Severe Hypercapnia and Outcome of Mechanically Ventilated Patients with Moderate or Severe Acute Respiratory Distress Syndrome

PURPOSE: To analyze the relationship between hypercapnia developing within the first 48 h after the start of mechanical ventilation and outcome in patients with acute respiratory distress syndrome (ARDS). PATIENTS AND METHODS: We performed a secondary analysis of three prospective non-interventional cohort studies focusing on ARDS patients from 927 intensive care units (ICUs) in 40 countries. These patients received mechanical ventilation for more than 12 h during 1-month periods in 1998, 2004, and 2010. We used multivariable logistic regression and a propensity score analysis to examine the association between hypercapnia and ICU mortality. MAIN OUTCOMES: We included 1899 patients with ARDS in this study. The relationship between maximum PaCO2 in the first 48 h and mortality suggests higher mortality at or above PaCO2 of ≥50 mmHg. Patients with severe hypercapnia (PaCO2 ≥50 mmHg) had higher complication rates, more organ failures, and worse outcomes. After adjusting for age, SAPS II score, respiratory rate, positive end-expiratory pressure, PaO2/FiO2 ratio, driving pressure, pressure/volume limitation strategy (PLS), corrected minute ventilation, and presence of acidosis, severe hypercapnia was associated with increased risk of ICU mortality [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.32 to 2.81; p = 0.001]. In patients with severe hypercapnia matched for all other variables, ventilation with PLS was associated with higher ICU mortality (OR 1.58, CI 95% 1.04-2.41; p = 0.032). CONCLUSIONS: Severe hypercapnia appears to be independently associated with higher ICU mortality in patients with ARDS.info:eu-repo/semantics/publishedVersio

Immune response of macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonas gingivalis

Periodontal disease is a chronic inflammatory gum disease that in severe cases leads to tooth loss. Porphyromonas gingivalis (Pg) is a bacterium closely associated with generalized forms of periodontal disease. Clinical onset of generalized periodontal disease commonly presents in individuals over the age of 40. Little is known regarding the effect of aging on inflammation associated with periodontal disease. In the present study we examined the immune response of bone marrow derived macrophages (BMM) from young (2-months) and aged (1-year and 2-years) mice to Pg strain 381. Pg induced robust expression of cytokines; tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10, chemokines; neutrophil chemoattractant protein (KC), macrophage colony stimulating factor (MCP)-1, macrophage inflammatory protein (MIP)-1α and regulated upon activation normal T cell expressed and secreted (RANTES), as well as nitric oxide (NO, measured as nitrite), and prostaglandin E2 (PGE2) from BMM of young mice. BMM from the 2-year age group produced significantly less TNF-α, IL-6 and NO in response to Pg as compared with BMM from 2-months and 1-year of age. We did not observe any difference in the levels of IL-1β, IL-10 and PGE2 produced by BMM in response to Pg. BMM from 2-months and 1-year of age produced similar levels of all chemokines measured with the exception of MCP-1, which was reduced in BMM from 1-year of age. BMM from the 2-year group produced significantly less MCP-1 and MIP-1α compared with 2-months and 1-year age groups. No difference in RANTES production was observed between age groups. Employing a Pg attenuated mutant, deficient in major fimbriae (Pg DPG3), we observed reduced ability of the mutant to stimulate inflammatory mediator expression from BMMs as compared to Pg 381, irrespective of age. Taken together these results support senescence as an important facet of the reduced immunological response observed by BMM of aged host to the periodontal pathogen Pg

Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity

Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors - including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule - concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.We hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IkappaBalpha- and IRAK-1-dependent manner.These studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen

Incidence, risk factors and outcome of barotrauma in mechanically ventilated patients.

OBJECTIVE: To determine the incidence, risk factors, and outcome of barotrauma in a cohort of mechanically ventilated patients where limited tidal volumes and airway pressures were used. DESIGN AND SETTING: Prospective cohort of 361 intensive care units from 20 countries. PATIENTS AND PARTICIPANTS: A total of 5183 patients mechanically ventilated for more than 12 h. MEASUREMENTS AND RESULTS: Baseline demographic data, primary indication for mechanical ventilation, daily ventilator settings, multiple-organ failure over the course of mechanical ventilation and outcome were collected. Barotrauma was present in 154 patients (2.9%). The incidence varied according to the reason for mechanical ventilation: 2.9% of patients with chronic obstructive pulmonary disease; 6.3% of patients with asthma; 10.0% of patients with chronic interstitial lung disease (ILD); 6.5% of patients with acute respiratory distress syndrome (ARDS); and 4.2% of patients with pneumonia. Patients with and without barotrauma did not differ in any ventilator parameter. Logistic regression analysis identified as factors independently associated with barotrauma: asthma [RR 2.58 (1.05-6.50)], ILD [RR 4.23 (95%CI 1.78-10.03)]; ARDS as primary reason for mechanical ventilation [RR 2.70 (95%CI 1.55-4.70)]; and ARDS as a complication during the course of mechanical ventilation [RR 2.53 (95%CI 1.40-4.57)]. Case-control analysis showed increased mortality in patients with barotrauma (51.4 vs 39.2%; p=0.04) and prolonged ICU stay. CONCLUSIONS: In a cohort of patients in whom airway pressures and tidal volume are limited, barotrauma is more likely in patients ventilated due to underlying lung disease (acute or chronic). Barotrauma was also associated with a significant increase in the ICU length of stay and mortality

Finding peculiar patterns of kinetoplastida enzymes to be exploited in drug design

If a parasite and host metabolic ways differ, such as an enzyme is present only in parasite, obviously this is a good target in drug design. Also, essential enzymes present in both can be good targets if we exploit selective patterns of the parasite enzyme. At this aim, comparison of the pentose phosphate pathway (PPP) 2nd dehydrogenase, 6-phosphogluconate dehydrogenase (6PGDH), between mammal host and Trypanosoma brucei, has been done in our lab. PPP provides above all necessary NADPH to all cell reduction reactions, including those contrasting both oxidative, parasite environment and host response. Although kinetoplastids 6PGDH shows only 33% amino acid identity with mammal 6PGDH, 3D-structure and general acid-base mechanism are similar, with many conserved residues in the active site. Anyway, by studying enzymes in more detail, several differences were found. Looking for the affinity of some polycyclic compounds, preferential binding of T. brucei 6PGDH to triphenylmethane with either nitrogen or oxygen as substituent in two rings and a sulfonate in the 3rd ring was found compared to the mammal enzyme. A selectivity of 40 was shown by Brilliant Green and this is probably due to the shorter distance between two active site lysines than in mammal. By studying homotropic cooperativity other significant differences were found. In fact substrate binding to one subunit increases homodimer catalytic efficiency; even if the two subunits have an identical sequence they are implied in different steps. This was shown by several ways, for instance in presence of the substrate 6PG there is a NADP half-site reactivity, also 6PG activates decarboxylation following 6PG oxidation, but differently from the liver enzyme the parasite's one is able to catalyse this step even in absence of an activator. Besides, allosteric modulation for the parasite enzyme is not apparent when reverse reaction is studied, while it is shown by yeast enzyme, which is very similar to the liver's one. Thus, diversity exists which allowed to find ligands more than 250-fold selective, as transition state analogues 4-phospho-erythronoxamate and 4-phospho-erythronate. This characterization has disclosed lead compounds for medicinal chemists to transform those into pro-drugs and derivatives with good stability and solubility. Last difference found is that parasite 6PGDH shows a ligand-modulated tetramerization, which is not present in mammal enzyme representing further drug exploitable potential

Outcome of mechanically ventilated patients who require a tracheostomy

OBJECTIVE: To estimate the prevalence of, the risk factors associated with, and the outcome of tracheostomy in a heterogeneous population of mechanically ventilated patients. DESIGN: Prospective, observational cohort study. SETTING: A total of 361 intensive care units from 12 countries. PATIENTS: A cohort of 5,081 patients mechanically ventilated for >12 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 546 patients (10.7%) had a tracheostomy during their stay in the intensive care unit. Tracheostomy was performed at a median time of 12 days (interquartile range, 7-17) from the beginning of mechanical ventilation. Variables associated with the performance of tracheostomy were duration of mechanical ventilation, need for reintubation, and neurologic disease as the primary reason of mechanical ventilation. The intensive care unit stay of patients with or without tracheostomy was a median of 21 days (interquartile range, 12-32) vs. 7 days (interquartile range, 4-12; p < .001), respectively, and the hospital stay was a median 36 days (interquartile range, 23-53) vs. 15 days (interquartile range, 8-26; p < .001), respectively. Adjusting by other variables, tracheostomy was independently related with survival in the intensive care unit (odds ratio, 2.22; 95% confidence interval, 1.72-2.86). Mortality in the hospital was similar in both groups (39% vs. 40%, p = .65). CONCLUSIONS: Tracheostomy is a common surgical procedure in the intensive care unit that is associated with a lower mortality in the unit but with a longer stay and a similar mortality in the hospital than in patients without tracheostom

Evolution of mechanical ventilation in response to clinical research.

RATIONALE: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. OBJECTIVES: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. METHODS: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). MEASUREMENTS AND MAIN RESULTS: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes decreased (7.4 vs. 9.1 ml/kg, P < 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H(2)O, P = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. CONCLUSIONS: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally

Evolution of mechanical ventilation in response to clinical research.

none23RATIONALE: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. OBJECTIVES: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. METHODS: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). MEASUREMENTS AND MAIN RESULTS: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes decreased (7.4 vs. 9.1 ml/kg, P < 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H(2)O, P = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. CONCLUSIONS: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally.http://ajrccm.atsjournals.org/content/177/2/170.longESTEBAN A.;FERGUSON N.D.;MEADE M.O.;FRUTOS-VIVAR F.;APEZTEGUIA C.;BROCHARD L.;RAYMONDOS K.;NIN N.;HURTADO J.;TOMICIC V.;GONZÁLEZ M.;ELIZALDE J.;NIGHTINGALE P.;ABROUG F.;P. PELOSI;ARABI Y.;MORENO R.;JIBAJA M.;D'EMPAIRE G.;SANDI F.;MATAMIS D.;MONTAÑEZ A.M.;ANZUETO A.Esteban, A.; Ferguson, N. D.; Meade, M. O.; FRUTOS VIVAR, F.; Apezteguia, C.; Brochard, L.; Raymondos, K.; Nin, N.; Hurtado, J.; Tomicic, V.; González, M.; Elizalde, J.; Nightingale, P.; Abroug, F.; Pelosi, PAOLO PASQUALINO; Arabi, Y.; Moreno, R.; Jibaja, M.; D'Empaire, G.; Sandi, F.; Matamis, D.; Montañez, A. M.; Anzueto, A