COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.

BACKGROUND: Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk. METHODS: We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models. RESULTS: Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk. CONCLUSIONS: Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Temporal trends in pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUND: Since 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival. METHODS: We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010-2014 and 2015-2019. RESULTS: A total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010-2014 and 2015-2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2-90.9%) and 90.8% (95% CI 89.3-92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0-70.8%) and 70.5% (95% CI 67.8-73.4%), respectively). CONCLUSIONS: The use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

Life-threatening antineutrophil cytoplasmic antibody-associated vasculitis after influenza A H1N1 infection requiring veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Antineutrophil cytoplasmic autoantibody-associated vasculitis is an immune-mediated necrotizing vasculitis, affecting small- and medium-sized vessels. CASE REPORT: A 22-year-old female patient with free medical history presented with life-threatening pulmonary hemorrhage due to antineutrophil cytoplasmic autoantibody-associated vasculitis, temporarily associated with influenza A H1N1 infection. Due to rapidly worsening respiratory failure, despite conventional management, veno-venous peripheral extracorporeal membrane oxygenation was initiated and continued for 26 days, with subsequent renal replacement therapy. DISCUSSION: We present a case of severe antineutrophil cytoplasmic autoantibody-associated pulmonary vasculitis, managed with veno-venous extracorporeal membrane oxygenation at the initial phase. Despite the significant challenges raised with the use of extracorporeal membrane oxygenation in pulmonary hemorrhage cases, extracorporeal membrane oxygenation may have a significant impact on outcome in this setting, by providing adequate time for a successful immunosuppressive treatment.

The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through a derivation and a validation cohort.

BACKGROUND: Since the Sepsis-3 criteria, change in Sequential Organ Failure Assessment (SOFA) score has become a key component of sepsis identification. Thus, it could be argued that reversal of this change (ΔSOFA) may reflect sepsis response and could be used as measure of efficacy in interventional trials. We aimed to assess the predictive performance of ΔSOFA for 28-day mortality. METHODS: Data from two previously published randomized controlled trials were studied: the first reporting on patients with severe Gram-negative infections as a derivation cohort and the second reporting on patients with ventilator-associated pneumonia as a validation cohort. Only patients with sepsis according to the Sepsis-3 definition were included in this analysis. SOFA scores were calculated on days 1, 2, 3, 5, 7, 14, and 28. RESULTS: We included 448 patients within the derivation cohort and 199 within the validation cohort. Mean SOFA scores on day 1 were 6.06 ± 4.07 and 7.84 ± 3.39, and 28 day mortality 22.8% and 29.6%, respectively. In the derivation cohort, the earliest time point where ΔSOFA score predicted mortality was day 7 (AUROC (95% CI) 0.84 (0.80-0.89); p < 0.001). The best tradeoff for prediction was found with 25% changes (78% sensitivity, 80% specificity); less than 25% decrease of admission SOFA was associated with increased mortality (odds ratio for death 14.87). This finding was confirmed in the validation cohort. CONCLUSIONS: ΔSOFA on day 7 is a useful early prognostic marker of 28-day mortality and could serve as an endpoint in future sepsis trials alongside mortality. TRIAL REGISTRATION: ClinicalTrials.gov numbers NCT01223690 and NCT00297674.

Platelet and coagulation disorders in newly diagnosed patients with pulmonary arterial hypertension.

There is a complex and not fully elucidated association between pulmonary arterial hypertension (PAH) and coagulation disorders. The goal of this study was to evaluate platelet function, coagulation and fibrinolysis in PAH patients at diagnosis, before PAH-specific treatment initiation. We enrolled 20 healthy controls and 30 PAH patients (20 with connective tissue disease (CTD-PAH) and 10 idiopathic (iPAH)). None of the participants was on any antiplatelet or anticoagulation therapy. Blood samples from PAH patients were collected during the initial right heart catheterization. All subjects were assessed with platelet function analyzer-100 (PFA-100), epinephrine (Epi) and ADP-induced light transmission aggregometry (LTA), thromboelastometry (ROTEM) and endogenous thrombin potential (ETP). Our results showed that Epi and ADP-LTA values were significantly lower in newly diagnosed PAH patients compared to controls. Disaggregation was present in 73% of patients, a characteristic not seen in healthy individuals. In ROTEM assay, CT and CFT measurements were significantly higher and a angle lower compared to controls. ETP testing revealed significantly reduced outcomes in AUC, Cmax and Tmax. When CTD-PAH and iPAH patient groups were compared, iPAH ADP-LTA values were significantly decreased compared to CTD-PAH. In conclusion, newly diagnosed PAH patients presented with decreased platelet aggregation, clot propagation and thrombin generation, along with delayed initiation of the coagulation process. These hemostatic deficits could indicate an "exhaustion" of the coagulation process that could be caused by endothelial dysfunction and chronic activation of the procoagulant pathways. Further studies are warranted to confirm these laboratory findings and assess their potential clinical significance.

Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients.

Abbreviated versions of the risk stratification strategy of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines have been recently validated in patients with pulmonary arterial hypertension. We aimed to investigate their prognostic value in medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients from the COMPERA registry, which collects six variables of interest (World Health Organization Functional Class, 6-min walk distance, brain natriuretic peptide, right atrial pressure, cardiac index and mixed venous oxygen saturation).We included patients with at least one follow-up visit, no pulmonary endarterectomy and at least three of the six variables available, and classified the patients into low-, intermediate- and high-risk groups. As a secondary analysis, the number of noninvasive low-risk criteria was counted. The association between risk assessment and survival was evaluated.Data from inclusion and follow-up (median 7 months) visits were available for 561 and 231 patients, respectively. Baseline 1- and 5-year survival estimates were significantly different (p<0.0001) in the baseline low-risk (98.6% and 88.3%, respectively), intermediate-risk (94.9% and 61.8%, respectively) and high-risk (75.5% and 32.9%, respectively) cohorts. Follow-up data were even more discriminative, with 100%, 92% and 69% 1-year survival, respectively. The number of low-risk noninvasive criteria was also associated with survival.These analyses suggest that the ESC/ERS risk assessment may be applicable in patients with medically treated CTEPH.

Pulmonary hypertension in patients with interstitial lung disease.

Interstitial lung diseases (ILDs) comprise a broad and heterogeneous group of more than two hundred diseases with common functional characteristics. Their diagnosis and management require a multidisciplinary approach. This multidisciplinary approach involves the assessment of comorbid conditions including pulmonary hypertension (PH) that exerts a dramatic impact on survival. The current World Health Organization (WHO) classification of PH encompasses many of the interstitial lung diseases into WHO Group 3, while sarcoidosis, Pulmonary Langerhans Cell Histiocytosis and lymphangioleiomyomatosis are placed into WHO Group 5 as diseases with unclear or multifactorial mechanisms. Connective tissue diseases could span any of the 5 WHO groups based on the primary phenotype into which they manifest. Interestingly, several challenging phenotypes present with features that overlap between two or more WHO PH groups. Currently, PH-specific treatment is recommended only for patients classified into WHO Group 1 PH. The lack of specific treatment for other groups, including PH in the setting of ILD, reflects the poor outcomes of these patients. Thus, identification of the optimal strategy for ILD patients with PH remains an amenable need. This review article provides a brief overview of biomarkers indicative of vascular remodeling in interstitial lung disease, summarizes the current state of knowledge regarding patients with PH and ILD and highlights future perspectives that remain to be addressed.

Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome.

BACKGROUND: Evidence on the changes in the absolute counts of monocyte subpopulations in sepsis is missing. METHODS: Firstly, absolute counts of circulating CD14pos/HLA-DRpos/CD45pos monocytes were measured by flow cytometry in 70 patients with Gram-negative sepsis and in 10 healthy volunteers. In the second phase, immunophenotyping was performed and the absolute count of circulating inflammatory monocytes and of circulating CD14dim/CD16pos/CD45pos patrolling monocytes were measured in another 55 patients and 10 healthy volunteers. Measurements were repeated on days 3, 7, and 10. Results were correlated with survival after 28 days. RESULTS: Greater numbers of CD14pos/HLA-DRpos/CD45pos monocytes were found on day 1 in survivors compared to nonsurvivors (p = 0.030). Receiver operating characteristic (ROC) analysis showed that a cutoff higher than 337 cells/mm3 on day 1 could discriminate between survivors and nonsurvivors with a positive predictive value (PPV) of 91.1%. Logistic regression including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score showed that an absolute count greater than 337 cells/mm3 was independently associated with unfavorable outcome (odds ratio (OR) 0.19, p = 0.050). The absolute counts of inflammatory and of CD14dim/CD16pos/CD45pos monocytes were greater in patients than healthy controls during the entire 10 days of follow-up. The absolute counts on day 3 of CD14dim/CD16pos/CD45pos monocytes were greater in survivors than nonsurvivors (p = 0.027). ROC analysis revealed that the cutoff at 27 cells/mm3 could discriminate between survivors and nonsurvivors with PPV of 94.1%. Logistic regression including age, SOFA score, and APACHE II score showed that an absolute count greater than 27 cells/mm3 was independently associated with unfavorable outcome (OR 0.06, p = 0.033). Logistic regression analysis showed that intra-abdominal infection on day 1 was predictive of low CD14dim/ CD16pos/CD45pos count on day 3. CONCLUSION: Circulating counts of inflammatory and patrolling monocytes are greatly increased in Gram-negative sepsis. Absolute counts of CD14pos/HLA-DRpos/CD45pos monocytes on day 1 and CD14dim/CD16pos/CD45pos monocytes on day 3 are independently associated with final outcome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01223690 . Registered retrospectively on 18 October 2010.

Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.

BACKGROUND: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis. METHODS: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3. RESULTS: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109). CONCLUSIONS: MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.

Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome.

BACKGROUND: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood. METHODS: We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression. RESULTS: PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3. CONCLUSIONS: Defective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01223690 . Registered on 18 October 2010.

Metabolite Profiles in Sepsis: Developing Prognostic Tools Based on the Type of Infection.

OBJECTIVES: Currently used biomarkers insufficiently discriminate between patients with systemic inflammatory response syndrome of non-infectious origin and sepsis. The aim of this study was to identify surrogate markers that distinguish between systemic inflammatory response syndrome and sepsis as well as the underlying type of infection by targeted metabolomics. DESIGN: Retrospective analysis. SETTINGS: Six sites of the Hellenic Sepsis Study Group and at Jena University Hospital. PATIENTS: A total of 406 patients were analyzed: 66 fulfilling criteria for diagnosis of systemic inflammatory response syndrome, 100 for community-acquired pneumonia, 112 for urinary tract infection, 83 for intra-abdominal infection and 45 for bloodstream infection. Patients were divided into test cohort (n = 268) and confirmation cohort (n = 138). INTERVENTIONS: A total of 186 metabolites were determined by liquid chromatography tandem mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of most acylcarnitines, glycerophospholipids and sphingolipids were altered in sepsis compared to systemic inflammatory response syndrome. A regression model combining the sphingolipid SM C22:3 and the glycerophospholipid lysoPCaC24:0 was discovered for sepsis diagnosis with a sensitivity of 84.1% and specificity of 85.7%. Furthermore, specific metabolites could be used for the discrimination of different types of infection. The glycerophospholipid lysoPCaC26:1 identified patients with community-acquired pneumonia in sepsis or severe sepsis/septic shock. Within severe sepsis/septic shock, patients with bloodstream infection could be discriminated by a decrease of acetylornithine. Changes of metabolites between sepsis and severe sepsis/septic shock also varied according to the underlying type of infection, showing that putrescine, lysoPCaC18:0 and SM C16:1 are associated with unfavorable outcome in community-acquired pneumonia, intra-abdominal infections and bloodstream infections, respectively. CONCLUSIONS: Using a metabolomics approach, single metabolites are identified that allow a good, albeit at about 14% false positive rate of sepsis diagnosis. Additionally, metabolites might be also useful for differentiation and prognosis according to the type of underlying infection. However, confirmation of the findings in ongoing studies is mandatory before they can be applied in the development of novel diagnostic tools for the management of sepsis.

Early changes of the kinetics of monocyte trem-1 reflect final outcome in human sepsis.

BACKGROUND: TREM-1 (triggering receptor expressed on myeloid cells), a receptor expressed on neutrophils and monocytes, is upregulated in sepsis and seems to tune the inflammatory response. We explored the expression of TREM-1 at the gene level and on cell membranes of monocytes and association with clinical outcome. METHODS: Peripheral venous blood was sampled from 75 septic patients (39 patients with sepsis, 25 with severe sepsis and 11 with septic shock) on sepsis days 1, 3 and 7. TREM-1 on monocytes was measured by flow cytometry; gene expression of TREM-1 in circulating mononuclear cells was assessed by real-time PCR. sTREM-1 was measured in serum by an enzyme immunoassay. RESULTS: Although surface TREM-1, sTREM-1 and TREM-1 gene expression did not differ between sepsis, severe sepsis and septic shock on day 1, survivors had greater expression of surface TREM-1 on days 3 and 7 compared to non-survivors. sTREM-1 on non-survivors decreased on day 3 compared to baseline. Patients with increase of monocyte gene expression of TREM-1 from day 1 to day 3 had prolonged survival compared to patients with decrease of gene expression of TREM-1 from day 1 to day 3 (p: 0.031). CONCLUSIONS: Early decrease of gene expression of TREM-1 in monocytes is associated with poor outcome. A reciprocal decrease of the pro-inflammatory surface receptor TREM-1 linked with sepsis-induced immunosuppression may be part of the explanation.

Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial.

BACKGROUND: A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis. METHODS: Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes. RESULTS: The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1% (51 deaths) in the placebo arm and 18.5% (56 deaths) in the clarithromycin arm (P = 0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1%) compared with 15 out of 28 clarithromycin-treated patients (53.6%, P = 0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P = 0.037). The cost of hospitalization was lower after treatment with clarithromycin (P = 0.044). Serious adverse events were observed in 1.3% and 0.7% of placebo- and clarithromycin-treated patients, respectively (P = 0.502). CONCLUSIONS: Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.

The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis.

BACKGROUND: The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS). METHODS: Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously. RESULTS: According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The meta-regression analyses showed that the levels of triglycerides (p=0.005), cholesterol (p=0.037) and PAI-1 (p=0.021) in controls were associated with the MI risk conferred by the 4G carriers. CONCLUSIONS: The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.

IL-6 Polymorphism as a Predisposing Genetic Factor for Gestational Diabetes or Preeclampsia Development in Pregnancy with Obesity in Relation to VEGF and VEGFF Receptor Gene Expression Modalities.

The increased prevalence of obesity worldwide has been implicated in the alarming rise of the incidence of gestational diabetes and preeclampsia, which are both considered threatening conditions for both mother and fetus. We studied gene polymorphisms of the proinflammatory cytokine Interleukin 6 (IL-6) and the gene expression levels of VEGF (vascular endothelial growth factor) and VEGF-R (endothelial growth factor receptor), all known to be involved in pregnancy complications, aiming to identify possible predisposing risk factors in pregnancies with obesity. The G allele of IL-6 was found to correspond with an increased risk for gestational diabetes and preeclampsia occurrence. Furthermore, in obese pregnant mothers with either gestational diabetes or pre-existing type 2 diabetes and those who developed preeclampsia, it was confirmed that gene expression levels of VEGF were reduced while they were increased for VEGF receptors. We conclude that the genetic profile of an obese pregnant woman shares a common background with that of a patient with pre-existing type 2 diabetes mellitus, and therefore predisposes them to complications in pregnancy.

Implementation of a Cardiogenic Shock Team in a Tertiary Academic Centre.

BACKGROUND: Observational studies have shown that the management of patients with cardiogenic shock (CS) by dedicated multidisciplinary teams improve clinical outcomes. Nevertheless, these studies reflect a specific organisational setting with most patients being transfers from referring hospitals, hospitalised in cardiac intensive care units (ICU), or treated with mechanical circulatory support (MCS) devices. The purpose of this study was to document the organisation and outcomes of a CS team offering acute care in all-comer population. METHODS: A CS team was developed in a large academic tertiary institution. The team consisted of emergency care physicians, critical care cardiologists, interventional cardiologists, cardiac surgeons, ICU physicians and heart failure specialists and was supported by predefined operating protocol, dedicated communication platform and regular team meetings. RESULTS: Over 12 months, 70 CS patients (69±13 years old, 67% males) were included. Acute myocardial infarction (AMI-CS) was the most common cause (64%); 31% of the patients presented post-resuscitated cardiac arrest and 56% needed invasive mechanical ventilation (IMV). Coronary angiography was performed in 70% and 53% had percutaneous coronary intervention. MCS was used in 10% and 6% were referred for urgent cardiac surgery. The in-hospital mortality in our centre was 40% with 39% of the patients dying within 24-hours from presentation. 76% of the alive patients were discharged home. CONCLUSIONS: Across an all-comer population, AMI was the most common cause of CS. A significant number of patients presented post cardiac arrest, and the majority required IMV. Mortality was high with a significant number dying within hours of presentation.

Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration.

This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

The role of procalcitonin and IL-6 in discriminating between septic and non-septic causes of ALI/ARDS: a prospective observational study.

BACKGROUND: The aim was to evaluate the clinical usefulness of a single plasma and bronchoalveolar lavage fluid (BALF) PCT and IL-6 measurement in discriminating septic from non-septic causes of acute respiratory distress syndrome (ARDS) and forecasting clinical outcomes. METHODS: One hundred patients were enrolled within 48 h of ALI/ARDS recognition. Demographic, clinical data, severity indices were recorded and PCT and IL-6 concentrations were measured in plasma and BALF. RESULTS: Plasma PCT and IL-6 values were significantly higher in septic compared to non-septic individuals (p=0.001 and 0.0005, respectively), while there were no differences in their respective BALF values. As far as identification of septic vs. non-septic ARDS is concerned, the comparison of the areas under the curves favored PCT vs. IL-6 [0.88, (95% CI 0.81-0.95) vs. 0.71, (95% CI 0.60-0.81); χ(2)=9.04, p=0.003]. A plasma PCT level of 0.815 ng/mL was associated with 74.1% sensitivity and 97.6% specificity in identifying septic ARDS cases; this corresponded to a diagnostic odds ratio value of 116. Linear regression multivariable analysis disclosed a significant relation of plasma PCT with SOFA score in septic ARDS patients (p<0.001), while neither BALF PCT nor IL-6 levels were associated with clinical outcome. CONCLUSIONS: Early plasma - but not BALF - PCT concentrations can discriminate between septic and non-septic ARDS causes and are associated with the severity of multiple organ dysfunction syndrome in septic ARDS patients. However, neither plasma or BALF IL-6 levels nor BALF PCT levels carry any prognostic potential. A single plasma PCT value higher than 0.815 ng/mL makes a non-septic cause of ARDS highly unlikely.

Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome.

INTRODUCTION: The aim of this study was to investigate the kinetics of immunoglobulin M (IgM) during the different stages of sepsis. METHODS: In this prospective multicenter study, blood sampling for IgM measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. Among these 83 patients, 30 patients with severe sepsis progressed into shock and IgM was monitored daily for seven consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated from 55 patients and stimulated for IgM production. RESULTS: Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome (SIRS) and patients with severe sepsis. Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock. Serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors. Production of IgM by PBMCs was significantly lower at all stages of sepsis compared with healthy controls. CONCLUSIONS: Specific changes of circulating IgM occur when patients with severe sepsis progress into septic shock. The distribution of IgM is lower among non-survivors.