Hans Stricker

Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response.

ObjectivesTo examine the hypothesis that the response to inhaled prostacyclin (PGI2) on oxygenation and pulmonary hemodynamics may be related to different morphologic features that are supposed to be present in acute respiratory distress syndrome (ARDS) originating from pulmonary (primary ARDS [ARDSPR]) and from extrapulmonary disease (secondary ARDS [ARDSSEC]). DesignProspective, nonrandomized interventional study. SettingMultidisciplinary intensive care unit, secondary care center. PatientsFifteen consecutive, mechanically ventilated patients with ARDS and severe hypoxemia, defined as Pao2/Fio2 of <150 torr at the time of admission. InterventionsAfter an initial stable period of at least 60 mins, patients received nebulized PGI2 in 15-min steps; the drug was titrated to find the dose with the best improvement of Pao2, starting with 2 ng/kg/min up to an allowed maximum dose of 40 ng/kg/min. Measurements and Main ResultsBlood gas, gas exchange, and hemodynamic measurements were performed at the following time points: a) baseline; b) during the optimal or maximum dose of PGI2; and c) 1 hr after withdrawal of the drug. Patients underwent a computed tomographic (CT) scan using a basal CT section to compute the mean CT numbers and the density histogram. Patients were considered responders to PGI2 if an increase in Pao2 of ≥7.5 torr or an increase in Pao2/Fio2 ratio of ≥10% occurred. For the group as a whole, mean pulmonary artery pressure decreased from 32 ± 1 to 29 ± 1 mm Hg during PGI2 nebulization, whereas pulmonary vascular resistance decreased 1 hr after withdrawal of nebulization from 177 ± 18 to 153 ± 16 dyne·sec/cm5; oxygenation did not change significantly. Eight patients responded to PGI2 nebulization on oxygenation (all were in the ARDSSEC subgroup), whereas seven did not (all but one were in the ARDSPR subgroup). Among the physiologic variables examined to assess any difference between the two ARDS groups at time of PGI2 nebulization, there was a significant difference concerning the mean CT density number, which was −445 ± 22 Hounsfield Units in the ARDSSEC group and −258 ± 16 Hounsfield Units in the ARDSPR group. In patients presenting with an ARDSPR, PGI2 induced a reduction in Pao2/Fio2 and a reduction in Pao2 from 87 ± 2 to 79 ± 2 torr, whereas in patients with an ARDSSEC there was an increase in Pao2/Fio2 and in Pao2 from 76 ± 4 to 84 ± 4 torr with a decrease in mean pulmonary artery pressure. ConclusionsBased on the data from this study, the clinical recognition of the two types of the syndrome together with the CT number frequency distribution analysis may be associated with a prediction of the PGI2 nebulization response on oxygenation.

The influence of a prolonged sitting position on the biochemical markers of coagulation activation in healthy subjects: evidence of reduced thrombin generation

Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1–5]. The frequency of symptomatic thromboembolic events increases with the distance flown, but appears to be low [3]. In a recent study, however, Scurr et al. found symptomless calf vein thrombosis detected by ultrasonography in up to 10% of long-haul travelers [4]. Given the limited sensitivity of the method [6], the true incidence of travel-associated distal thrombi may even be higher. Taken together, these data suggest that subclinical thrombosis may be frequent during air travel but usually resolves once mobility is resumed. Accordingly, symptomatic thromboembolic events would reflect a rare situation where activation of coagulation escapes the natural control systems. The prolonged sitting position during an air trip is associated with venous stasis, decreased blood flow and hemoconcentration, and is widely assumed to be the main causal factor for thrombus formation in this setting. If this assumption is correct, prolonged immobility in a sitting position by itself would be sufficient to activate coagulation. Subclinical activation of coagulation a so-called prethrombotic state [7] can be assessed by sensitive biochemical markers of thrombin generation (prothrombin fragment 1þ 2, F1þ 2), of ongoing fibrin formation (fibrinopeptide A, FPA) and lysis (D-dimer, DD). The aim of this study was to test the hypothesis that prolonged immobility in a sitting position similar to the one occurring during air traveling activates coagulation. Forty healthy subjects of either sex (median age 29.5 years, range 19–58) with a negative personal and family history and no known risk factor for thromboembolism were kept seated for 6 h on normal chairs, with their knees bent; during this period they were allowed to drink, eat, read or watch television. At baseline and after 3 and 6 h of immobilization, blood was collected in CTADPPACK anticoagulant from sitting probands with a clean venepuncture from an antecubital vein under controlled venous stasis for measurement of F1þ 2 (Enzygnost F1þ 2 Behring), FPA (RIA reagents supplied by Imco), and DD (mini-VIDAS, BioMérieux). Hemoglobin concentration and hematocrit were determined as well. In order to control for the circadian variations of the hemostatic system [8], we used the same protocol for blood sampling in a subgroup of 18 volunteers who were allowed to move freely (control group). Statistical probability was assessed with repeated measures ANOVA on ranks followed by pairwise multiple comparison procedures (Student–Newman–Keuls method) for non-normally distributed data. A linear regression was done for correlation between data at baseline and after 6 h. A difference was considered significant when P <0.05. Over the 6 h of sitting position there was no change in the plasma levels of FPA and DD, whereas F1þ 2 levels decreased from a median of 0.49 to 0.40 nmol L 1 (P< 0.0001, Table 1). The F1þ 2 decrease was both relevant in quantitative terms ( 20% of the baseline values) and consistent among the volunteers (being present in 80% of them). For the three markers, there was a significant correlation between the values at baseline and those measured after 6 h (F1þ 2: r1⁄4 0.63, P< 0.0001; FPA: r1⁄4 0.52, P< 0.0007; DD: r1⁄4 0.83, P< 0.0001). Plasma volume did not change over the 6 h as indicated by stable values for hemoglobin and hematocrit. In the control group, values for F1þ 2 significantly decreased in the sitting position but did not change under ambulant conditions (Table 2). Overall, the quality of blood sampling and processing was very high, as reflected by individual values for FPA which were within the normal range in 168/176 samples (96%), were slightly increased in seven samples, and were above 5.5 nmol L 1 (and thus likely to represent a faulty venepuncture) in one sample (0.6%). Using the biochemical markers of thrombin generation and of ongoing fibrin formation and lysis, we were not able to confirm the hypothesis of activation of coagulation in subjects immobilized in a sitting position. While the failed increase in FPA and DD would not by itself definitively reject the study hypothesis (small quantities of fibrin deposited in the lower limbs could have escaped detection due to the effect of dilution of these markers in circulating blood), the significant decrease of F1þ 2 indicates a reduced rate of thrombin generation during sitting. The decrease in F1þ 2 cannot be explained solely by circadian variations and was the consequence of the prolonged immobilization in a sitting position. It is tempting to speculate that the reduction in thrombin generation reflects a protective down-regulation of the hemostatic system to counter the effect of venous stasis. This suggestion, however, has to be tempered by the fact that thrombin has both procoagulant and anticoagulant effects [9], and that the protein C system mediated anticoagulant effect may even be prevalent under physiologic conditions and in the presence of an intact vascular bed. Journal of Thrombosis and Haemostasis, 1: 380–399

Long-Term Data from the Swiss Pulmonary Hypertension Registry

Background: Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. Objective: To provide long-term data of the Swiss PH registry of 1998-2012. Methods: PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. Results: From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. Conclusion: Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.

Adherence to the medical regime in patients with heart failure

To assess adherence to medical treatment in patients with heart failure (HF) using a specific questionnaire and measurement of the serum concentration of digoxin.

Variation in coagulation inhibitors during prolonged sitting: possible pathogenetic mechanisms for travel-associated thrombosis

Epidemiological studies have shown an increased risk of venous thrombosis after (air) travel [1,2]. Blood stasis is one of the mechanisms involved in deep vein thrombosis, but so far limited information is available on the pathophysiologic relationship between stasis and thrombosis. We [3] and others [4,5] have found a decrease in thrombin generation during sitting in an experimental setting or during a long-haul flight. This finding is intriguing, as it does not fit the conventional concept of a prethrombotic state defined by an increased level of prothrombin fragment 1 + 2 (F1+2) but a normal concentration of fibrinopeptide A (FPA) [6]. On the other hand, less thrombin may be a hazard in an intact vascular bed; in fact, thrombin on a molecular basis has a pivotal influence on hemostasis by its action as a procoagulant in damaged vessels, and as an anticoagulant in an intact vascular bed by binding thrombomodulin (TM) and thus activating protein C, which in concert with protein S inactivates factor (F) Va and FVIIIa [7]. With this background we tried to elucidate the mechanism(s) of the decrease in thombin generation during sitting and to answer the question whether this decrease may represent a hypercoagulable state. To this end, we measured biological markers of thrombin formation and fibrinolysis, concentrations of the three main inhibitors of coagulation, activity of different coagulation factors and an inhibitor of fibrinolysis (thrombin activatable fibrinolysis inhibitor, TAFI) in a in vivo model of venous stasis. Twenty healthy subjects (11 men, mean age 29 ± 6 years) with no known personal or familial risk factors for venous thromboembolic disease were kept seated on a chair, as described [3]. At baseline (08.00 hours 1⁄4 T0), and after 3 (T3) and 6 (T6) hours, blood was drawn with a clean venipuncture from an antecubital vein under manometrically controlled venous stasis of 50 mmHg into a 10 mL plastic syringe (Monovette, Sarstedt, Nümbrecht, Germany) containing 1 mL 0.106 M trisodium citrate, and into a 5 mL syringe (Monovette) containing 1 mL of CTADPPACK and immediately put on melting ice. Plasma was separated by cold centrifugation, and aliquots were stored at )70 C until processing. All analyses for every single parameterwere donewithin a single working session, using the same reagent batches, and the technicians performing the tests were blinded as to the origin of the samples and other results. The study was approved by the local ethics committee, and all subjects gave informed consent. F1+2 was measured with a commercial ELISA (Enzygnost by Dade Behring, Marburg, Germany), FPA with RIA (reagents supplied by Imco, Stockholm, Sweden), and Ddimers (DD) with ELISA (miniVidas by bioMérieux, Lyon, France). Plasma concentrations of TM were measured with micro-ELISA (Asserachrom Thrombomodulin, Diagnostica Stago, Asnières, France). Total tissue factor pathway inhibitor (TFPI) was measured by ELISA (Asserachrom Diagnostica Stago). The quantitative determination of the heparin cofactor activity of antithrombin (AT) was performed using a commercial kit (Coamatic LR Antithrombin, Chromogenix, Mölndal, Sweden). Conventional one-stage assays detected activity of FV (FV:C); the respective FVIII:C was measured by an activated partial thromboplastin based assay using Pathrombin SL (Dade Behring) and a factor-deficient plasma. VonWillebrand factor antigen and ristocetin cofactor activity levels (vWF:AG and vWF:RF) were measured using an ELISA kit from Dako (Glostrup, Denmark), and BC von Willebrand Reagent from Dade Behring, respectively. Antigen determination of TAFI was performed with a commercially available kit from Milan Analytica (LaRoche, Switzerland). Other investigations (at baseline and after 6 h) included hematocrit, creatinine, global coagulation tests, and fibrinogen. Statistical probability was assessed with Friedman repeated measures analysis of variance on ranks (ANOVA) followed by pairwise multiple comparison procedures (Student-NewmanKeuls method) for non-normally distributed data, otherwise a one way repeated measures ANOVA was used. For single comparison a paired t-test/a Wilcoxon signed rank test for normally/not normally distributed data was used. A linear Correspondence: Hans Stricker, Author Ospedale La Carità, Department of Medicine, Via all’Ospedale, CH-6600 Locarno, Switzerland. Tel.: +4191 8114549; fax: +4191 8114783; e-mail: hans.stricker@ eoc.ch

Individual dosage of digoxin in patients with heart failure

BACKGROUND After the publication of DIG trial, the therapeutic target of serum digoxin concentration (SDC) for the treatment of heart failure (HF) has been lowered (0.40-1.00 ng/ml). However, the majority of equations to calculate digoxin dosages were developed for higher SDCs. Recently, a new equation was validated in Asian population for low SDCs by Konishi et al., but results in Caucasians are unknown. AIM This study was aimed to test the Konishi equation in Caucasians specifically targeting low SDCs. Furthermore, the Konishi equation was compared with other frequently used equations. DESIGN This was a prospective, multicenter study. METHODS Clinically indicated digoxin was given in 40 HF patients. The dosage was calculated with the Konishi equation. The SDC was measured at 1 and 6 months after starting digoxin. Adherence to digoxin was monitored with a specific questionnaire. RESULTS After exclusion of patients admitting poor adherence, we found a reasonable correlation between predicted and measured SDC (r=0.48; P<0.01) by the Konishi equation. Excluding patients with poor adherence and relevant worsening of renal function, the measured SDC (n=54 measurements) was within the pre-defined therapeutic range in 95% of the cases. The mean, maximal and minimal measured SDC were 0.69±0.19, 1.00 and 0.32 ng/ml, respectively. The correlation was weaker for the Jelliffe, the Koup and Jusko, and the Bauman equations. CONCLUSION This study supports the clinical validity of the Konishi equation for calculating individual digoxin dosage in Caucasians, targeting SDCs according to current HF guidelines.

Venous stasis and thrombin generation

Central Hematology Laboratory, Inselspital, University Hospital, Bern, Switzerland; *Department of Internal Medicine, Ospedale Regionale diLocarno, Switzerland; and Thrombosis Research Laboratory, Inselspital, University Hospital, Bern, SwitzerlandTo cite this article: Colucci G, Stricker H, Roggiani W, Haeberli A, Mombelli G. Venous stasis and thrombin generation. J Thromb Haemost 2004;2: 1008–9.

Haemosiderin-Laden Sputum Macrophages for Diagnosis in Pulmonary Veno-Occlusive Disease

Aims Pulmonary veno-occlusive disease (PVOD) is a rare condition of pulmonary arterial hypertension (PAH), in which post-capillary veins are affected. Since the therapeutic approach in PVOD differs from other forms of PAH, it is crucial to establish the diagnosis. Due to the fact that affected patients are often hemodynamically unstable, minimal invasive procedures are necessary for the diagnostic work-up. Chronic alveolar haemorrhage has been observed during bronchoalveolar lavage in PVOD cases. This study therefore investigates whether signs of alveolar haemorrhage can also be found in the sputum of these patients. Methods and Results Six patients suffering from PVOD were included in this analysis. As controls, patients with idiopathic PAH (n = 11), chronic thromboembolic PH (n = 9) and with sclerodermia-associated PH (n = 10) were assessed. Sputum from every patient was obtained by a non-invasive manner. The amount of haemosiderin-laden macrophages was determined using the Golde score. There were statistically significant more haemosiderin-laden macrophages in the sputum of patients suffering from PVOD as compared to the other groups (P<0.05). Assuming a cut-off of 200 on the Golde score, all of the 6 PVOD patients surpassed this value compared with only 1 out of the 30 cases with precapillary PH. Thus, sensitivity and specificity with respect to the diagnosis of PVOD was 100% and 97%, respectively. Conclusion The content of haemosiderin-laden macrophages in the sputum of patients suffering from PVOD is significantly higher as compared to other forms of PH and may be useful in the non-invasive diagnostic work-up of these patients.

Multicentre observational screening survey for the detection of CTEPH following pulmonary embolism

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of pulmonary embolism. Its incidence following pulmonary embolism is debated. Active screening for CTEPH in patients with acute pulmonary embolism is yet to be recommended. This prospective, multicentre, observational study (Multicentre Observational Screening Survey for the Detection of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Following Pulmonary Embolism (INPUT on PE); ISRCTN61417303) included patients with acute pulmonary embolism from 11 centres in Switzerland from March 2009 to November 2016. Screening for possible CTEPH was performed at 6, 12 and 24 months using a stepwise algorithm that included a dyspnoea phone-based survey, transthoracic echocardiography, right heart catheterisation and radiological confirmation of CTEPH. Out of 1699 patients with pulmonary embolism, 508 patients were assessed for CTEPH screening over 2 years. CTEPH incidence following pulmonary embolism was 3.7 per 1000 patient-years, with a 2-year cumulative incidence of 0.79%. The Swiss pulmonary hypertension registry consulted in December 2016 did not report additional CTEPH cases in these patients. The survey yielded 100% sensitivity and 81.6% specificity. The second step echocardiography in newly dyspnoeic patients showed a negative predictive value of 100%. CTEPH is a rare but treatable disease. A simple and sensitive way for CTEPH screening in patients with acute pulmonary embolism is recommended. Chronic thromboembolic pulmonary hypertension is an uncommon disease; active screening of CTEPH in patients after acute pulmonary embolism should be considered http://ow.ly/mmFI30j3Lca

Acute effect of smoking and of 2 weeks of folate substitution on hemostasis and homocysteine in healthy chronic smokers

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