Favipiravir pharmacokinetics in COVID-19 patients with moderate to severe kidney dysfunction: Lessons learned.

OBJECTIVE: There is limited information on favipiravir pharmacokinetics in critically ill patients and no studies on pharmacokinetics in patients with moderate and severe kidney dysfunction. The aim was to determine favipiravir pharmacokinetics (oral, 1,600 mg, q12h on day 1, then 600 mg, q12h for 4 days) in critically ill COVID-19 patients with kidney dysfunction and to compare those with observations reported in healthy adults. MATERIALS AND METHODS: In a descriptive study, blood samples taken from patients meeting the relevant criteria (estimated glomerular filtration rate < 60 mL/min) were collected and analyzed. Analysis of blood samples was done by high performance liquid chromatography (HPLC), and the maximal concentration (Cmax), the time of maximal concentration (tmax), half-life (T1/2) and area under the curve (AUC0-12h) of favipiravir were calculated (WinNonlin) and compared to reported data in healthy subjects after first administration. RESULTS: Based on analysis of samples collected in 7 patients, the Cmax (29.99 vs. 64.5 µg/mL) of favipiravir was decreased, T1/2 (5.8 vs. 4.8 hours) longer, tmax delayed, while total exposure was lower (AUC0-12: 192.53 vs. 446.09 µg/mL) compared to reported data in healthy subjects after first administration. Exposure remained lower up to day 5. CONCLUSION: In patients with kidney dysfunction related to COVID-19, favipiravir did not reach the expected exposure. This may be due to poorer and delayed absorption, and subsequent altered disposition. Population pharmacokinetic and mechanistic studies are needed to better explore the relevant covariates and to determine the optimal dose in these patients, as this drug is likely of relevance for other indications.

Approach of pulmonologists in Turkey to noninvasive mechanical ventilation use at home for chronic respiratory failure.

INTRODUCTION: To define approach of pulmonologists in Turkey to noninvasive mechanical ventilation (NIV) use for chronic respiratory failure (CRF), the most currently applied technique for home mechanical ventilation. PATIENTS AND METHODS: A 38-question survey, developed and tested by the authors, was distributed throughout Turkey to 2205 pulmonologists by e-mail. RESULT: Twenty-seven percent of the pulmonologists responded (n=596). Domiciliary NIV was reported to be prescribed by 340 physicians [57.1% of all responders and 81% of pulmonologists practicing NIV at clinical practice (n= 420)]. NIV prescription was associated with physician's title, type of hospital, duration of medical license, total number of patients treated with NIV during residency and current number of patients treated with NIV per week (p< 0.05). Main estimated indications were listed as chronic obstructive pulmonary disease (median, 25-75 percentile of the prescriptions: 75%, 60-85), obesity hypoventilation syndrome (10%, 2-15), overlap syndrome (10%, 0-20) and restrictive lung disease (5%, 2-10). For utilization of NIV at home, Bilevel positive airway pressure-spontaneous mode (40%, 0-80) and oronasal mask (90%, 60-100) were stated as the most frequently recommended mode and interface, respectively. Pressure settings were most often titrated based on arterial blood gas findings (79.2%). Humidifier was stated not to be prescribed by approximately half of the physicians recommending domicilliary NIV, and the main reason for this (59.2%) was being un-refundable by social security foundation. CONCLUSION: There is a wide variation in Turkey for prescription of NIV, which is supposed to improve clinical course of patients with CRF. Further studies are required to determine the possible causes of these differences, frequency of use and patient outcomes in this setting.

Approach of pulmonologists in Turkey to noninvasive mechanical ventilation use in acute respiratory failure.

INTRODUCTION: Noninvasive mechanical ventilation (NIV) has been increasingly used worldwide for acute respiratory failure (ARF), especially in patients with chronic lung disorders. We aimed to define the approach of pulmonologists in Turkey to NIV use for ARF management. MATERIALS AND METHODS: A 38-question survey, developed and tested by authors, was distributed by e-mail to a total of 2.205 pulmonologists in Turkey. RESULT: Response rate was 27% (n= 596). Seventy-one percent of responders were practicing NIV in clinic. NIV use was found to be associated with responder's academic title, age, duration of medical license, type of physician's hospital and its region, patient load, NIV experience during residency, and duration of NIV and intensive care unit (ICU) experience (p< 0.001). Based on sub-group analysis of responders using NIV, median number of NIV patients followed-up per week was 4 [interquartile range (IQR): 2-6]. Most of the NIV users reported employment of wards (90%) and/or ICUs (86%) to follow-up patients, while 8.4% of the responders were applying NIV only in ICU's. Chronic obstructive lung disease (COPD) (99.5%), obesity hypoventilation syndrome (93.7%) and restrictive lung disease (89.4%) were the most common indications. Majority of NIV users (87%) were applying NIV to > 60% of patients with COPD, and success rate in COPD was reported as over 60% by 93% of users. Oronasal mask (median and IQR 90, 80-100%, respectively) and home care NIV ventilators (median and IQR 50, 10-85%, respectively) were the most commonly utilized equipment. CONCLUSIONS: NIV use in ARF varies based on hospital type, region and, especially, experience of the physician. Although consistent with guidelines and general practice, NIV use can still be improved and increased.

Timing of noninvasive ventilation failure: causes, risk factors, and potential remedies.

BACKGROUND: Identifying the predictors of noninvasive ventilation (NIV) failure has attracted significant interest because of the strong link between failure and poor outcomes. However, very little attention has been paid to the timing of the failure. This narrative review focuses on the causes of NIV failure and risk factors and potential remedies for NIV failure, based on the timing factor. RESULTS: The possible causes of immediate failure (within minutes to <1 h) are a weak cough reflex, excessive secretions, hypercapnic encephalopathy, intolerance, agitation, and patient-ventilator asynchrony. The major potential interventions include chest physiotherapeutic techniques, early fiberoptic bronchoscopy, changing ventilator settings, and judicious sedation. The risk factors for early failure (within 1 to 48 h) may differ for hypercapnic and hypoxemic respiratory failure. However, most cases of early failure are due to poor arterial blood gas (ABGs) and an inability to promptly correct them, increased severity of illness, and the persistence of a high respiratory rate. Despite a satisfactory initial response, late failure (48 h after NIV) can occur and may be related to sleep disturbance. CONCLUSIONS: Every clinician dealing with NIV should be aware of these risk factors and the predicted parameters of NIV failure that may change during the application of NIV. Close monitoring is required to detect early and late signs of deterioration, thereby preventing unavoidable delays in intubation.

Exposure to COVID-19 among unvaccinated healthcare personnel and risk for infection: a single-center retrospective study.

INTRODUCTION: Characteristics of exposure and infection risk, are important in strategy development for infection control among healthcare workers (HCWs). Our objective was to investigate the characteristics of exposure of HCWs to SARS-CoV-2 and determine the risk of COVID-19 development. METHODOLOGY: This is a retrospective single-center cohort study, conducted between March and December 2020. Unvaccinated and exposed HCWs were asked to complete a standard form, including demographic data and characteristics of exposure(s). Exposures were stratified according to national guidelines. STROBE checklist was used. RESULTS: Among a total of 4,385 healthcare workers, 1,483 HCWs (33.8%) with a total of 1,903 exposures to SARS-CoV-2 were identified. Median age was 31 (IQR: 26-40) years and 45.4% were male (N = 673). Following exposure, 78 HCWs became SARS-CoV-2-positive (attack rate: 3.9%) and secondary attack rate was 4/16. In terms of infection, exposure to SARS-CoV-2-positive HCWs posed a greater risk compared to contact with patients (8.9%, [n = 66] vs. 3.8% [n = 12], respectively, p = 0.003). PCR positivity rates were 11.5%, 6.3%, and 8.4% for low, medium, and high-risk contacts (p = 0.152). Median time to infection post-exposure was 7 (IQR: 4-13) days. CONCLUSIONS: Given the attack rates, there was no correlation between risk levels and PCR test positivity rates. There was no difference between HCWs with or without work restrictions, in terms of PCR positivity. Due to feasibility issues, prioritizing universally applied symptom screening and resource control strategies and suspending contact tracing and work restrictions, appear to be safe during high prevalence period.

Evaluation of whole blood thiamine pyrophosphate concentrations in critically ill patients receiving chronic diuretic therapy prior to admission to Turkish intensive care units: A pragmatic, multicenter, prospective study.

BACKGROUND/OBJECTIVES: Thiamine plays a pivotal role in energy metabolism. The aim of the study was to determine serial whole blood TPP concentrations in critically ill patients receiving chronic diuretic treatment before ICU admission and to correlate TPP levels with clinically determined serum phosphorus concentrations. SUBJECTS/METHODS: This observational study was performed in 15 medical ICUs. Serial whole blood TPP concentrations were measured by HPLC at baseline and at days 2, 5 and 10 after ICU admission. RESULTS: A total of 221 participants were included. Of these, 18% demonstrated low TPP concentrations upon admission to the ICU, while 26% of participants demonstrated low levels at some point during the 10-day study period. Hypophosphatemia was detected in 30% of participants at some point during the 10-day period of observation. TPP levels were significantly and positively correlated with serum phosphorus levels at each time point (P < 0.05 for all). CONCLUSIONS: Our results show that 18% of these critically ill patients exhibited low whole blood TPP concentrations on ICU admission and 26% had low levels during the initial 10 ICU days, respectively. The modest correlation between TPP and phosphorus concentrations suggests a possible association due to a refeeding effect in ICU patients requiring chronic diuretic therapy.

Detection of latent tuberculosis infection in rheumatologic diseases before anti-TNFα therapy: tuberculin skin test versus IFN-γ assay.

We aimed to evaluate tuberculin skin test (TST) and interferon-gamma (IFN-γ) test results for latent tuberculosis infection (LTBI) in patients with rheumatologic diseases prior to anti-TNFα therapy. Ninety patients were evaluated in the study at the Departments of Chest Diseases and Rheumatology for anti-TNFα therapy for their rheumatologic diseases. Tuberculin skin test was performed (Mantoux method) and peripheral blood samples were collected for IFN-γ assay (QuantiFeron TB-Gold In Tube) before the anti-TNFα therapy. Of 90 patients, TST positivity was detected in 56 (62.2%) patients, while IFN-γ positivity was detected in 34 (37.8%) patients. Among 56 TST positive patients, IFN-γ positivity was detected in 24 (42.9%) patients, and among 34 TST negative patients, IFN-γ positivity was detected in 10 (29.4%) patients. There was no significant agreement between TST and IFN-γ assay results (Kappa = 0.12, P = 0.2). Forty-three (47.8%) patients were using immunosuppressive drugs owing to their rheumatologic diseases. In this group, TST and IFN-γ positivity is significantly lower than in those who did not receive immunosuppressive treatment (P < 0.05). We conclude that the IFN-γ assay may not be preferred to TST as a diagnostic test in patients with rheumatologic diseases prior to anti-TNFα treatment.

[The effect of non-invasive mechanical ventilation in postoperative respiratory failure]. / Postoperatif hastada gelisen solunum yetmezliginde noninvaziv mekanik ventilasyonun yeri.

Postoperative respiratory failure is related with the highest mortality and morbidity among all perioperative complications. The most common underlying mechanism of postoperative respiratory failure is the development of atelectasis. Anaesthesia, medications which cause respiratory depression, high FiO2 use, postoperative pain and disruption of muscle forces due to surgery leads to decrease in functional residual capacity and results in atelectasis formation. Atelectasis causes severe hypoxemia due to ventilation, perfusion mismatch, shunt and increased peripheral vascular resistance. Intrathoracic positive pressure is an effective therapeutic option in both prevention and treatment of atelectasis. Non-invasive mechanical ventilation is related with a lower mortality and morbidity rate due to lack of any potential complication risks of endotracheal intubation. Non-invasive mechanical ventilation can be applied as prophylactic or curative. Both of these techniques are related with lower reintubation rates, nosocomial infections, duration of hospitalization and mortality in patients with postoperative respiratory failure. The differences of this therapy from standard application and potential complications should be well known in order to improve prognosis in these group of patients. The primary aim of this review is to underline the pathogenesis of postoperative respiratory failure. The secondary aim is to clarify the optimum method, effect and complications of non-invasive mechanical ventilation therapy under the light of the studies which was performed in specific patient groups.

[Endobronchial capillary hemangioma: a very rare cause of massive hemoptysis]. / Masif hemoptizinin nadir bir nedeni: Endobronsiyal kapiller hemanjiyom.

Tracheal capillary hemangioma is a very rare benign tumor of trachea which may present as massive hemoptysis. Minor to massive hemoptysis can be observed in these patients. Due to its small size and tracheal localization, diagnosis cannot be easily performed by using radiological investigations. Fifty-years-old male patient who was diagnosed as tracheal capillary hemangioma with bronchoscopic biopsy was presented in this case report. According to our knowledge, this is the eighth case report in the world literature. Tracheal capillary hemangioma must be kept in mind in patients with massive hemoptysis with normal radiologic features and bronchoscopic procedures (excision, argon, laser etc.) should be the first choice of therapy when diagnosed.

Worse pre-admission quality of life is a strong predictor of mortality in critically ill patients.

Objectives: In this study, we aimed to investigate whether quality of life (QoL) before intensive care unit (ICU) admission could predict ICU mortality in critically ill patients. Patients and methods: Between January 2019 and April 2019, a total of 105 ICU patients (54 males, 51 females; mean age: 58 years; range, 18 to 91 years) from two ICUs of a tertiary care hospital were included in this cross-sectional, prospective study. Pre-admission QoL was measured by the Short Form (SF)-12- Physical Component Scores (PCS) and Mental Component Scores (MCS) and EuroQoL five-dimension, five-level scale (EQ-5D-5L) within 24 h of ICU admission and mortality rates were estimated. Results: The overall mortality rate was 28.5%. Pre-admission QoL was worse in the non-survivors independent from age, sex, socioeconomic and education status, and comorbidities. During the hospitalization, the rate of sepsis and ventilator/hospital-acquired pneumonia were similar among the two groups (p>0.05). Logistic regression analysis adjusted for sex, age, education status, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores showed that pre-admission functional status as assessed by the SF-12 MCS (odds ratio [OR]: 14,2; 95% confidence interval [CI]: 2.5-79.0), SF-12 PCS (OR: 10.6; 95% CI: 1.8-62.7), and EQ-5D-5L (OR: 8.0; 95% CI: 1.5-44.5) were found to be independently associated with mortality. Conclusion: Worse pre-admission QoL is a strong predictor of mortality in critically ill patients. The SF-12 and EQ-5D-5L scores are both valuable tools for this assessment. Not only the physical status, but also the mental status before ICU admission should be evaluated in terms of QoL to better utilize ICU resources.

Is there any link between oxidative stress and lung involvement due to inflammatory bowel disease: an experimental study.

BACKGROUND/AIMS: Lung involvement due to inflammatory bowel disease (IBD) is frequent, however the pathogenic mechanism is still debatable. Although the evidence of inflammation in colonic and lung tissue has been documented, the possible effect of oxidative stress in lung tissue has not been evaluated to date. We sought to assess the effects of oxidant/antioxidants on lung tissue in a model of experimental colitis. METHODOLOGY: Colitis was induced with intra-colonic administration of 4% acetic acid. Control group received isotonic saline. Serum and lung tissue markers of oxidative stress were explored. RESULTS: Serum total oxidant status was significantly higher in the colitis group than the controls while total antioxidant status was similar. The determinants of oxidants including lipid peroxidation assay and myeloperoxidase activity were significantly higher in the lung tissue of the colitis group whereas the indicators of antioxidant capacity determined as superoxide dismutase, catalase, glutathione and glutathione peroxidase were decreased (p<0.05). CONCLUSIONS: This study showed that oxidative stress is not restricted to the bowel and the lung is a main target of oxidant overload. Pulmonary injury caused by increased oxidant stress may be the underlying reason of pulmonary involvement due to IBD.

COVID-19 patients' sera induce epithelial mesenchymal transition in cancer cells.

Covid-19 Pneumonia of SARS-CoV-2 pandemic infection, persists to have high disease burden especially in cancer patients. Increased inflammation and thromboembolic processes are blamed to influence cancer patients more than the others but due to lack of knowledge regarding the pathophysiology of the both the virus itself and the response of the host, more basic and translational disease modeling research is needed to understand Cancer-Covid-19 interaction. In this study, serum samples from the patients, who were hospitalized due to Covid-19 pneumonia, applied to different cancer cells and cytotoxicity, motility, proliferation and gene expression analysis were performed. Serum samples derived from healthy volunteers and the fetal bovine serum that is used regularly in cell culture experiments used as controls. Hospitalized Covid-19 patients who had also cancer, were retrospectively screened, and their clinical course were recorded. Overall 12 Patient (PS) and 4 healthy serums (CS) were included in the experiments. PS applied cells showed increased motility in A549 cells as well as lost cell to cell connection in MCF7 and HCT116 cells, and induced expression of VIM, ZEB1 and SNAIL2 mRNA levels. Eight cancer diagnosed patients who were hospitalized due to Covid-19 between April and September 2020 were also reviewed retrospectively, which 5 of them were dead during SARS-CoV-2 infection. Thorax CT images of the 2 patients showed increased metastatic nodules in the lungs as of January 2021. The results of the study indicate that metastasis may be one of the prolonged consequences of COVID-19 pandemic in cancer sufferers.

Clinical Outcomes and Independent Risk Factors for 90-Day Mortality in Critically Ill Patients with Respiratory Failure Infected with SARS-CoV-2: A Multicenter Study in Turkish Intensive Care Units.

BACKGROUND: There are limited data on the long-term outcomes of COVID-19 from different parts of the world. AIMS: To determine risk factors of 90-day mortality in critically ill patients in Turkish intensive care units (ICUs), with respiratory failure. STUDY DESIGN: Retrospective, observational cohort. METHODS: Patients with laboratory-confirmed COVID-19 and who had been followed up in the ICUs with respiratory failure for more than 24 hours were included in the study. Their demographics, clinical characteristics, laboratory variables, treatment protocols, and survival data were recorded. RESULTS: A total of 421 patients were included. The median age was 67 (IQR: 57-76) years, and 251 patients (59.6%) were men. The 90-day mortality rate was 55.1%. The factors independently associated with 90-day mortality were invasive mechanical ventilation (IMV) (HR 4.09 [95% CI: [2.20-7.63], P < .001), lactate level >2 mmol/L (2.78 [1.93-4.01], P < .001), age ≥60 years (2.45 [1.48-4.06)], P < .001), cardiac arrhythmia during ICU stay (2.01 [1.27-3.20], P = .003), vasopressor treatment (1.94 [1.32-2.84], P = .001), positive fluid balance of ≥600 mL/day (1.68 [1.21-2.34], P = .002), PaO2/FiO2 ratio of ≤150 mmHg (1.66 [1.18-2.32], P = .003), and ECOG score ≥1 (1.42 [1.00-2.02], P = .050). CONCLUSION: Long-term mortality was high in critically ill patients with COVID-19 hospitalized in intensive care units in Turkey. Invasive mechanical ventilation, lactate level, age, cardiac arrhythmia, vasopressor therapy, positive fluid balance, severe hypoxemia and ECOG score were the independent risk factors for 90-day mortality.

[The role of physiologic dead space measurement in predicting extubation success]. / Fizyolojik ölü bosluk ölçümünün ekstübasyon basarisini tahmin etmedeki rolü.

Dead space ventilation (Vd/Vt) is a valuable parameter which indicates the ventilated but not perfused lung areas. The normal range is between 30-50% in mechanically ventilated patients. Increased levels could be observed in many pulmonary diseases such as pulmonary embolism, acute respiratory distress syndrome and chronic obstructive pulmonary disease. Vd/Vt is also used for the prediction of extubation success and a value of < 55-60% indicates successful extubation according to several studies. The aim of this study is to evaluate the value of baseline capnographic measurements on extubation success. A total of 35 patients were included in this prospective study; and 25 (71%) of them who were extubated successfully were named as group 1 and the remaining 10 (29%) patients with extubation failure were named as group 2. When the two groups were compared, Vd/Vt value, measured at the first 24 hours of hospitalization, was found to be higher in group 2 (0.66 vs. 0.54, p< 0.05). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of baseline Vd/Vt ≥ 0.60 for predicting extubation failure according to ROC curve were 70%, 72%, 58%, 81% and 71%, respectively. In conclusion, results of this study suggest that, higher Vd/Vt values measured on the first day of hospitalization may be an early predictor of extubation failure.

Mortality prediction in community-acquired pneumonia requiring mechanical ventilation; values of pneumonia and intensive care unit severity scores.

Severe community-acquired pneumonia (CAP) is an important cause of intensive care unit (ICU) admissions. Many different pneumonia scoring systems have been developed in order to assess the severity of pneumonia and to decide the ICU follow-up and treatment. But still debate is going on about their performances and also they have not been tested yet if they can predict ICU mortality in severe CAP patients requiring mechanical ventilation. The aim of this study is to evaluate the performances of pneumonia and ICU scores in predicting mortality in CAP patients requiring mechanical ventilation. A retrospective observational cohort study. The files of mechanically ventilated CAP patients were reviewed and demographic, clinic and laboratory characteristics were recorded. Scoring systems of pneumonia [revised American Thoracic Society (ATS) criteria, CURB-65, pneumonia severity index (PSI)] and ICU [Acute Physiology Assessment and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment] were compared for mortality prediction. Thirty eight female and 63 male, a total of 101 severe CAP patients, with the mean age of 68 +/- 16 years, were included in the study. ICU mortality rate was assessed as 55%. Ninety percent of all patients met the revised ATS criteria and 92% of them met the PSI scoring system for ICU admissions. Although the CURB-65, PSI, revised ATS criteria were not found valuable to predict mortality, the increased APACHE II score was found to be related with increased mortality rate (for APACHE II > 20 odds ratio: 3, 95% CI: 1.2-7, p= 0.024). These results suggest that instead of the pneumonia scoring systems the APACHE II score can best predict the ICU mortality. So, more attention should be paid for severe CAP patients with APACHE II score > 20.

The effect of low-dose inhaled budesonide on PC20 AMP levels in patients with mild asthma: a 3-month follow-up study.

Adenosine monophosphate (AMP) challenge is a diagnostic tool for asthma. The aim of this study is to evaluate the effect of low dose inhaled budesonide (IB) on PC(20)AMP levels. Seventeen stable mild asthmatic patients were prospectively recruited. After initial testing, patients were administered 400 microg of inhaled budesonide. AMP challenge was then repeated at the 12th hour and 5th,15th, 30th, and 90th days of the treatment. AMP challenge resulted in negative in 47% of the patients at 12(-)hour testing. This study suggests that low-dose IB may return airway responsiveness as early as 12 hours and AMP challenge may be effectively used for treatment monitorization.

The frequency of diastolic dysfunction in patients with sarcoidosis and it's relationship with HLA DRB1* alleles.

BACKGROUND: Impaired systolic function is common in sarcoidosis however the frequency of diastolic dysfunction (DD) and it's possible genetic basis has not been fully elucidated yet. The aim of this study is to evaluate the frequency of left ventricular DD(LVDD) and right ventricular DD(RVDD) and it's possible relationship between Human Leukocyte Antigen(HLA)-DRB1* alleles in patients with sarcoidosis. METHODS: Seventy seven patients (51 females, mean age 41.1±8.2yrs) without known sarcoid related or any other structured heart disease and 77 healthy controls with a similar age and gender (38.7±7.8yrs,51 females) were included in the case control study. DD was diagnosed with echocardiography. RVDD was defined as early(E)/late(A) ratio<1 or >2 on tricuspit valve. LVDD was defined as E/A ratio<1 or >2 on mitral valve, with isovolumetric relaxation time(IVRT)>90 miliseconds(msn) or deceleration rate of early diastolic flow(Edec)>220msn respectively. All patients were HLAtyped with the Sequence Specific Oligonucleotide Probe(SSOP) method. RESULTS: The frequencies of LVDDs and RVDDs were significantly higher in sarcoidosis patients than the controls (26.0% vs. 2.6% for LVDD; and 42.9% vs. 18.2% for RVDD)(p<0.05). No significant difference was found in patients according to the presence of RVDD and LVDD in terms of age, gender or respiratory function test parameters. Although the frequency of HLA DRB1* alleles were comparable among patients with RVDD, HLA DRB1*14 alleles were more frequent in patients with LVDD. CONCLUSIONS: Biventricular DD is common in patients with sarcoidosis without manifest cardiac involvement. HLA DRB1*14 allele seems to be related with LVDD in this study population.

Early propranolol treatment ameliorates endothelial dysfunction in experimental septic lung.

BACKGROUND: Recent reports have indicated an improved prognosis in sepsis with ß-blocker agents; however, the underlying action mechanism is still under debate. OBJECTIVES: The aim of this study was to investigate the potential effect of propranolol on endothelial dysfunction in septic rats. MATERIAL AND METHODS: The cecal ligation and puncture model (CLP) was used to generate sepsis. Adult male Wistar-Albino rats were divided into 4 groups: group 1 was a sham group, group 2 received sterile saline, group 3 received 10 mg/kg of propranolol 3 days before the intervention, and group 4 received 10 mg/kg of propranolol 30 min after CLP. Six rats from each group were sacrificed 24 h postoperatively. The remaining rats were followed for survival. We have also evaluated the effects on systemic inflammation, coagulation and the lung tissue with immunohistochemical and electron microscopic evaluation. RESULTS: Serum tumor necrosis factor alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1) levels, as well as tissue TNF-α scores were elevated in septic rats. Electron microscopic examination of the lung tissue showed endothelial dysfunction in the sepsis group. Pretreatment significantly improved survival. Moreover, pre-treatment altered serum vascular endothelial growth factor receptor-1 (VEGFR-1) levels and post-treatment reduced serum PAI-1 and VEGFR-1 levels. In both the preand post-treatment groups, electron microscopic examination revealed improvement of the destroyed lung endothelium and showed only mild alterations in the cytoplasmic organelles, especially in the mitochondria of the endothelial cells. CONCLUSIONS: These results suggest that the improved outcome with ß-blockers in sepsis may be due to the ameliorated endothelial dysfunction. Further studies focusing on the potential effect of ß-blockers on the endothelium may lead to a better understanding of sepsis.

Risk factors for treatment failure in patients with ventilator-associated pneumonia receiving appropriate antibiotic therapy.

PURPOSE: The aim of this study was to investigate modifiable risk factors and predictors for treatment failure (TF) in patients with ventilator-associated pneumonia (VAP) receiving appropriate antibiotic therapy. MATERIALS AND METHODS: An observational cohort study performed in an intensive care unit (ICU) of a University hospital. Eighty-nine patients with VAP were enrolled in the study consecutively. Treatment failure was defined as lack of clinical and microbiological response to therapy within 2 weeks. Potential risk factors for TF, related with patients, microorganisms, and ICU therapies, were evaluated. RESULTS: Mean age was 72 +/- 13 years. Fifty-three of the patients had TF. Patients with TF were older, had more comorbidities, higher admission and Acute Physiology and Chronic Health Evaluation Score (APACHE II)-VAP scores, lower daily carbohydrate intake, and lymphocyte number below 1000/mm(3) than the treatment success group. Transfusions, bacteremia, infection with multidrug-resistant microorganisms, initial bacterial load (CFU/mL), and steroid therapy were similar across the groups. Comorbidity (odds ratio [OR], 4.4; 95% CI, 1.2-16.8; P = .030), VAP-APACHE II scores above 16 (OR, 6.4; 95% CI, 2.1-18.6; P = .001), daily carbohydrate intake below 190 g/d (OR, 3; 95% CI,1.1-8.6; P = .038), lymphocyte number below 1000/mm3 (OR, 4.1; 95% CI, 1.3-12.9; P = .014) were independent predictors for TF. CONCLUSIONS: Patients with comorbidities, who are severely ill and lymphocytopenic at the time of VAP diagnosis, are at high risk for TF.