Differences in cerebral oxygenation during exercise in patients with idiopathic pulmonary fibrosis with and without exertional hypoxemia: does exercise intensity matter?

INTRODUCTION AND OBJECTIVES: Patients with idiopathic pulmonary fibrosis (IPF) present respiratory derangements at rest and during exercise, accompanied by exercise intolerance. Some patients may develop profound exertional desaturation even without resting hypoxemia. Evidence suggests the involvement of reduced cerebral-oxygenation in exercise intolerance. We aimed to examine (i) differences in cerebral-oxygenation during exercise between IPF patients with and without isolated exertional desaturation, (ii) whether the impairments in cerebral-oxygenation are detected at similar exercise intensity, and (iii) correlations between cerebral-oxygenation indices, disease severity, and 6-min walk test (6MWT). MATERIALS AND METHODS: Patients with IPF (n = 24; 62.1 ± 9.3 years) without resting hypoxemia underwent cardiopulmonary exercise testing (CPET) with cerebral-oxygenation monitoring via near-infrared-spectroscopy (NIRS). Βased on their pulse-oxymetry saturation (SpO2) during CPET, patients were divided into the "exertional-desaturators" group (SpO2nadir≤89% and ≥6% drop in SpO2) and the "non-exertional-desaturators" group (SpO2nadir≥90% and ≤5% drop). RESULTS: During CPET, the "exertional-desaturators" group exhibited lower oxygenated-hemoglobin (-0.67 ± 1.48 vs. 0.69 ± 1.75 µmol/l; p < 0.05) and higher deoxygenated-hemoglobin (1.67 ± 1.13 vs. 0.17 ± 0.62 µmol/l; p < 0.001) than the "non-exertional-desaturators" group. A different pattern (p < 0.01) in cerebral-oxygenation responses was observed in the two groups. In exertional-desaturators oxygenated-hemoglobin declined below baseline even at low/moderate-intensity exercise (p < 0.05), whereas, in non-exertional-desaturators cerebral-oxygenation declined (p < 0.05) at high-intensity exercise. Cerebral-NIRS indices correlated (p < 0.05) with CPET-duration, dyspnea, diffusion capacity, and 6MWT. CONCLUSIONS: During incremental exercise, patients with IPF and exertional desaturation present a significant decline in cerebral-oxygenation even during low-intensity exercise. Our findings support the implementation of longer-duration rehabilitation programs in IPF so that lower intensity exercise can be applied at the initial stages. (NCT03683082).

Phenotyping exercise limitation of patients with Interstitial Fibrosing Lung Disease: the importance of exercise hemodynamics.

INTRODUCTION AND OBJECTIVE: Left-heart dysfunction and pulmonary vasculopathy are increasingly recognized as contributing factors of exercise capacity limitation in interstitial fibrosing lung disease (IFLD). Moreover, the clinical significance of exercise pulmonary hypertension (ePH) in pulmonary and cardiac diseases has been documented, representing a risk factor for decreased exercise capacity and survival, progression to resting pulmonary hypertension (PH) and overall clinical worsening. We conducted a prospective study aiming at: (a) assessing the prevalence of PH and ePH in a cohort of 40 functionally limited patients with IFLD, (b) determining the post-capillary (postC) or pre-capillary (preC) etiology of either PH or ePH in this cohort, and (c) examining the correlations between invasively and non-invasively measured exercise variables among hemodynamic groups. PATIENTS AND METHODS: 40 IFLD patients underwent cardiopulmonary evaluation, including: clinical examination, lung function tests, 6-minute walking test, heart ultrasonography, cardiopulmonary exercise test and, finally, right heart catheterization (RHC). Resting hemodynamic evaluation was followed by the exercise protocol proposed by Herve et al, using a bedside cycle ergometer in the supine position. Abnormal elevation of mean pulmonary artery pressure (mPAP) above 30mmHg during exercise, with respect to abnormal elevation of cardiac output (CO) below 10 L/min (mPAP-CO ratio ⩾3 mmHg·min·L-1) was used to define ePH (Herve et al, 2015). Secondary hemodynamic evaluation involved detection of abnormal pulmonary arterial wedge pressure (PAWP) increase at peak exercise in relation to CO. Specifically, ΔPAWP/ΔCO >2 mmHg/L per minute determined an abnormal PAWP elevation (Bentley et al, 2020). RESULTS: Among the 40-patient cohort, 25% presented postC PH, 37.5% preC PH, 27.5% ePH, with the remaining 10% recording normal hemodynamics. PAWP evaluation during exercise revealed a postC etiology in 4 out of the 11 patients presenting ePH, and a postC etiology in 6 out of the 15 patients presenting resting preC PH. Mean values of non-invasive variables did not display statistically significant differences among hemodynamic groups, except for: diffusing capacity for carbon monoxide (DLCO), carbon monoxide transfer coefficient (KCO) and the ratio of functional vital capacity to DLCO (FVC%/DLCO%), which were lower in both ePH and PH groups (p < 0.05). Resting values of CO, cardiac index (CI), stroke volume (SV) and pulmonary vascular compliance (PVC) were significantly impaired in ePH, preC-PH and postC-PH groups when compared to the normal group. CONCLUSIONS: Both PH and ePH were highly prevalent within the IFLD patient group, suggesting that RHC should be offered more frequently in functionally limited patients. Diffusion capacity markers must thus guide decision making, in parallel to clinical evaluation. ePH was associated to lower resting CO and PVC, in a similar way to resting PH, indicating the relevance of cardiopulmonary function to exercise limitation. Finally, the use of the ΔPAWP/ΔCO>2 criterion further uncovered PH of postcapillary etiology, highlighting the complexity of hemodynamics in IFLD. CLINICALTRIALS: gov ID: NCT03706820.

Nursing errors in intensive care unit and their association with burnout, anxiety, insomnia and working environment: a cross-sectional study.

BACKGROUND: In intensive care units (ICU), commonly identified nursing errors may have a negative impact on short- and long-term patient outcomes. Current data is scarce regarding nurses' burnout, insomnia, and anxiety impact on medication and several other types of nursing errors. This study aimed to record the commonness of various nursing errors, including checking patient data, medication preparation and administration, and infection control measures. It also aimed to investigate if "nurse-related" or "ICU-related" features may be associated with nursing error occurrence. MATERIAL-METHODS: A sample of nurses employed in four Greek ICUs was evaluated using the self-completed Athens Insomnia Scale, the State-Trait Anxiety Inventory Form Y, and the Maslach Burnout Inventory. Moreover, we also recorded the sociodemographic characteristics of the ICU nurses, data regarding nursing errors and common practices, and variables regarding the working environment. We conducted a multinominal regression analysis to identify the variables independently associated with each error/mistake. RESULTS: Ninety ICU nurses from the 99 addressed returned the completed questionnaires. The most frequent mistakes referred to drug preparation and administration, with 43.3 % of nurses reporting being "always/very often" distracted when preparing a drug and 90 % that "half of the times" they administer medication at unscheduled hours, followed in frequency by errors regarding the proper use of antiseptic solutions. Medication errors were independently predicted by state anxiety, satisfaction regarding training, emotional exhaustion score, number of ICU beds, and weekdays off work per month. In contrast, errors regarding infection control were independently associated with weekdays off work per month. CONCLUSION: Medication errors are the commonest type of nursing error. Although several risk factors have been identified, no universal "nurse-related" or "ICU-related" factor can predict all types of errors. HIPPOKRATIA 2022, 26 (3):110-117.

Burnout syndrome among emergency medicine physicians: an update on its prevalence and risk factors.

OBJECTIVE: Training in and practising emergency medicine are very stressful conditions that pose a significant emotional burden on physicians, placing them at high risk of developing burnout. The purpose of the current manuscript is to review the published literature on burnout prevalence among emergency medicine physicians and to identify the risk factors associated with its occurrence. MATERIALS AND METHODS: A search of MEDLINE (January 1980-March 2019) was conducted using the terms "burnout", "emergency", "physicians", "emotional exhaustion", "depersonalization" in various combinations. All studies, which assessed burnout prevalence (as primary or secondary outcome) among emergency medicine physicians and were published as full-text articles in English, were included in the review. RESULTS: Twenty-seven studies met eligibility criteria. Although the prevalence of burnout among emergency medicine physicians is high, the exact incidence widely varies ranging between 25% and 77.8%, because of the unique characteristics of each population under study, and also due to the different definitions, tools, and cut-offs used for burnout diagnosis. Several work-related parameters (heavy work-load, low job satisfaction, a problematic co-workers relationship, and difficulty in balancing personal with professional life), personality traits and stress-copying methods, life-style parameters, and other mental disorders (such as stress and sleep disorders) are associated with the establishment of burnout. CONCLUSIONS: Emergency medicine physicians are of a high risk of burnout, although further agreement is needed regarding the use of the Maslach Burnout Inventory as a diagnostic tool. Furthermore, the identification of the potential risk factors for this disorder is crucial so that high-risk groups could be early identified and properly addressed.

Tuberculosis treatment outcome in Thessaloniki, Greece - a single center study.

BACKGROUND: Greece is one of the few countries in the European Union/European Economic Area, which do not report tuberculosis (TB) treatment outcome. This study aimed to assess treatment outcomes and identify possible intervening factors in patients with TB in Thessaloniki, Greece, over the period 2012-2017. METHODS: All patients diagnosed with TB -excluding rifampicin-resistant/multidrug-resistant (RR/MDR)-TB- during 2015-2017 were included in the study. Data on demographic characteristics, localization, diagnostic methods, resistance, and treatment outcome were recorded and compared to the period 2012-2014. RESULTS: During the period 2015-2017, 82 patients (48 men) with a mean age of 53.8 ± 15.6 years were diagnosed with TB. No significant differences in demographics, microbiological, or treatment characteristics were detected between the two three-year periods, except for the percentage of immunocompromised patients, which was higher during 2015-2017 (15.9 % vs 5.6 %, p =0.029). In the total number of patients, two factors were significantly different between patients with a positive and negative outcome. The percentage of favorable outcome was higher for patients with extrapulmonary compared to pulmonary TB (90.9 % vs 70.5 %, p =0.044). Furthermore, the percentage of immunocompetent patients with a positive outcome was significantly higher in the second treatment period compared to the first (treatment success rate 66.7 % in 2012-2014 vs 84.1 % in 2015-2017, p =0.014). This difference was attributed to the presence of a social nurse who joined the center in 2015. CONCLUSIONS: TB treatment success rate in Greece is below the World Health Organization standards. Interventions such as appropriate multidisciplinary staffing of TB centers may prove valuable in improving TB care in Greece. HIPPOKRATIA 2019, 23(4): 154-159.

Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study.

SETTING: Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB). OBJECTIVE: To study the MFX-RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen. DESIGN: Patients with pulmonary TB followed up by the Tuberculosis Out-patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2). RESULTS: The participants did not significantly differ in body mass index, days of MFX treatment or MFX dose/kg. Neither the peak concentration (Cmax) nor the 24 h area under the curve (AUC24) differed significantly between the two groups (Group 1, Cmax median 3.9 [range 1.9-4.5] mg/l; AUC24 29.1 [10-47.4] mg·h/l and Group 2, Cmax 4.1 [2-6.4] mg/l; AUC24 36.5 [14.6-54.2] mg·h/l). CONCLUSION: Although a decrease in MFX exposure was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co-administration.

Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and therapeutic options.

Infections due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) have emerged as a public health problem worldwide given their spread dynamics and the limited therapeutic options. Our aim was to study the clinical outcome of patients with CR-KP infections in relation to antimicrobial treatment. CR-KP infections that occurred in a 10-month period (September 2009 to June 2010) in patients admitted to 19 intensive care units all over Greece were studied. A total of 127 CR-KP infections were reported. Central venous catheter bacteraemia was the most frequent infection, followed by ventilator-associated pneumonia (39 (30.7%) and 35 (27.6%) cases, respectively). Resistance to colistin, tigecycline, gentamicin and amikacin was detected in 20%, 33%, 21% and 64% of isolates, respectively. Regarding treatment, 107 cases received active treatment, including 1 or ≥2 active antibiotics in 65 (60.7%) and 42 (39.3%) cases, respectively. The most frequent combination was colistin plus aminoglycoside and tigecycline plus aminoglycoside (17 and 11 cases, respectively). Forty-eight (45.2%) of the cases that received active treatment were considered clinical failures, with 23.5% mortality at 14 days. Logistic regression analysis revealed that age ≤55 years, non-immunocompromised patients and patients who received colistin had higher successful response rates, while patients ≤55 years old had lower mortality rates at 14 days after the introduction of active treatment. CR-KP infections are associated with a significant clinical failure rate. Colistin remains a valuable antimicrobial agent for treating these infections, while the rise of resistance to the last available antibiotics further limits treatment options.

Multidrug-resistant tuberculosis in an adult with cystic fibrosis.

Mycobacterium tuberculosis infection in patients with cystic fibrosis (CF) is rare. We report a 22-year-old CF patient with high fever, dyspnea and weight loss that progressively worsened over 2 weeks before admission. The patient suffered from liver cirrhosis, was colonized with Pseudomonas aeruginosa and had been repeatedly hospitalized for pulmonary infections. The patient was treated initially as for an exacerbation of P. aeruginosa infection, but tuberculosis (TBC) was suspected due to lack of improvement. A CT of the chest revealed enlarged bilateral cavities in the upper and middle lobes. A tuberculin skin test was positive, and M. tuberculosis nucleic acid was isolated from sputum samples. After receiving first-line anti-TBC drugs for 1 month, the patient's condition continued to worsen so molecular drug susceptibility testing was performed. Multidrug-resistant TBC was discovered, leading to a change in regimen. The patient was treated with ethionamide, moxifloxacin, linezolid, amikacin, imipenem/cilastatin and rifabutin and showed a remarkable clinical improvement. Although nontuberculous mycobacteria are more common in CF, the possibility of TBC should not be ignored. In that setting, early suspicion of infection due to resistant M. tuberculosis can be life saving.

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases.

BACKGROUND: Macrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the "cytokine storm" of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. METHODS: A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases. RESULTS: Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function. CONCLUSION: This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.

Association of pharmacokinetic and pharmacodynamic aspects of linezolid with infection outcome.

Linezolid is the first antibiotic of a new class (oxazolidinones). It inhibits protein synthesis by binding to the bacterial 23S ribosomal RNA of the 50S subunit, thus blocking the formation of the functional 70S initiation complex, but it does not inhibit peptidyl transferase. Therefore, its mechanism of action is unique and cross resistance is unlikely to occur; however, resistant strains have already been reported, but the rate of resistance is low in surveillance programs. Linezolid has a favorable pharmacokinetic profile. It is rapidly absorbed when administered orally, and it is 100% bioavailable, thus allowing early switch from intravenous to oral administration. The maximum plasma concentration (range between 13.1+/-1.8 to 19.5+/-4.5 microg/ml according to the route of administration, studied population and dosages administered to subjects) is achieved 1-2 hours after the first dosage. It penetrates readily to most tissues of the human body at concentrations much higher than that of the minimal inhibitory concentrations of the targeted pathogens. It is metabolized by oxidation in two major inactive metabolites and is eliminated mainly through the kidneys. Linezolid is bacteriostatic for staphylococci and enterococci but bactericidal for pneumococci and kills bacteria in a time-dependent fashion. It has been studied in several randomized controlled trials and has been approved for the treatment of patients with Gram positive bacterial infections (community-acquired and nosocomial pneumonia, skin and soft tissue infections, and infections due to vancomycin-resistant enterococci) including these due to multidrug-resistant strains. Careful and judicious use is warranted to preserve the activity of this important antibiotic.

Visceral leishmaniasis infection in a patient with rheumatoid arthritis treated with etanercept.

Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised patients. Antitumor necrosis factor-alpha (TNF-alpha) treatment of rheumatoid arthritis can result in clinical benefits, but with an increased risk of opportunistic infections. Leishmania infection in patients treated with TNF-alpha antagonists is extremely rare; for this reason, we report a patient with VL after etanercept treatment who had an unfavorable outcome.

Effects of prostacyclin on bronchoconstriction and neutropenia induced by inhaled platelet-activating factor in man.

We studied the effects of prostacyclin (PGI2) on the airway responses to platelet-activating factor (PAF) in a randomized and crossover study in eight normal subjects. PGI2 or diluent (glycine buffer) was continuously infused on 2 separate days. Two breaths of PAF (21 micrograms) were inhaled three times every 15 minutes and airflow at 30% of vital capacity from partial flow-volume curves (Vp30) was measured. PGI2 (4 ng/kg/min) had no effect on Vp30 or blood pressure, whereas heart rate increased from 70.3 +/- 3.9 to 73.7 +/- 4.0 beats/min (mean +/- SEM; p less than 0.01). Two subjects did not complete the study because of transient hypotension. PGI2 had no effect on PAF-induced bronchoconstriction with maximal decreases in Vp30 of 42.0 +/- 8.0% (p less than 0.01) during PGI2 and 49.8 +/- 14.2% (p less than 0.02) during diluent infusion. Ex vivo platelet aggregation to PAF (10(-9) to 10(-7) mol/L) was significantly inhibited by PGI2. Circulating neutrophils decreased from 4.7 +/- 0.9 x 10(9)/L to 1.5 +/- 0.3 x 10(9)/L (p less than 0.05) 5 minutes after the first PAF inhalation during diluent infusion, whereas there was no significant change with PGI2. Thus, PGI2 does not influence PAF-induced bronchoconstriction in man despite causing marked inhibition of ex vivo PAF-induced platelet aggregation and preventing the fall of neutrophils.

Effect of nedocromil sodium on down-regulation of pulmonary beta-adrenoceptors.

1. We have studied the effect of the anti-inflammatory anti-asthma drug, nedocromil sodium, on down-regulation of pulmonary beta-adrenoceptors in guinea-pig lung. 2. Incubation of minced lung with isoprenaline (10 mumol/l) resulted in a reduction in maximum binding capacity of [125I]iodocyanopindolol to lung membranes from 246 +/- 4 to 169 +/- 6 fmol/mg of protein (mean +/- SEM, P less than 0.01, n = 18). 3. Nedocromil sodium, which had no direct effect on [125I]iodocyanopindolol binding, prevented isoprenaline-induced down-regulation, giving complete protection at a dose of 100 mumol/l. 4. The mechanism of this effect is not certain, but nedocromil sodium may interfere with the internalization of beta-adrenoceptors in pulmonary parenchymal cells. This may have some therapeutic relevance.

Effect of inhaled platelet-activating factor on circulating neutrophils and platelets in vivo and ex vivo in man.

We studied the effect of five successive inhalations of platelet-activating factor (PAF) on airway calibre, circulating neutrophil and platelet counts and the activation of these cells ex vivo in normal subjects. PAF (24 ug) caused a mean maximal fall of the expiratory flow rate at 70% vital capacity from a partial manoeuvre (Vp30) of 46.4 +/- 6.2% (p less than 0.001); there was a tachyphylactic response to further doses of PAF. Circulating neutrophil counts fell by 54.3 +/- 10.6% (p less than 0.005) with immediate recovery and with a rebound neutrophilia by the fifth inhalation. Platelet counts showed no significant changes. Aggregation of platelets in platelet-rich plasma to PAF and ADP in vitro at 15 min after the first, second and fifth PAF inhalations was not significantly altered. Chemiluminescence responses of neutrophils to PAF (0.01, 0.1, 1 and 10 microM) in vitro were reduced at 15 min after the fifth PAF inhalation, but this was only significant at 1 microM PAF. Methacholine inhalation did not cause any changes in responsiveness of neutrophils to PAF ex vivo. We conclude that ex vivo platelet desensitisation cannot be used as an index of endogenous PAF release, but reduced responsiveness of neutrophils ex vivo is not a sensitive indicator.