Stefan Guth

Treatment of fungal infections in hematology and oncology: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

The Infectious Diseases Working Party of the German Society of Haematology and Oncology presents their guidelines for the treatment of fungal infections in patients with hematological and oncological malignancies. These guidelines are evidence-based, considering study results, case reports and expert opinions, using the evidence criteria of the Infectious Diseases Society of America (IDSA). The recommendations for major fungal complications in this setting are summarized here. The primary choice of therapy for chronic candidiasis should be fluconazole, reserving caspofungin or amphotericin B (AmB) for use in case of progression of the Candida infection. Patients with candidemia (except C. krusei or C. glabrata) who are in a clinically stable condition without previous azole prophylaxis should receive fluconazole, otherwise AmB or caspofungin. Voriconazole is recommended for the first-line treatment of invasive aspergillosis. The benefit of a combination of AmB and 5-flucytosine has not been demonstrated except in patients with cryptococcal meningitis. Mucormycosis is relatively rare. The drug therapy of choice consists of AmB, desoxycholate or liposomal formulation, in the highest tolerable dosage. Additional surgical intervention has been shown to achieve a lower fatality rate than with antifungal therapy alone. The role of interventional strategies, cytokines/G-CSF, and granulocyte transfusions in invasive fungal infections are further reviewed. These guidelines offer actual standards and discussions on the treatment of oropharyngeal and esophageal candidiasis, invasive candidiasis, cryptococcosis and mould infections.

Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations of the Cologne Consensus Conference 2011 ✩

In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added.

Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy

BACKGROUND In primary pulmonary hypertension, aerosolized prostanoids selectively reduce pulmonary vascular resistance and improve right ventricular function. In this study, hemodynamic effects of inhaled iloprost, a stable prostacyclin analogue, were evaluated in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and early after pulmonary thromboendarterctomy (PTE). METHODS Ten patients (mean age 49 years old [32 to 70 years old], New York Heart Association functional class III and IV) received a dose of 33 micro g aerosolized iloprost immediately before surgery (T1), after intensive care unit admission (T2), and 12-hours postoperatively (T3). Effects on pulmonary and systemic hemodynamics and gas exchange were recorded and compared with preinhalation baseline values. RESULTS Preoperatively, inhaled iloprost did not significantly change mean pulmonary artery pressure (mPAP), cardiac index (CI), or pulmonary vascular resistance (PVR). Postoperatively, inhaled iloprost induced a significant reduction of mPAP and PVR and a significant increase of CI at T2 and T3. Preinhalation versus postinhalation PVR was as follows: at T1, 847 versus 729 dynes. s. cm(-5), p = 0.45; at T2, 502 versus 316 dynes. s. cm(-5), p = 0.008; and at T3, 299 versus 227 dynes. s. cm(-5), p = 0.004. CONCLUSIONS In patients with CTEPH, inhalation of iloprost elicits no significant pulmonary vasodilation before surgery, and may have detrimental effects on systemic hemodynamics. Postoperatively, it significantly reduces mPAP and PVR, and enhances CI. Following PTE, inhalation of iloprost is useful to improve early postoperative hemodynamics.

Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.

Background Aim of this prospective study was to evaluate the effects of exercise training in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH). Methods Thirty-five consecutive patients with invasively confirmed inoperable or residual CTEPH (16 women;19 men; mean age 61±15 years, mean pulmonary artery pressure, 63±20 mmHg; primary inoperable n = 33, persisting pulmonary hypertension after pulmonary endarterectomy n = 2) on stable disease-targeted medication received exercise training in-hospital for 3 weeks and continued at home for 15 weeks. Medication remained unchanged during the study period. Efficacy parameters have been evaluated at baseline, after 3 and 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of median 36.4 months (interquartile range 26.6–46.6 months). Results All patients tolerated exercise training without severe adverse events. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 61±54 meters after 3 weeks (p<0.001) and by 71±70 meters after 15 weeks (p = 0.001), as well as scores of quality-of-life questionnaire, peak oxygen consumption and maximal workload. NT-proBNP improved significantly after 3 weeks of exercise training (p = 0.046). The 1-year survival rate was 97%, 2-year survival rate was 94% and the 3-year-survival 86% respectively. Conclusion Training as add-on to medical therapy may be effective in patients with CTEPH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further multicentric randomized controlled studies are needed to confirm these promising results. Trial Registration ClinicalTrials.gov NCT01398345

Aprotinin inhibits leukocyte–endothelial cell interactions after hemorrhage and reperfusion

BACKGROUND The serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte-endothelial cell interactions after ischemia and reperfusion. METHODS The effects of aprotinin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion. RESULTS Intravenous bolus administration of aprotinin treatment (20,000 U/kg) significantly reduced leukocyte rolling from 55 +/- 8 to 17 +/- 3 cells/min (p < 0.01) and adherent cells from 12 +/- 2 to 7 +/- 1.4 cells (p < 0.05) along the venous endothelium of the rat mesentery after thrombin activation. In addition, aprotinin pretreatment significantly inhibited transmigration of leukocytes from 11.3 +/- 1.2 to 6.0 +/- 1.1 cells (p < 0.05) through the microvascular endothelial wall. Similarly, aprotinin decreased leukocyte-endothelium interaction after hemorrhagic shock. Moreover, immunohistochemistry demonstrated that aprotinin significantly attenuated P-selectin expression by the intestinal vascular endothelium. CONCLUSIONS. Our data demonstrate that aprotinin potently inhibits recruitment of leukocytes in the microvasculature by interfering with endothelial cell-polymorphonuclear neutrophil interaction, and is a potent endothelial protective agent in clinically relevant doses. Thus, aprotinin pretreatment may be useful for primary prevention of inflammatory tissue injury mediated by ischemia-reperfusion injury such as shock, trauma, open heart operation, or other extensive vascular surgical procedures.

Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience

Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention. BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure-related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%. BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk–benefit assessments. BPA improves haemodynamics and exercise capacity in patients with inoperable CTEPH but complications are not uncommon http://ow.ly/mMYY30b1rch

Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND Pulmonary endarterectomy (PEA) is a curative treatment option for more than 60% of patients with chronic thromboembolic pulmonary hypertension (CTEPH). For selected inoperable patients, interventional balloon pulmonary angioplasty (BPA) has recently been established in addition to medical treatment. This approach disrupts scar tissue occluding the pulmonary arteries, leading to an improvement in parenchymal perfusion. CTEPH is occasionally heterogeneous, with operable disease on one side but peripheral, inoperable changes on the contralateral side. Performing unilateral PEA (on the operable side only) in these patients may lead to a worse hemodynamic outcome and increased mortality compared with patients who that can be surgically corrected bilaterally. We sought to determine the feasibility, safety, and benefits of BPA applied to the contralateral lung in several patients with predominantly unilateral disease that was amenable to treatment by PEA. METHODS Standard unilateral PEA in deep hypothermic circulatory arrest was performed in 3 CTEPH patients with poor pulmonary hemodynamics, and inoperability of the contralateral pulmonary artery obstructions was confirmed. The inoperable side was treated by BPA. The intervention was performed during the rewarming phase of cardiopulmonary bypass. RESULTS A dramatic improvement in pulmonary hemodynamics, with a mean reduction in pulmonary vascular resistance of 842 dyne · sec/cm(5), was achieved in all patients. World Health Organization Functional Class was also significantly improved at the midterm follow-up. CONCLUSIONS The combination of surgical PEA and interventional BPA is a new treatment option for highly selected high-risk CTEPH patients. A multidisciplinary CTEPH expert team is a basic pre-requisite for this complex concept.

Pulmonary Hemodynamic Response to Exercise in Chronic Thromboembolic Pulmonary Hypertension before and after Pulmonary Endarterectomy.

Background: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension. Objective: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA. Methods: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed. Results: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 ± 7.6 to 53.8 ± 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 ± 5.6 to 30.3 ± 9.6 mm Hg, cardiac output (CO) from 4.4 ± 0.8 to 6.5 ± 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 ± 4.9 to 20.7 ± 12.7 mm Hg. Post-PEA mPAP increased from 23.7 ± 6.6 at rest to 43.2 ± 7.1 mm Hg, while CO increased to a higher extent from 5.1 ± 0.9 to 8.4 ± 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028). Conclusions: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA.

Divinyl Sulfone Cross-Linked Hyperpolymeric Human Haemoglobin as an Artificial Oxygen Carrier in Anaesthetized Spontaneously Breathing Rats

The production of hyperpolymer haemoglobins, exhibiting sufficiently low colloid osmotic pressure and sufficiently low viscosity is possible, even in concentrations, and therewith oxygen transport capacity, high enough to supply an organism adequately with oxygen. Such hyperpolymers, when infused, are tolerated by anaesthetized rats in acute blood exchange experiments. Ex vivo determinations of plasma colloid osmotic pressure and both, plasma and whole blood kinematic viscosity during blood exchange showed, that corresponding properties found in vivo were refound within the animal. Furthermore we could show that hyperpolymers produced from desoxygenated human haemoglobin with divinyl sulfone as a crosslinker take part in tissue supply of oxygen to a substantial degree (about 50%) without and with increased inspiratory oxygen fraction, demonstrating the principal ability of hyperpolymers to transport oxygen in blood and to deliver it to tissues.

N-terminal pro–B-type natriuretic peptide for monitoring after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

BACKGROUND Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success. METHODS In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU. RESULTS The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm5; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (rrs = 0.43, p = 0.002) and PVR (rrs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77). CONCLUSIONS Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring.