P = 0.968), the antifungal treatment (P = 0.656) or the indication of treatment (P = 0.997). In most cases of discordance (n = 13/17, 76%), the CDSS recommended fluconazole whereas caspofungin was prescribed. The clinical usability evaluated by five clinicians was satisfactory. CONCLUSIONS: Our results demonstrated the high correlation between current antifungal clinical practice and this user-friendly and institutional guidelines-based CDSS.

oXiris® Use in Septic Shock: Experience of Two French Centres.

BACKGROUND: Sepsis is a dysregulated host response to an infection and can result in organ dysfunctions and death. Extracorporeal blood purification techniques aim to improve the prognosis of these patients by modulating the unbalanced immune response. This study reports our experience with the use of the oXiris® membrane for septic shock patients requiring continuous renal replacement therapy (CRRT). SUMMARY: Thirty-one patients were diagnosed with septic shock and underwent CRRT with the oXiris® membrane between 2014 and 2019. We compared the observed hospital mortality with that predicted by the Simplified Acute Physiology Score II (SAPS II). Change in the Sequential Organ Failure Assessment (SOFA) score and of the main clinical and biological parameters over time were analyzed. Hospital mortality was lower than predicted for the most severe patients (60 vs. 91% for the [74-87] SAPS II quartile and 70 vs. 98% for the [87-163] SAPS II quartile, p < 0.02). There was no significant improvement in the SOFA score from 0h to 48 h. An 88% relative decrease in norepinephrine infusion was observed (median at 0 h was 1.69 [0.52-2.45] µg/kg/min; at 48 h it was 0.20 [0.09-1.14] µg/kg/min, p = 0.002). Lactataemia and pH were significantly improved over time. Patients with intra-abdominal sepsis as well as those with Gram-negative bacilli (GNB) infections seemed to benefit the most from the therapy. Key Messages: CRRT with the oXiris® haemofilter resulted in higher observed survival than predicted by a severity score (SAPS II) for the most severe patients. Haemodynamic status and lactataemia appeared to improve, especially in intra-abdominal sepsis and GNB infections.

Prone positioning in severe acute respiratory distress syndrome.

BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

Prevalence and risk factors of hypotension associated with preload-dependence during intermittent hemodialysis in critically ill patients.

BACKGROUND: Hypotension is a frequent complication of intermittent hemodialysis (IHD) performed in intensive care units (ICUs). Passive leg raising (PLR) combined with continuous measurement of cardiac output is highly reliable to identify preload dependence, and may provide new insights into the mechanisms involved in IHD-related hypotension. The aim of this study was to assess prevalence and risk factors of preload dependence-related hypotension during IHD in the ICU. METHODS: A single-center prospective observational study performed on ICU patients undergoing IHD for acute kidney injury and monitored with a PiCCO® device. Primary end points were the prevalence of hypotension (defined as a mean arterial pressure below 65 mm Hg) and hypotension associated with preload dependence. Preload dependence was assessed by the passive leg raising test, and considered present if the systolic ejection volume increased by at least 10% during the test, as assessed continuously by the PiCCO® device. RESULTS: Forty-seven patients totaling 107 IHD sessions were included. Hypotension was observed in 61 IHD sessions (57%, CI95%: 47-66%) and was independently associated with inotrope administration, higher SOFA score, lower time lag between ICU admission and IHD session, and lower MAP at IHD session onset. Hypotension associated with preload dependence was observed in 19% (CI95%: 10-31%) of sessions with hypotension, and was associated with mechanical ventilation, lower SAPS II, higher pulmonary vascular permeability index (PVPI) and dialysate sodium concentration at IHD session onset. ROC curve analysis identified PVPI and mechanical ventilation as the only variables with significant diagnostic performance to predict hypotension associated with preload dependence (respective AUC: 0.68 (CI95%: 0.53-0.83) and 0.69 (CI95%: 0.54-0.85). A PVPI ≥ 1.6 at IHD session onset predicted occurrence of hypotension associated with preload dependence during IHD with a sensitivity of 91% (CI95%: 59-100%), and a specificity of 53% (CI95%: 42-63%). CONCLUSIONS: The majority of hypotensive episodes occurring during intermittent hemodialysis are unrelated to preload dependence and should not necessarily lead to reduction of fluid removal by hemodialysis. However, high PVPI at IHD session onset and mechanical ventilation are risk factors of preload dependence-related hypotension, and should prompt reduction of planned fluid removal during the session, and/or an increase in session duration.

A mixed grape and blueberry extract is safe for dogs to consume.

BACKGROUND: Grape and blueberry extracts are known to protect against age-related cognitive decline. However, beneficial effects achieved by mixing grape and blueberry extracts have yet to be evaluated in dogs, or their bioavailability assessed. Of concern to us were cases of acute renal failure in dogs, after their ingestion of grapes or raisins. The European Pet Food Industry Federation (2013) considers only the grape or raisin itself to be potentially dangerous; grape-seed extracts per-se, are not considered to be a threat. Our aim was therefore to evaluate the renal and hepatic safety, and measure plasma derivatives of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) in dogs. Polyphenol expression was analyzed by UHPLC-MS/MS over 8 hours, for dogs given PEGB at 4 mg/kg. Safety was evaluated using four groups of 6 dogs. These groups received capsules containing no PEGB (control), or PEGB at 4, 20, or 40 mg/kg BW/d, for 24 weeks. Blood and urine samples were taken the week prior to study commencement, then at the end of the 24-wk study period. Routine markers of renal and liver damage, including creatinine (Creat), blood urea nitrogen, albumin, minerals, alkaline phosphatase (ALP), and alanine transaminase (ALT) were measured. Biomarkers for early renal damage were also evaluated in plasma (cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL)), and urine (CysC, clusterin (Clu), and NGAL). Ratios of urinary biomarkers to Creat were calculated, and compared with acceptable maximal values obtained for healthy dogs, as reported in the literature. RESULTS: While several PEGB-specific polyphenols and metabolites were detected in dog plasma, at the end of the PEGB consumption period, our biomarker analyses presented no evidence of either renal or liver damage (Creat, BUN, ionogram, albumin and ALT, ALP). Similarly, no indication of early renal damage could be detected. Plasma CysC, urinary CysC/Creat, Clu/Creat, and NGAL/Creat ratios were all beneath reported benchmarked maximums, with no evidence of PEGB toxicity. CONCLUSIONS: Long-term consumption of a pet specific blend of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium), was not associated with renal or hepatic injury, and can therefore be considered safe.

Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial.

INTRODUCTION: In septic shock, pulse pressure or cardiac output variation during passive leg raising are preload dependence indices reliable at predicting fluid responsiveness. Therefore, they may help to identify those patients who need intravascular volume expansion, while avoiding unnecessary fluid administration in the other patients. However, whether their use improves septic shock prognosis remains unknown. The aim of this study was to assess the clinical benefits of using preload dependence indices to titrate intravascular fluids during septic shock. METHODS: In a single-center randomized controlled trial, 60 septic shock patients were allocated to preload dependence indices-guided (preload dependence group) or central venous pressure-guided (control group) intravascular volume expansion with 30 patients in each group. The primary end point was time to shock resolution, defined by vasopressor weaning. RESULTS: There was no significant difference in time to shock resolution between groups (median (interquartile range) 2.0 (1.2 to 3.1) versus 2.3 (1.4 to 5.6) days in control and preload dependence groups, respectively). The daily amount of fluids administered for intravascular volume expansion was higher in the control than in the preload dependence group (917 (639 to 1,511) versus 383 (211 to 604) mL, P = 0.01), and the same held true for red cell transfusions (178 (82 to 304) versus 103 (0 to 183) mL, P = 0.04). Physiologic variable values did not change over time between groups, except for plasma lactate (time over group interaction, P <0.01). Mortality was not significantly different between groups (23% in the preload dependence group versus 47% in the control group, P = 0.10). Intravascular volume expansion was lower in the preload dependence group for patients with lower simplified acute physiology score II (SAPS II), and the opposite was found for patients in the upper two SAPS II quartiles. The amount of intravascular volume expansion did not change across the quartiles of severity in the control group, but steadily increased with severity in the preload dependence group. CONCLUSIONS: In patients with septic shock, titrating intravascular volume expansion with preload dependence indices did not change time to shock resolution, but resulted in less daily fluids intake, including red blood cells, without worsening patient outcome. TRIAL REGISTRATION: Clinicaltrials.gov NCT01972828. Registered 11 October 2013.

Expiratory flow-volume loop profile and patient outcome in chronic obstructive pulmonary disease in acute respiratory failure: a prospective observational study in a single intensive care unit.

BACKGROUND: Expiratory flow-volume (EFV) loops are continuously displayed on the screen of intensive care unit (ICU) ventilators. OBJECTIVES: It was the aim of this study to investigate the relationships of EFV to chronic obstructive pulmonary disease (COPD) patient outcome. METHODS: This is a prospective study on COPD patients who received invasive mechanical ventilation for acute respiratory failure in the ICU. Within the 24-hour post-intubation period, the angle of the EFV slope during the last 50% of expiration was computed and patients were stratified into 4 quartiles. Resistance, compliance of the respiratory system and change in end-expiratory lung volume above relaxation volume were assessed. Patients were followed up to hospital discharge. The main outcome was hospital mortality. Secondary outcomes were ICU mortality, length of ICU stay, duration of invasive ventilation, number of intubations, oxygen and non-invasive ventilation. RESULTS: Thirty-eight patients were analysed. The first quartile comprised 9 patients (median angle 11°, interquartile range 8-12), the second 10 patients (median angle 26°, range 19-30), the third 10 patients (median angle 42°, range 39-46), and the fourth 9 patients (median angle 53°, range 49-64). Hospital and ICU mortality were not different between groups. Lengths of ICU and hospital stay and length of invasive ventilation were significantly different between groups, with the highest values observed in the first quartile. The rate of oxygen use and non-invasive ventilation in the ICU and at hospital discharge was significantly different between groups, with the highest rate observed in the first quartile. There was a significant negative correlation between angle and resistance, compliance of the respiratory system and change in end-expiratory lung volume above the relaxation volume. CONCLUSION: The slope of the angle during the last 50% of expired volume in the COPD patients was associated with worsened respiratory mechanics and higher morbidity.

Comparison of Alpha 200 and CoughAssist as intermittent positive pressure breathing devices: a bench study.

BACKGROUND: Intermittent positive pressure breathing (IPPB) is used in non-intubated patients to increase lung volume and to enhance coughing. Alpha 200 (Salvia Lifetec, Kronberg, Germany) is a specific IPPB device. CoughAssist (Respironics France, Carquefou, France) is a mechanical insufflator-exsufflator used to remove secretions in patients with inefficient cough. Both can also be used for intubated or tracheotomized patients. We assessed the impact of various artificial airways on the ability of the Alpha 200 and CoughAssist to generate insufflated volume. METHODS: We measured the insufflated volume and pressure at the airway opening in a lung model under 2 conditions of compliance (30 or 60 mL/cm H(2)O) at single resistance of 5 cm H(2)O/L/s. The devices were used at 2 set pressures: 30 and 40 cm H(2)O. The Alpha 200 was set at 2 inflation flows: 0.5 and 1 L/s, whereas CoughAssist was set at its highest value of 10 L/s. Measurements were done without (control) and with different size endotracheal tubes and tracheostomy cannulae. The relationships between insufflated volume and measured pressure were analyzed using linear regressions. RESULTS: The slopes and intercepts of the control relationship between insufflated volume and pressure were significantly greater with Alpha 200 at each set flow than with CoughAssist. As artificial airways were used, the insufflated volume did not differ from the control with CoughAssist, while with Alpha 200 it increased at each flow setting and for all mechanical conditions. The largest differences in insufflated volume between the 2 devices were observed for the largest endotracheal tubes and tracheostomy cannulas and for the lowest inflation flow setting in Alpha 200. These results can be explained in terms of how the devices function, as CoughAssist adapts by increasing flow, while Alpha 200 adapts by increasing inspiratory time. CONCLUSIONS: This bench study has shown that in the presence of artificial airways the value of the insufflated volume generated by the CoughAssist device was significantly lower than that generated by the Alpha 200 device.

Effect of citrus polyphenol- and curcumin-supplemented diet on inflammatory state in obese cats.

Among obesity-associated disorders, low-grade inflammation has been described. The putative therapeutic properties of citrus and curcumin polyphenols could be associated with their anti-inflammatory properties. Two diets supplemented either with hesperidin (0.05 %) and naringin (0.1 %) from citrus extract or with highly bioavailable curcumin from Curcuma longa extract (0.09 %) were fed to eight obese cats for two 8-week periods (cross-over study design) while maintaining animals in an obese state. Plasma acute-phase protein (APP; α1-acid glycoprotein (AGP), serum amyloid A and haptoglobin) levels were assessed before and at the end of each test period. TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-ß, interferon (IFN)-γ mRNA levels were determined in peripheral blood mononuclear cells (PBMC) by real-time PCR. Compared with pre-study values, supplementation with citrus polyphenols resulted in lower plasma AGP and haptoglobin concentrations, while that with curcumin resulted in lower plasma AGP concentration. There were no differences between the supplementations. TNF-α, IL-1ß, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-ß, mRNA levels remained unaffected by either dietary supplementation. In contrast, IFN-γ and IL-2 mRNA levels were lower at the end of the citrus and the curcumin supplementation, respectively. There were no differences between the supplementations. The present study results show a slight effect of citrus and curcumin supplementation on inflammatory markers expressed by PBMC, and a decreased concentration of APP, which are mainly expressed by the liver. This would confirm that hesperidin and naringin or highly bioavailable curcumin extract have beneficial effects, targeted in the liver and could improve the obesity-related inflammatory state.

Lipid profile and insulin sensitivity in rats fed with high-fat or high-fructose diets.

The occurrence and severity of obesity- and insulin resistance-related disorders vary according to the diet. The aim of the present longitudinal study was to examine the effects of a high-fat or a high-fructose diet on body weight (BW), body fat mass, insulin sensitivity (IS) and lipid profiles in a rat model of dietary-induced obesity and low IS. A total of eighteen, 12-week-old male Wistar rats were divided into three groups, and were fed with a control, a high-fat (65 % lipid energy) or a high-fructose diet (65 % fructose energy) for 10 weeks. BW, body fat mass ((2)H2O dilution method), IS (euglycaemic-hyperinsulinaemic clamp technique), plasma glucose, insulin, NEFA, TAG and total cholesterol were assessed before and at the end of 10-week period. Cholesterol was measured in plasma lipoproteins separated from pooled samples of each group and each time period by using fast-protein liquid chromatography. All rats had similar BW at the end of the 10-week period. Body fat mass was higher in the high-fat group compared to the control group. There was no change in basal glycaemia and insulinaemia. The IS was lower in the high-fat group and was unchanged in the high-fructose group, compared to the control group. Plasma TAG concentration and cholesterol distribution in lipoproteins did not change over time in any group. Plasma NEFA concentration decreased, whereas plasma TAG concentration increased over time, regardless of the diet in both cases. The 10-week high-fat diet led to obesity and low IS, whereas rats fed with the high-fructose diet exhibited no change in IS and lipidaemia. The high-fat diet had more deleterious response than high-fructose diet to induce obesity and low IS in rats.

Performance of the coughassist insufflation-exsufflation device in the presence of an endotracheal tube or tracheostomy tube: a bench study.

BACKGROUND: The CoughAssist is a mechanical insufflator-exsufflator designed to assist airway secretion clearance in patients with ineffective cough. The device may benefit intubated and tracheotomized patients. We assessed the impact of various artificial airways on peak expiratory flow (PEF) with the CoughAssist. METHODS: We measured PEF and pressure at the airway opening in a lung model during insufflation-exsufflation with the CoughAssist, at 3 set pressures: 30/-30, 40/-40, and 50/-50 cm H(2)O, first without (control), and then with different sizes (6.5 to 8.5 mm inner diameter) of endotracheal tube (ETT) and tracheostomy tube (6, 7, and 8 mm inner diameter), compliance settings of 30 and 60 mL/cm H(2)O, and resistance settings of 0 and 5 cm H(2)O/L/s). We analyzed the relationship between PEF and pressure with linear regression. RESULTS: With compliance of 30 mL/cm H(2)O and 0 resistance the slope of the control relationship between PEF and pressure was statistically significantly greater than during any conditions with ETT or tracheostomy tube. Therefore, in comparison to the control, the relationship of PEF to pressure significantly went in the direction from top to bottom as the ETT or tracheostomy tube became narrower. The findings were the same with compliance of 30 mL/cm H(2)O and resistance of 5 cm H(2)O/L/s. With compliance of 60 mL/cm H(2)O the highest set pressure values were not achieved and some relationships departed from linearity. The control slope of the relationship between PEF and pressure with compliance of 60 mL/cm H(2)O and 0 resistance did not significantly differ with any ETT or tracheostomy tube. CONCLUSIONS: The artificial airways significantly reduced PEF during insufflation-exsufflation with CoughAssist; the narrower the inner diameter of the artificial airway, the lower the PEF for a given expiratory pressure.

Management and long-term outcome of patients with chronic neuromuscular disease admitted to the intensive care unit for acute respiratory failure: a single-center retrospective study.

BACKGROUND: Patients with chronic neuromuscular disease represent less than 10% of those receiving mechanical ventilation in the intensive care unit (ICU). Little has been reported regarding either ICU management of acute respiratory failure (ARF) in the era of noninvasive mechanical ventilation (NIV) or long-term outcomes. OBJECTIVE: To describe the respiratory management of patients with chronic neuromuscular diseases admitted to our university hospital ICU for ARF, and the long-term outcomes. METHODS: We retrospectively analyzed patients with chronic neuromuscular diseases admitted to our ICU for a first episode of ARF between January 1, 1996, and February 27, 2007. We assessed severity of illness on ICU admission, respiratory management during ICU stay, and outcomes on June 15, 2008. RESULTS: During the study period, 87 patients (44 with hereditary and 43 with acquired neuromuscular diseases) had their first ARF episode that required ICU admission. In the hereditary-diseases group and the acquired-diseases group, respectively, the rates of NIV use during the ICU stay were 82% and 63% (P = .040), the intubation rates were 30% and 56% (P = .02), and the tracheotomy rates were 9% and 12% (difference not significant). At the final assessment (median 3 years) the mortality rate was 58%, and mortality was not significantly related to the type of neuromuscular disease. At final assessment, 46% of the patients were on NIV and 29% had tracheotomy. CONCLUSIONS: In our ICU, chronic neuromuscular disease is an uncommon cause of ARF, for which we often use NIV. These patients had a low probability of death in the ICU. Long-term outcome was independent of the type of neuromuscular disease.

Nicotinic acid decreases apolipoprotein B100-containing lipoprotein levels by reducing hepatic very low density lipoprotein secretion through a possible diacylglycerol acyltransferase 2 inhibition in obese dogs.

Apolipoprotein B100 (apoB100) is an essential component of very low density lipoprotein (VLDL) and low-density lipoprotein (LDL), both independent markers of cardiovascular risk. Nicotinic acid (NA) is an efficacious drug for decreasing VLDL and LDL, but the underlying mechanisms are unclear. For this purpose, six obese insulin-resistant dogs were given 350 mg/day of NA for 1 week and then 500 mg/day for 3 weeks. Turnover of apoB100-containing lipoproteins was investigated using stable isotope-labeled tracers. Multicompartmental modeling was used to derive kinetic parameters before and at the end of NA treatment. Hepatic diacylglycerol acyltransferase 2 (DGAT2), microsomal triglyceride transfer protein (MTP), hepatic lipase (HL), and adipose lipoprotein lipase (LPL) mRNA expression was also determined. NA treatment decreased plasma triglyceride (TG) (p < 0.001), VLDL-TG (p < 0.05), total cholesterol (p < 0.0001), and LDL cholesterol (p < 0.05), whereas plasma nonesterified fatty acids were unchanged. The decrease in VLDL-apoB100 concentration (p < 0.001) was the result of a lower absolute production rate (APR) (p < 0.001), despite a moderate decrease (p < 0.05) in fractional catabolic rate (FCR). LDL-apoB100 concentration was reduced (p < 0.05), an effect related to a decrease in LDL APR (p < 0.05) and no change in FCR. NA treatment reduced DGAT2 expression (p < 0.05), whereas MTP, HL, and LPL expression was unchanged. Our results suggest that NA treatment reduced VLDL and LDL concentration as a consequence of a decrease in VLDL production.

A case of pneumomediastinum in a patient with acute respiratory distress syndrome on pressure support ventilation.

During mechanical ventilation for acute respiratory distress syndrome, tidal volume (V(T)) must be reduced. Once switched to pressure-support ventilation, there is a risk that uncontrolled large V(T) may be delivered. A 63-year-old man with community-acquired pneumonia required tracheal intubation and mechanical ventilation, with a V(T) of 6 mL/kg predicted body weight, PEEP of 10 cm H2O, a respiratory rate of 30 breaths/min, and F(IO2) of 0.60. Plateau pressure was 22 cm H2O. He improved and received pressure-support. Twelve days later a chest radiograph showed suspected air leaks, confirmed via computed tomogram (CT), which showed anterior pneumomediastinum. V(T) received over the previous 3 days had averaged 14 mL/kg predicted body weight. The patient was put back onto volume-controlled mode, and 2 days later there were no air leaks. In pressure-support ventilation, V(T) must be closely monitored to ensure lung-protective mechanical ventilation.

Quantitative analysis of acid-base disorders in patients with chronic respiratory failure in stable or unstable respiratory condition.

BACKGROUND: The Stewart approach theorizes that plasma pH depends on P(aCO2), the strong ion difference, and the plasma total concentration of non-volatile weak acids (A(tot)). The conventional approach measures standardized base excess, bicarbonate (HCO3⁻), and the anion gap. OBJECTIVE: To describe acid-base disorders with the Stewart approach and the conventional approach in patients with chronic respiratory failure. METHODS: This was an observational prospective study in a medical intensive care unit and a pneumology ward of a university hospital. There were 128 patients included in the study, of which 14 had more than one admission, resulting in 145 admissions. These were allocated to 4 groups: stable respiratory condition and elevated HCO3⁻ (Group 1, n = 23), stable respiratory condition and non-elevated HCO3⁻ (Group 2, n = 41), unstable respiratory condition and elevated HCO3⁻ (Group 3, n = 44), and unstable respiratory condition and non-elevated HCO3⁻ (Group 4, n = 37). Elevated HCO3⁻ was defined as ≥ 3 standard deviations higher than the mean value we found in 8 healthy volunteers. Measurements were taken on admission. RESULTS: In groups 1, 2, 3, and 4, the respective mean ± SD values were: HCO3⁻ 33 ± 3 mM, 26 ± 3 mM, 37 ± 4 mM, and 27 ± 3 mM (P < .001); strong ion difference 45 ± 3 mM, 38 ± 4 mM, 46 ± 4 mM, and 36 ± 4 mM (P < .001); and A(tot) 12 ± 1 mM, 12 ± 1 mM, 10 ± 1 mM, 10 ± 2 mM (P < .001). Non-respiratory disorders related to high strong ion difference were observed in 12% of patients with elevated HCO3⁻, and in none of those with non-elevated HCO3⁻ (P = .003). Non-respiratory disorders related to low strong ion difference were observed in 9% of patients with non-elevated HCO3⁻, and in none of those with elevated HCO3⁻ (P = .02). Hypoalbuminemia was common, especially in unstable patients (group 3, 66%; group 4, 65%). Normal standardized base excess (16%), HCO3⁻ (28%), and anion gap (30%) values were common. The Stewart approach detected high effective strong ion difference in 13% of normal standardized base excess, and in 20% of normal anion gap corrected for albuminemia, and low effective strong ion difference in 22% of non-elevated HCO3⁻. CONCLUSIONS: In patients with chronic respiratory failure the acid-base pattern is complex, metabolic alkalosis is present in some patients with elevated HCO3⁻, and metabolic acidosis is present in some with non-elevated HCO3⁻. The diagnostic performance of the Stewart approach was better than that of the conventional approach, even when corrected anion gap was taken into account.

Deciphering heterogeneity of septic shock patients using immune functional assays: a proof of concept study.

The complexity of sepsis pathophysiology hinders patient management and therapeutic decisions. In this proof-of-concept study we characterised the underlying host immune response alterations using a standardised immune functional assay (IFA) in order to stratify a sepsis population. In septic shock patients, ex vivo LPS and SEB stimulations modulated, respectively, 5.3% (1/19) and 57.1% (12/21) of the pathways modulated in healthy volunteers (HV), highlighting deeper alterations induced by LPS than by SEB. SEB-based clustering, identified 3 severity-based groups of septic patients significantly different regarding mHLA-DR expression and TNFα level post-LPS, as well as 28-day mortality, and nosocomial infections. Combining the results from two independent cohorts gathering 20 HV and 60 patients, 1 cluster grouped all HV with 12% of patients. The second cluster grouped 42% of patients and contained all non-survivors. The third cluster grouped 46% of patients, including 78% of those with nosocomial infections. The molecular features of these clusters indicated a distinctive contribution of previously described genes defining a "healthy-immune response" and a "sepsis-related host response". The third cluster was characterised by potential immune recovery that underlines the possible added value of SEB-based IFA to capture the sepsis immune response and contribute to personalised management.

Effects of High-Fat Diet at Two Energetic Levels on Fecal Microbiota, Colonic Barrier, and Metabolic Parameters in Dogs.

Increased consumption of energy-rich foods is a key factor in overweight, obesity, and associated metabolic disorders. This would be, at least in part, related to microbiota disturbance. In rodent models of obesity, microbiota disruption has been associated with alteration of the intestinal barrier, endotoxemia, inflammation grade, and insulin sensitivity. The aim of the present study was to assess the effects of a high-fat diet (HFD), fed at two energetic levels, on microbiota, intestinal barrier, and inflammatory and metabolic parameters in dogs. A HFD (33% fat as fed, 4,830 kcal/kg) was given to 24 healthy Beagle dogs at 100% (HF-100; n = 8) and at 150% (HF-150; n = 16) of their maintenance energy requirements for 8 weeks. Analysis of similarity revealed a significant difference in gut microbiota ß-diversity following the diet compared to week 0 in both groups while α-diversity was lower only in the HF-150 group. Firmicutes/Bacteroidetes ratio was higher in the HF-150 group compared to the HF-100 group at weeks 2 and 8. A reduction in insulin sensitivity was observed over time in the HF150 group. Neither endotoxemia nor inflammation was observed in either group, did not find supporting data for the hypothesis that the microbiota is involved in the decline of insulin sensitivity through metabolic endotoxemia and low-grade inflammation. Colonic permeability was increased at week 4 in both groups and returned to initial levels at week 8, and was associated with modifications to the expression of genes involved in colonic barrier function. The increase in intestinal permeability may have been caused by the altered intestinal microbiota and increased expression of genes encoding tight junction proteins might indicate a compensatory mechanism to restore normal permeability. Although simultaneous changes to the microbiota, barrier permeability, inflammatory, and metabolic status have not been observed, such a causal link cannot be excluded in dogs overfed on a HFD. Further studies are necessary to better understand the link between HFD, intestinal microbiota and the host.

Effects of green tea on insulin sensitivity, lipid profile and expression of PPARalpha and PPARgamma and their target genes in obese dogs.

As in man, canine obesity is associated with insulin resistance, dyslipidaemia and other chronic diseases. This study was designed to examine the effects of a nutritional supplement (green tea) on insulin sensitivity and plasma lipid concentrations in an obese insulin-resistant dog model. We also determined mRNA expression of two transcription factors, PPARgamma and PPARalpha, and some of their target genes, including GLUT4, lipoprotein lipase (LPL) and adiponectin. Obese dogs were divided into two groups: a green tea group (n 6); a control group (n 4). Dogs in the green tea group were given green tea extract (80 mg/kg per d) orally, just before their single daily meal, for 12 weeks. Insulin sensitivity (using a euglycaemic-hyperinsulinaemic clamp) and concentrations of plasma TAG, total cholesterol and NEFA were assessed in each group. Gene expression was measured in visceral and subcutaneous adipose tissues and in liver and skeletal muscle, by real-time PCR. At 12 weeks in the green tea group, mean insulin sensitivity index was 60 (SEM 11) % higher (P < 0.05) and TAG concentration 50 (SEM 10) % lower (P < 0.001), than baseline. PPARgamma, GLUT4, LPL and adiponectin expression were significantly higher in both adipose tissues, whilst PPARalpha and LPL expression were significantly higher in skeletal muscle, compared with baseline. These findings show that nutritional doses of green tea extract may improve insulin sensitivity and lipid profile and alter the expression of genes involved in glucose and lipid homeostasis.

Source of Circulating Pentraxin 3 in Septic Shock Patients.

Sepsis, which is the leading cause of death in intensive care units (ICU), has been acknowledged as a global health priority by the WHO in 2017. Identification of biomarkers allowing early stratification and recognition of patients at higher risk of death is crucial. One promising biomarker candidate is pentraxin-3 (PTX3); initially elevated and persistently increased plasma concentration in septic patients has been associated with increased mortality. PTX3 is an acute phase protein mainly stored in neutrophil granules. These cells are responsible for rapid and prompt release of PTX3 in inflammatory context, but the cellular origin responsible for successive days' elevation in sepsis remains unknown. Upon inflammatory stimulation, PTX3 can also be produced by other cell types, including endothelial and immune cells. As in septic patients immune alterations have been described, we therefore sought to investigate whether such cells participated in the elevation of PTX3 over the first days after septic shock onset. To address this point, PTX3 was measured in plasma from septic shock patients at day 3 after ICU admission as well as in healthy volunteers (HV), and the capacity of whole blood cells to secrete PTX3 after inflammatory stimulation was evaluated ex vivo. A significantly mean higher (100-fold) concentration of plasma PTX3 was found in patients compared to HV, which was likely due to the inflammation-induced initial release of the pre-existing PTX3 reservoir contained in neutrophils. Strikingly, when whole blood was stimulated ex vivo with LPS no significant difference between patients and HV in PTX3 release was found. This was in contrast with TNFα which decreased production was illustrative of the endotoxin tolerance phenomenon occurring in septic patients. Then, the release of PTX3 protein from a HV neutrophil-free PBMC endotoxin tolerance model was investigated. At the transcriptional level, PTX3 seems to be a weakly tolerizable gene similar to TNFα. Conversely, increased protein levels observed in anergy condition reflects a non-tolerizable phenotype, more likely to an anti-inflammatory marker. Hence, altered immune cells still have the ability to produce PTX3 in response to an inflammatory trigger, and therefore circulating white blood cell subset could be responsible of the sustained PTX3 plasma levels over the first days of sepsis setting.

Effect of activated protein C on pulmonary blood flow and cytokine production in experimental acute lung injury.

OBJECTIVE: In acute lung injury (ALI) activated protein C (APC) may reopen occluded lung vessels and minimize lung inflammation. We aimed at assessing the effect of APC on regional lung perfusion, aerated lung volume, cytokine production and oxygenation in experimental ALI. DESIGN AND SETTING: Prospective, controlled study in an imaging facility. PARTICIPANTS: Pigs tracheotomized and mechanically ventilated. INTERVENTION: Pigs were randomly given intravenously APC (n = 8) or saline (n = 8). Thirty minutes later, ALI was induced by injecting oleic acid. MEASUREMENTS AND RESULTS: Lung perfusion and aerated lung volume measured with positron emission tomography, plasma cytokines and arterial blood gas were determined just before ALI and 110 and 290 min thereafter. Lung cytokines were measured at the end of the experiment. PaO2 under F I O2 1 was significantly lower in the APC group before lung injury (473+/-129 vs. 578+/-54 mmHg) and 110 min (342+/-138 vs. 446+/-103 mmHg) and 290 min (303+/-171 vs. 547+/-54 mmHg) thereafter (p < 0.05). Lung perfusion nonsignificantly tended to redistribute towards dorsal lung regions with APC. Total aerated lung volume was not different between APC and control before ALI (10.0+/-1.5 vs. 11.0+/-2.5 ml/kg) (p > 0.05) or thereafter. Plasma IL-6 and IL-8 at 110 min were greater with APC (p < 0.05). CONCLUSIONS: In contrast to studies using other models, pretreatment with APC was associated with worsening oxygenation in the present investigation. This might be due to ventilation-perfusion mismatch, with more perfusion to dependent nonaerated areas.