Exhaled breath condensate acidification in acute lung injury

AbstractLung injury in ventilated lungs may occur due to local or systemic disease and is usually caused by or accompanied by inflammatory processes. Recently, acidification of exhaled breath condensate pH (EBC-pH) has been suggested as marker of inflammation in airway disease. We investigated pH, ammonia, lactate, pCO2, HCO3−, IL-6 and IL-8 in EBC of 35 ventilated patients (AECC-classification: ARDS: 15, ALI: 12, no lung injury: 8).EBC-pH was decreased in ventilated patients compared to volunteers (5.85±0.32 vs. 7.46±0.48; P<0.0001). NH4+, lactate, HCO3−, pCO2, IL-6 and IL-8 were analyzed in EBC and correlated with EBC-pH. We observed correlations of EBC-pH with markers of local (EBC IL-6: r=−0.71, P<0.0001, EBC IL-8: r=−0.68, P<0.0001) but not of systemic inflammation (serum IL-6, serum IL-8) and with indices of severity of lung injury (Murray's Lung Injury Severity Score; r=−0.73, P<0.0001, paO2/FiO2; r=0.54, P<0.001). Among factors potentially contributing to pH of EBC, EBC-lactate and EBC-NH4+ were found to correlate with EBC-pH.Inflammation-induced disturbances of regulatory mechanisms, such as glutaminase systems may result in EBC acidification. EBC-pH is suggested to represent a marker of acute lung injury caused by or accompanied by pulmonary inflammation

Safety, Tolerability and Clinical Effects of a Rapid Dose Titration of Subcutaneous Treprostinil Therapy in Pulmonary Arterial Hypertension: A Prospective Multi-Centre Trial

Background: Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. Objectives: The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. Methods: Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study. Results: Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved. Conclusions: Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome. (C) 2016 S. Karger AG, Basel

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care

Exercise Dependence of N-Terminal Pro-Brain Natriuretic Peptide in Patients with Precapillary Pulmonary Hypertension

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is secreted by cardiac ventricular myocytes upon pressure and volume overload and is a prognostic marker to monitor the severity of precapillary pulmonary hypertension and the extent of right heart failure. Objectives: The impact of physical exercise on NT-proBNP levels in patients with left heart disease was demonstrated previously. No data regarding patients with isolated right heart failure and the influence of acute exercise on NT-proBNP serum levels exist. Methods: Twenty patients with precapillary pulmonary hypertension were examined. Hemodynamic parameters were measured during right heart catheterization. Serum NT-proBNP of patients was measured at rest, after a 6-min walking test, during ergospirometry and during recovery, all within 7 h. Significant differences in sequential NT-proBNP values, relative changes compared to values at rest and the correlation between NT-proBNP and obtained parameters were assessed. Results: At rest, the mean serum level of NT-proBNP was 1,278 ± 998 pg/ml. The mean level of NT-proBNP at maximal exercise was increased (1,592 ± 1,219 pg/ml), whereas serum levels decreased slightly during recovery (1,518 ± 1,170 pg/ml). The relative increase of serum NT-proBNP during exercise correlated with pulmonary vascular resistance (r = 0.45; p = 0.026) and cardiac output (r = –0.5; p = 0.015). Conclusions: In this study, we demonstrated acute changes in NT-proBNP levels due to physical exercise in a small group of patients with precapillary pulmonary hypertension. Our results also confirm the predominant usefulness of NT-proBNP as an intraindividual parameter of right heart load.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Tobacco-smoking induced GPR15-expressing T cells in blood do not indicate pulmonary damage

Abstract Background Recently, it was shown that chronic tobacco smoking evokes specific cellular and molecular changes in white blood cells by an excess of G protein-coupled receptor 15 (GPR15)-expressing T cells as well as a hypomethylation at DNA CpG site cg05575921 in granulocytes. In the present study, we aimed to clarify the general usefulness of these two biomarkers as putative signs of non-cancerous change in homeostasis of the lungs. Methods In a clinical cohort consisting of 42 patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pneumonia and a control cohort of 123 volunteers, the content of GPR15-expressing blood cells as well as the degree of methylation at cg05575921 were analysed by flow-cytometry and pyrosequencing, respectively. Smoking behaviour was estimated by questionnaire and cotinine level in plasma. Results Never-smoking patients could be distinguished from former and current smokers by both the proportion of GPR15-expressing T cells as well as cg05575921 methylation in granulocytes, with 100% and 97% specificity and 100% sensitivity, respectively. However, both parameters were not affected by lung diseases. The degrees of both parameters were not changed neither in non-smoking nor smoking patients, compared to appropriate control cohorts of volunteers. Conclusions The degree of GPR15-expressing cells among T cells as well as the methylation at cg05575921 in granulocytes in blood are both rather signs of tobacco-smoking induced systemic inflammation because they don’t indicate specifically non-cancerous pathological changes in the lungs

Perioperative Anesthesiological Management of Patients with Pulmonary Hypertension

Pulmonary hypertension is a major reason for elevated perioperative morbidity and mortality, even in noncardiac surgical procedures. Patients should be thoroughly prepared for the intervention and allowed plenty of time for consideration. All specialty units involved in treatment should play a role in these preparations. After selecting each of the suitable individual anesthetic and surgical procedures, intraoperative management should focus on avoiding all circumstances that could contribute to exacerbating pulmonary hypertension (hypoxemia, hypercapnia, acidosis, hypothermia, hypervolemia, and insufficient anesthesia and analgesia). Due to possible induction of hypotonic blood circulation, intravenous vasodilators (milrinone, dobutamine, prostacyclin, Na-nitroprusside, and nitroglycerine) should be administered with the greatest care. A method of treating elevations in pulmonary pressure with selective pulmonary vasodilation by inhalation should be available intraoperatively (iloprost, nitrogen monoxide, prostacyclin, and milrinone) in addition to invasive hemodynamic monitoring. During the postoperative phase, patients must be monitored continuously and receive sufficient analgesic therapy over an adequate period of time. All in all, perioperative management of patients with pulmonary hypertension presents an interdisciplinary challenge that requires the adequate involvement of anesthetists, surgeons, pulmonologists, and cardiologists alike

Monotherapy in patients with pulmonary arterial hypertension at four German PH centres

Background!#!Although combination therapy is the gold standard for patients with pulmonary arterial hypertension (PAH), some of these patients are still being treated with monotherapy.!##!Methods!#!We conducted a retrospective analysis at four German PH centres to describe the prevalence and characteristics of patients receiving monotherapy.!##!Results!#!We identified 131 incident PAH patients, with a mean age of 64 ± 13.8 years and a varying prevalence of comorbidities, cardiovascular risk factors and targeted therapy. As in other studies, the extent of prescribed PAH therapy varied with age and coexisting diseases, and younger, so-called 'typical' PAH patients were more commonly treated early with combination therapy (48% at 4-8 months). In contrast, patients with multiple comorbidities or cardiovascular risk factors were more often treated with monotherapy (69% at 4-8 months). Survival at 12 months was not significantly associated with the number of PAH drugs used (single, dual, triple therapy) and was not different between 'atypical' and 'typical' PAH patients (89% vs. 85%).!##!Conclusion!#!Although 'atypical' PAH patients with comorbidities or a more advanced age are less aggressively treated with respect to combination therapy, the outcome of monotherapy in these patients appears to be comparable to that of dual or triple therapy in 'typical' PAH patients

Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension

Background. Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury.Material and methods. PH patients with (n = 23) or Without (n = 25) an increase of alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression.Results. Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8).Conclusion. Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9

Die neue Definition und Klassifikation der pulmonalen Hypertonie

In der Neufassung der ESC/ERS-Leitlinien 2022 zur pulmonalen Hypertonie (PH) kam es zu wesentlichen Änderungen in der hämodynamischen Definition sowie zu einer weiteren Verfeinerung in der Klassifikation des Lungenhochdrucks.Als bedeutende Neuerung gilt die Einführung eines neuen Grenzwerts des mittleren pulmonalarteriellen Druckes (mPAP) für die Definition der PH. Eine PH wird nun durch eine Erhöhung des mPAP > 20 mmHg, ermittelt durch Rechtsherzkatheter, definiert. Des Weiteren wurde der Grenzwert des pulmonalen Gefäßwiderstands (PVR) zur Definition einer präkapillären PH verringert. Eine präkapilläre PH liegt nun bereits ab einem PVR > 2 WU und einem pulmonalarteriellen Verschlussdruck (PAWP) ≤ 15 mmHg vor. Die zunehmende Evidenz für die klinische Relevanz der pulmonalen Belastungshämodynamik führte schließlich auch zur Wiederaufnahme des Belastungs-PH-Terminus in die Leitlinien. Die Belastungs-PH wird als Verhältnis zum Herzzeitvolumen (CO) über einen pathologischen mPAP/CO-Slope > 3 mmHg/L/min definiert. In der Klassifikation werden weiterhin fünf Gruppen unterschieden: die pulmonalarterielle Hypertonie (Gruppe 1), PH assoziiert mit Linksherzerkrankungen (Gruppe 2), PH assoziiert mit Lungenerkrankungen und/oder Hypoxie (Gruppe 3), PH assoziiert mit pulmonalarterieller Obstruktion (Gruppe 4) und PH mit unklaren und/oder multifaktoriellen Mechanismen (Gruppe 5).In der folgenden Leitlinienübersetzung soll auf die Neuerungen eingegangen, deren Hintergründe näher beleuchtet und mögliche Schwierigkeiten in ihrer klinischen Anwendung diskutiert werden