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.

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.

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.

Metformin attenuates ventilator-induced lung injury.

INTRODUCTION: Diabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury. METHODS: Twenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ≈7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF. RESULTS: High-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation. CONCLUSIONS: Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.

Evaluation of the role of the new INNOVANCE PFA P2Y test cartridge in detection of clopidogrel resistance.

Light transmittance aggregometry (LTA) has been extensively used in monitoring clopidogrel therapy. However, the availability of simple and rapid point-of-care platelet function assays is of great clinical importance. Thus, the manufacturer of the Platelet Function Analyzer (PFA)-100 System has recently produced the INNOVANCE PFA P2Y test cartridge. We assessed the ability of this new test to reliably detect clopidogrel resistance. We enrolled 90 consecutive patients with coronary artery disease receiving chronic clopidogrel maintenance therapy in combination with aspirin. Twenty healthy volunteers served as controls. Clopidogrel resistance was simultaneously analysed by the INNOVANCE PFA P2Y test cartridge, ADP-induced LTA, the flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and the multiple electrode aggregometry (Multiplate). Agreement among the four platelet function methods by two was assessed using Cohen's kappa coefficient. According to the cut-off points for clopidogrel resistance proposed by the literature, agreement was fair between INNOVANCE PFA-100 P2Y and LTA (74.4%) and Multiplate (75.6%), while poor agreement was noticed in VASP assay (63.3%). Based on cut-off points indicating a higher thrombotic risk, agreement between the PFA-100 System and the other three methods did not significantly differ compared to the previous cut-offs (72.2%, 71.1% and 55.1%, respectively). The INNOVANCE PFA-100 P2Y test seems to be comparable to other established platelet function assays in detecting clopidogrel resistance. However, the modest agreement among platelet function methods makes the performance of platelet function testing crucial with more than one technique in order to reliably identify poor responders to clopidogrel treatment.

Ovarian hyperstimulation syndrome complicated by severe community-acquired pneumonia due to methicillin-resistant Staphylococcus aureus positive for Panton-Valentine leukocidin.

We report a case of severe ovarian hyperstimulation syndrome (OHSS) complicated by community-acquired methicillin-resistant Staphylococcus aureus-Panton-Valentine leukocidin positive (CAMRSA-PVL[+]) necrotizing pneumonia, sepsis and multiple organ failure (MOF) in a previously immunocompetent female. The patient required prolonged ventilatory support and intensive care unit (ICU) hospitalization. Multiple cavities and severely affected lung function persist 1 year after discharge.

Development and validation of a sepsis diagnostic scoring model for neonates with suspected sepsis.

Background: We aimed to develop and validate a diagnostic model for sepsis among neonates evaluated for suspected sepsis, by incorporating thromboelastometry parameters, maternal/neonatal risk factors, clinical signs/symptoms and laboratory results. Methods: This retrospective cohort study included 291 neonates with presumed sepsis, hospitalized in a NICU, from 07/2014 to 07/2021. Laboratory tests were obtained on disease onset and prior to initiating antibiotic therapy. Τhromboelastometry extrinsically activated (EXTEM) assay was performed simultaneously and Tοllner and nSOFA scores were calculated. Sepsis diagnosis was the outcome variable. A 10-fold cross-validation least absolute shrinkage and selection operator logit regression procedure was applied to derive the final multivariable score. Clinical utility was evaluated by decision curve analysis. Results: Gestational age, CRP, considerable skin discoloration, liver enlargement, neutrophil left shift, and EXTEM A10, were identified as the strongest predictors and included in the Neonatal Sepsis Diagnostic (NeoSeD) model. NeoSeD score demonstrated excellent discrimination capacity for sepsis and septic shock with an AUC: 0.918 (95% CI, 0.884-0.952) and 0.974 (95% CI, 0.958-0.989) respectively, which was significantly higher compared to Töllner and nSOFA scores. Conclusions: The NeoSeD score is simple, accurate, practical, and may contribute to a timely diagnosis of sepsis in neonates with suspected sepsis. External validation in multinational cohorts is necessary before clinical application.

TREM-1 expression on neutrophils and monocytes of septic patients: relation to the underlying infection and the implicated pathogen.

BACKGROUND: Current knowledge on the exact ligand causing expression of TREM-1 on neutrophils and monocytes is limited. The present study aimed at the role of underlying infection and of the causative pathogen in the expression of TREM-1 in sepsis. METHODS: Peripheral venous blood was sampled from 125 patients with sepsis and 88 with severe sepsis/septic shock. The causative pathogen was isolated in 91 patients. Patients were suffering from acute pyelonephritis, community-acquired pneumonia (CAP), intra-abdominal infections (IAIs), primary bacteremia and ventilator-associated pneumonia or hospital-acquired pneumonia (VAP/HAP). Blood monocytes and neutrophils were isolated. Flow cytometry was used to estimate the TREM-1 expression from septic patients. RESULTS: Within patients bearing intrabdominal infections, expression of TREM-1 was significantly lower on neutrophils and on monocytes at severe sepsis/shock than at sepsis. That was also the case for severe sepsis/shock developed in the field of VAP/HAP. Among patients who suffered infections by Gram-negative community-acquired pathogens or among patients who suffered polymicrobial infections, expression of TREM-1 on monocytes was significantly lower at the stage of severe sepsis/shock than at the stage of sepsis. CONCLUSIONS: Decrease of the expression of TREM-1 on the membrane of monocytes and neutrophils upon transition from sepsis to severe sepsis/septic shock depends on the underlying type of infection and the causative pathogen.

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and circulating ACE levels are not associated with outcome in critically ill septic patients.

BACKGROUND: In critically ill patients independent studies have shown contradictory findings regarding the prognostic significance of the D/D genotype of the I/D angiotensin converting enzyme (ACE) polymorphism. The study aim was to evaluate the effect of both ACE I/D polymorphism and ACE serum levels on the clinical outcomes of critically ill septic patients. METHODS: This study recruited 186 Caucasian patients with sepsis, severe sepsis or septic shock. Epidemiological, clinical data, co-morbidities and severity scores were recorded. Measurements of serum ACE activity and genotyping for ACE I/D polymorphism were carried out. Primary outcomes were the 28- and the 90-day mortality; secondary outcomes included the number of days without renal or cardiovascular failure and ventilation-free days over the 28-day period following study enrolment. RESULTS: Neither 28- nor 90-day mortality were associated with ACE I/D polymorphism (p=0.59 and 0.34, respectively) or circulating ACE levels (p=0.17 and 0.25, respectively). Similarly, ACE polymorphism and levels were not related to ventilation-free days (p=0.14 and 0.25, respectively), days without cardiovascular failure (p=0.14 and 0.81, respectively) and days without renal failure (p=0.64 and 0.27, respectively). CONCLUSIONS: Neither ACE I/D polymorphism nor serum ACE levels seem to be significant prognostic factors of clinical outcomes in septic, critically ill patients.

Life-threatening aortic thrombosis in a trauma patient homozygous for factor V Leiden mutation: Case report.

We report a case of near fatal aortic thrombosis in a trauma patient homozygous for mutation of Factor V Leiden. He responded well to vascular surgery and intensive care unit management and was discharged successfully from the hospital one month later.

Metabolic acidosis may be as protective as hypercapnic acidosis in an ex-vivo model of severe ventilator-induced lung injury: a pilot study.

BACKGROUND: There is mounting experimental evidence that hypercapnic acidosis protects against lung injury. However, it is unclear if acidosis per se rather than hypercapnia is responsible for this beneficial effect. Therefore, we sought to evaluate the effects of hypercapnic (respiratory) versus normocapnic (metabolic) acidosis in an ex vivo model of ventilator-induced lung injury (VILI). METHODS: Sixty New Zealand white rabbit ventilated and perfused heart-lung preparations were used. Six study groups were evaluated. Respiratory acidosis (RA), metabolic acidosis (MA) and normocapnic-normoxic (Control - C) groups were randomized into high and low peak inspiratory pressures, respectively. Each preparation was ventilated for 1 hour according to a standardized ventilation protocol. Lung injury was evaluated by means of pulmonary edema formation (weight gain), changes in ultrafiltration coefficient, mean pulmonary artery pressure changes as well as histological alterations. RESULTS: HPC group gained significantly greater weight than HPMA, HPRA and all three LP groups (P = 0.024), while no difference was observed between HPMA and HPRA groups regarding weight gain. Neither group differ on ultrafiltration coefficient. HPMA group experienced greater increase in the mean pulmonary artery pressure at 20 min (P = 0.0276) and 40 min (P = 0.0012) compared with all other groups. Histology scores were significantly greater in HP vs. LP groups (p < 0.001). CONCLUSIONS: In our experimental VILI model both metabolic acidosis and hypercapnic acidosis attenuated VILI-induced pulmonary edema implying a mechanism other than possible synergistic effects of acidosis with CO2 for VILI attenuation.

A Risk Score for Predicting the Incidence of Hemorrhage in Critically Ill Neonates: Development and Validation Study.

The aim of the study was to develop and validate a prediction model for hemorrhage in critically ill neonates which combines rotational thromboelastometry (ROTEM) parameters and clinical variables. This cohort study included 332 consecutive full-term and preterm critically ill neonates. We performed ROTEM and used the neonatal bleeding assessment tool (NeoBAT) to record bleeding events. We fitted double selection least absolute shrinkage and selection operator logit regression to build our prediction model. Bleeding within 24 hours of the ROTEM testing was the outcome variable, while patient characteristics, biochemical, hematological, and thromboelastometry parameters were the candidate predictors of bleeding. We used both cross-validation and bootstrap as internal validation techniques. Then, we built a prognostic index of bleeding by converting the coefficients from the final multivariable model of relevant prognostic variables into a risk score. A receiver operating characteristic analysis was used to calculate the area under curve (AUC) of our prediction index. EXTEM A10 and LI60, platelet counts, and creatinine levels were identified as the most robust predictors of bleeding and included them into a Neonatal Bleeding Risk (NeoBRis) index. The NeoBRis index demonstrated excellent model performance with an AUC of 0.908 (95% confidence interval [CI]: 0.870-0.946). Calibration plot displayed optimal calibration and discrimination of the index, while bootstrap resampling ensured internal validity by showing an AUC of 0.907 (95% CI: 0.868-0.947). We developed and internally validated an easy-to-apply prediction model of hemorrhage in critically ill neonates. After external validation, this model will enable clinicians to quantify the 24-hour bleeding risk.

Seeking Strategies to Optimize Blood Utilization: The Preliminary Experience with Implementing a Patient Blood Management Program in a Greek Tertiary Hospital.

OBJECTIVES: Our aim was to assess blood utilization after implementation of a patient blood management (PBM) program in a Greek tertiary hospital. METHODS: An electronic transfusion request form and a prospective audit of transfusion practice were implemented. After the one-year implementation period, a retrospective review was performed to assess transfusion practice in medical patients. RESULTS: Pre-PBM, a total of 9478 RBC units were transfused (mean: 1.75 units per patient) compared with 9289 transfused units (mean: 1.57 units per patient) post-PBM. Regarding the post-PBM period, the mean hemoglobin (Hb) level of the 3099 medical patients without comorbidities transfused was 7.19 ± 0.79 gr/dL. Among them, 2065 (66.6%) had Hb levels >7.0 gr/dL, while 167 (5.3%) had Hb levels >8.0 gr/dL. In addition, 331 (25.3%) of the transfused patients with comorbidities had Hb >8.0 gr/dL. The Hb transfusion thresholds significantly differed across the clinics (p < 0.001), while 21.8% of all medical non-bleeding patients received more than one RBC unit transfusion. CONCLUSION: A poor adherence with the restrictive transfusion threshold of 7.0 gr/dL was observed. The adoption of a less strict threshold might be a temporary step to allow physicians to become familiar with the program and be informed on the safety and advantages of the restrictive transfusion strategy.

Comparative Performance of Four Established Neonatal Disease Scoring Systems in Predicting In-Hospital Mortality and the Potential Role of Thromboelastometry.

BACKGROUND: To compare the prognostic accuracy of the most commonly used indexes of mortality over time and evaluate the potential of adding thromboelastometry (ROTEM) results to these well-established clinical scores. METHODS: The study population consisted of 473 consecutive term and preterm critically-ill neonates. On the first day of critical illness, modified Neonatal Multiple Organ Dysfunction (NEOMOD) scoring system, Score for Neonatal Acute Physiology (SNAP II), Perinatal extension of SNAP (SNAPPE), and SNAPPE II, were calculated and ROTEM standard extrinsically activated (EXTEM) assay was performed simultaneously. Time-to-event methodology for competing-risks was used to assess the performance of the aforementioned indexes in predicting in-hospital mortality over time. Time-dependent receiver operator characteristics curves for censored observation were compared across indexes. The addition of EXTEM parameters to each index was tested in terms of discrimination capacity. RESULTS: The modified NEOMOD score performed similarly to SNAPPE. Both scores performed significantly better than SNAP II and SNAPPE II. Amplitude recorded at 10 min (A10) was the EXTEM parameter most strongly associated with mortality (A10 < 37 mm vs. ≥37 mm; sHR = 5.52; p < 0.001). Adding A10 to each index apparently increased the prognostic accuracy in the case of SNAP II and SNAPPE II. However, these increases did not reach statistical significance. CONCLUSION: Although the four existing indexes considered showed good to excellent prognostic capacity, modified NEOMOD and SNAPPE scores performed significantly better. Though larger studies are needed, adding A10 to well-established neonatal severity scores not including biomarkers of coagulopathy might improve their prediction of in-hospital mortality.

Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: There is increasing interest for strategies that could curtail antibiotic resistance in the critical care setting. We sought to determine the effectiveness and safety of procalcitonin-guided algorithms in the management of septic patients in the intensive care unit. DATA SOURCES: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (through April 2010), reference lists of retrieved publications, and queries of corresponding authors. No language restrictions were applied. STUDY SELECTION: We included only randomized controlled studies reporting on antibiotic use and clinical outcomes of intensive care unit patients managed with a procalcitonin-guided algorithm or according to routine practice. DATA EXTRACTION: Data on study characteristics, interventions, and outcomes were retrieved by two independent reviewers. Pooled odds ratios, weighted mean differences, and 95% confidence intervals were calculated by implementing both the Mantel-Haenszel fixed effect model and the DerSimonian-Laird random effects model. DATA SYNTHESIS: Seven randomized controlled studies involving 1131 intensive care unit patients (adults = 1010; neonates = 121) were included. In comparison with routine practice, the implementation of procalcitonin-guided algorithms decreased the duration of antibiotic therapy for the first episode of infection by approximately 2 days (weighted mean difference = -2.36 days; 95% confidence interval, -3.11 to -1.61) and the total duration of antibiotic treatment by 4 days (fixed effect model: weighted mean difference: -4.19 days; 95% confidence interval, -4.98 to -3.39). The comparison between the procalcitonin and the routine practice group was not associated with any apparent adverse clinical outcome: 28-day mortality (fixed effect model: odds ratio = 0.93; 95% confidence interval, 0.69 to 1.26), intensive care unit length of stay (fixed effect model: pooled weighted mean difference = -0.49 days, 95% confidence interval, -1.55 to 0.57), and relapsed/persistent infection rate (fixed effect model: odds ratio = 0.97; 95% confidence interval, 0.56 to 1.69). CONCLUSIONS: The implementation of a procalcitonin-based algorithm may reduce antibiotic exposure in critically ill, septic patients without compromising clinical outcomes, but further research is necessary before the wide adoption of this strategy.

Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model.

OBJECTIVE: We hypothesized that pretreatment with atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, confers protection against lung injury caused by high-stretch mechanical ventilation. METHODS: Twenty-four isolated sets of normal rabbit lungs were utilized. Treated animals received atorvastatin (20 mg/kg body weight/day by mouth) for 3 days before surgery. Lungs were perfused constantly (300 mL/min) and ventilated for 1 hr with pressure-control ventilation at either 23 (high pressure; resulting in tidal volume approximately 22 mL/kg) or 11 (low pressure; tidal volume approximately 10 mL/kg) cm H2O peak inspiratory pressure and positive end-expiratory pressure of 3 cm H2O. Four groups were examined: high pressure-no statin, high pressure-statin pretreatment, low pressure-no statin, and low pressure-statin pretreatment. RESULTS: The high-pressure-no statin group sustained more damage than the low-pressure groups. In high-pressure groups, lungs of statin-pretreated vs. no statin-pretreated animals sustained a significantly lower increase in ultrafiltration coefficient (an accurate marker of alveolar capillary permeability; high-pressure-statin pretreatment vs. high-pressure-no statin, -0.013 +/- 0.017 g/min/mm Hg/100g vs. 1.723 +/- 0.495 g/min/mm Hg/100g; p < .001), lower weight gain (i.e., less edema formation; 4.62 +/- 1.50 grams vs. 17.75 +/- 4.71 grams; p = .005), improved hemodynamics (i.e., lower increase in mean pulmonary artery pressure; 0.56 +/- 0.51 mm Hg vs. 5.62 +/- 1.52 mm Hg; p = .04), lower protein concentration in bronchoalveolar lavage fluid (p < .001), and fewer histologic lesions (p = .013). Apoptosis of lung parenchyma cells was not different (p = .97). There was no difference between low-pressure-statin pretreatment and low-pressure-no statin groups regarding these outcomes. CONCLUSION: In this model, atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, attenuates lung injury caused by high-stretch mechanical ventilation.

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection.

INTRODUCTION: Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. METHODS: The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. RESULTS: Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. CONCLUSIONS: Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

COVID-19 Infection-Related Coagulopathy and Viscoelastic Methods: A Paradigm for Their Clinical Utility in Critical Illness.

Hypercoagulability and thrombosis remain a challenge to diagnose and treat in severe COVID-19 infection. The ability of conventional global coagulation tests to accurately reflect in vivo hypo- or hypercoagulability is questioned. The currently available evidence suggests that markedly increased D-dimers can be used in identifying COVID-19 patients who may need intensive care unit (ICU) admission and close monitoring or not. Viscoelastic methods (VMs), like thromboelastography (TEG) and rotational thromboelastometry (ROTEM), estimate the dynamics of blood coagulation. The evaluation of coagulopathy by VMs in severe COVID-19 infection seems an increasingly attractive option. Available evidence supports that COVID-19 patients with acute respiratory failure suffer from severe hypercoagulability rather than consumptive coagulopathy often associated with fibrinolysis shutdown. However, the variability in definitions of both the procoagulant profile and the clinical outcome assessment, in parallel with the small sample sizes in most of these studies, do not allow the establishment of a clear association between the hypercoagulable state and thrombotic events. VMs can effectively provide insight into the pathophysiology of coagulopathy, detecting the presence of hypercoagulability in critically ill COVID-19 patients. However, it remains unknown whether the degree of coagulopathy can be used in order to predict the outcome, establish a diagnosis or guide anticoagulant therapy.