Paul Bresser

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Results From an International Prospective Registry

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments. # Clinical Perspective {#article-title-40}Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (⩽6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments.

Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury

Background:Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury. Methods:Patients scheduled to undergo an elective surgical procedure (lasting ≥5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes. Results:Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P < 0.01). Levels of tumor necrosis factor α, IL-1α, IL-1β, IL-6, macrophage inflammatory protein 1α, and macrophage inflammatory protein 1β in the bronchoalveolar lavage fluid were not affected by mechanical ventilation. Plasma levels of IL-6 and IL-8 increased with mechanical ventilation, but there were no differences between the two ventilation groups. Conclusion:The use of lower tidal volumes and PEEP may limit pulmonary inflammation in mechanically ventilated patients without preexisting lung injury. The specific contribution of both lower tidal volumes and PEEP on the protective effects of the lung should be further investigated.

Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury.

Background: Alveolar fibrin deposition is a hallmark of acute lung injury, resulting from activation of coagulation and inhibition of fibrinolysis. Previous studies have shown that mechanical ventilation with high tidal volumes may aggravate lung injury in patients with sepsis and acute lung injury. The authors sought to determine the effects of mechanical ventilation on the alveolar hemostatic balance in patients without preexistent lung injury. Methods: Patients scheduled for an elective surgical procedure (lasting ≥ 5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h later bronchoalveolar lavage fluid and blood samples were obtained, and markers of coagulation and fibrinolysis were measured. Results: In contrast to mechanical ventilation with lower tidal volumes and PEEP (n = 21), the use of higher tidal volumes without PEEP (n = 19) caused activation of bronchoalveolar coagulation, as reflected by a marked increase in thrombin–antithrombin complexes, soluble tissue factor, and factor VIIa after 5 h of mechanical ventilation. Mechanical ventilation with higher tidal volumes without PEEP caused an increase in soluble thrombomodulin in lavage fluids and lower levels of bronchoalveolar activated protein C in comparison with lower tidal volumes and PEEP. Bronchoalveolar fibrinolytic activity did not change by either ventilation strategy. Conclusions: Mechanical ventilation with higher tidal volumes and no PEEP promotes procoagulant changes, which are largely prevented by the use of lower tidal volumes and PEEP.

Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2–26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0–46%). Three patients, treated for 3–9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.

Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Results From an International Prospective Registry

Background— Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results— A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90–95), 91% (95% CI, 87–93), and 89% (95% CI, 86–92) in operated patients (n=404), and only 88% (95% CI, 83–91), 79% (95% CI, 74–83), and 70% (95% CI, 64–76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension–targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49–11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76–12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95–1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20–1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36–6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18–3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension–targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions— The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.

Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies

Background: A study was undertaken to determine whether a short course of antibiotic treatment (⩽5 days) is as effective as the conventional longer treatment in acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD). Methods: MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to July 2006. Studies considered eligible were double-blind randomised clinical trials including adult patients ⩾18 years of age with a clinical diagnosis of exacerbation of COPD or chronic bronchitis, no antimicrobial therapy at the time of diagnosis and random assignment to antibiotic treatment for ⩽5 days versus >5 days. The primary outcome measure was clinical cure at early follow-up on an intention-to-treat basis. Results: 21 studies with a total of 10 698 patients were included. The average quality of the studies was high: the mean (SD) Jadad score was 3.9 (0.9). At early follow-up (<25 days), the summary odds ratio (OR) for clinical cure with short treatment versus conventional treatment was 0.99 (95% CI 0.90 to 1.08). At late follow-up the summary OR was 1.0 (95% CI 0.91 to 1.10) and the summary OR for bacteriological cure was 1.05 (95% CI 0.87 to 1.26). Similar summary ORs were observed for early cure in trials with the same antibiotic in both arms and in studies grouped by the antibiotic class used in the short-course arm. Conclusions: A short course of antibiotic treatment is as effective as the traditional longer treatment in patients with mild to moderate exacerbations of chronic bronchitis and COPD.

Systemic and local high mobility group box 1 concentrations during severe infection

Objective: High mobility group box 1 (HMGB1) has been implicated as a late mediator in sepsis. We here sought to determine the extent of HMGB1 release in patients with sepsis stratified to the three most common infectious sources and to determine HMGB1 concentrations at the site of infection during peritonitis or pneumonia. Design: Observational studies in patients and healthy humans challenged with lipopolysaccharide. Setting: Three intensive care units and one clinical research unit. Patients and Subjects: Three patient populations were studied: 1) 51 patients with sepsis due to pneumonia (n = 29), peritonitis (n = 12), or urinary tract infection (n = 10); 2) 17 patients with peritonitis; and 3) four patients with community‐acquired pneumonia. In addition, eight healthy subjects were studied after intravenous injection of lipopolysaccharide (4 ng/kg). Interventions: One population of healthy volunteers received lipopolysaccharide intravenously. Measurements and Main Results: Patients with severe sepsis due to pneumonia displayed elevated circulating HMGB1 concentrations at both days 0 and 3 after inclusion. Patients with sepsis due to peritonitis had elevated HMGB1 levels at day 0 but not at day 3, whereas urinary tract infection was associated with a delayed HMGB1 response, with elevated levels only at day 3. HMGB1 concentrations did not differ between survivors and nonsurvivors and were not correlated to either disease severity or concurrently measured cytokine levels. In line with these observations, although intravenous lipopolysaccharide injection clearly elevated plasma cytokine levels, HMGB1 remained undetectable. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were more than ten‐fold higher than in concurrently obtained plasma. In pneumonia patients, HMGB1 levels were higher in bronchoalveolar lavage fluid obtained from the site of infection than in lavage fluid from healthy controls. Conclusions: In severe sepsis, the kinetics of HMGB1 release may differ depending on the primary source of infection. In patients with severe infection, HMGB1 release may predominantly occur at the site of infection.

Right Ventricular Failure Following Chronic Pressure Overload Is Associated With Reduction in Left Ventricular Mass : Evidence for Atrophic Remodeling

OBJECTIVES We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. BACKGROUND The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. METHODS We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. RESULTS At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. CONCLUSIONS RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.

Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down's syndrome

Pulmonary arterial hypertension associated with congenital heart disease caused by systemic-to-pulmonary shunting was associated with a high risk of morbidity and mortality. In this retrospective study, the longer term treatment effect of bosentan on exercise capacity and quality of life (QoL) were evaluated in 58 adult patients (>18 years) with pulmonary arterial hypertension associated with congenital heart disease, including patients with Downs syndrome. All patients were evaluated at baseline and during follow-up using laboratory tests, 6-minute walk test, QoL questionnaires, and Doppler echocardiography. Treatment efficacy was analyzed separately for patients without (n = 30) and with Downs syndrome (n = 28). Median follow-up of all patients treated with bosentan was 22 months (range 3 to 36). In patients without Downs syndrome, mean 6-minute walk distance increased from 427 +/- 97 to 461 +/- 104 m (p <0.01) after 6 months of treatment, followed by a gradual return to baseline and disease stabilization. QoL improved significantly during treatment and was maintained during 18 months of follow-up (p <0.05). In patients with Downs syndrome, 6-minute walk distance and QoL were stable during treatment. In conclusion, findings suggested that in patients without Downs syndrome, longer term bosentan treatment resulted in a persistent improvement in QoL and stabilization of exercise capacity.

Lung Inflammation Induced by Lipoteichoic Acid or Lipopolysaccharide in Humans

RATIONALE Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways. OBJECTIVES We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria). METHODS Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation-dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured. MEASUREMENTS AND MAIN RESULTS Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release. CONCLUSIONS This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infection.