Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.

Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.

Clinical significance of coronary flow reserve: effect of papaverine and exercise.

BACKGROUND: The clinical significance of coronary flow reserve (CFR) was evaluated after pharmacological (papaverine) and physiological (exercise) vasodilation in patients with coronary artery disease (CAD). METHODS: CFR was determined using parametric imaging in 10 patients with normal coronary arteries (group 1) and in 10 with CAD (group 2). Contrast density and mean appearance time were measured (region of interest = 249 pixels) in the perfusion beds of the left circumflex and the left anterior descending coronary arteries at rest, 45 s after 10 mg intracoronary papaverine, and during supine bicycle exercise. CFR was calculated from coronary perfusion after papaverine divided by perfusion at rest and coronary perfusion during exercise divided by perfusion at rest. Perfusion zones in patients with CAD were subdivided into regions supplied by a non-stenosed (group 2a) and a stenosed (group 2b) coronary artery. RESULTS: In control patients, heart rate increased from 75 beats/min at rest to 125 beats/min during exercise, and in patients with CAD from 63 to 107 beats/min, respectively. Mean aortic pressure showed a significant increase during exercise in both groups. Mean pulmonary artery pressure increased significantly during exercise from 19 to 28 mmHg in control patients and from 22 to 42 mmHg in the CAD group (P < 0.001). Coronary driving pressure (mean aortic minus diastolic pulmonary artery pressure) tended to increase during exercise in the control group (from 90 to 101 mmHg, NS) and remained nearly unchanged in patients with CAD (from 92 to 94 mmHg, NS). In the control group, CFR was significantly higher during exercise than after papaverine (4.0 versus 3.5, respectively; P < 0.01). However, coronary resistance (coronary driving pressure divided by coronary flow index) was similar after papaverine and during exercise. In patients with CAD, papaverine-dependent CFR was significantly reduced in the perfusion zone of the stenosed (2.1) but not of the non-stenosed coronary artery (3.0). In contrast, CFR during exercise was significantly decreased in both perfusion zones (2.5 in non-stenosed arteries and 1.5 in stenosed vessels). CONCLUSIONS: In control patients, CFR is slightly but significantly larger during exercise than after papaverine because of the exercise-induced increase in coronary driving pressure. In contrast, CFR is smaller during exercise than after papaverine in patients with CAD, most probably as a result of secondary mechanisms such as exercise-induced narrowing of stenosed vessels or an increase in extravascular resistance. Thus, CFR based on papaverine appears to be of limited value for assessing the functional significance of a stenotic lesion.

Determination of ketoconazole in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

A simple, rapid and specific high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) has been developed and validated for the determination of ketoconazole in human plasma. The method used diethyl ether to extract the ketoconazole and the internal standard (I.S.) R51012 from alkalinized plasma sample. The LC separation was on a C(18) column (50 x 3 mm, 5 microm) using acetonitrile-water-formic acid (75:25:1, v/v/v) mobile phase. The retention times were approximately 1.8 min for both ketoconazole and the I.S. The MS-MS detection was by monitoring 531.2-->82.1 (m/z) for ketoconazole, and 733.5-->460.2 (m/z) for the I.S. The dynamic range was from 20.0 to 10000 ng/ml based on 0.1 ml plasma, with linear correlation coefficient of > or =0.9985. The run time was 2.5 min/injection. The recoveries of ketoconazole and the I.S. were 102 and 106%, respectively. The precision and accuracy of the control samples were with the relative standard deviations (RSDs) of < or =4.4% (n=6) and the relative errors (REs) from -0.6 to 1.4% for intra-day assay, and < or =8.6% RSD (n=18) and -1.4 to 0.9% RE for inter-day assay. The partial volume tests demonstrated good dilution integrity. Three freeze-thaw cycles, keeping plasma samples at ambient for 24 h, storing extracted samples at ambient for 24 h, and storing frozen plasma samples at approximately -20 degrees C for up to 2 months did not show substantial effects.

[Digital subtraction angiography for the assessment of myocardial perfusion]. / Digitale Subtraktionsangiographie zur Bestimmung der Myokardperfusion.

Coronary angiography does not only permit to evaluate the severity of coronary disease but also to assess coronary flow reserve in various myocardial perfusion areas by digital processing. Use of colour flow mapping allows the assessment of both, density as well as distribution velocity of contrast-medium (= parametric imaging). The advantage of this technique is given by the possibility to assess coronary flow reserve not only at rest but also under physiologic situations such as bicycle ergometry. Clinical investigations have shown that coronary flow reserve determined after papaverine administration does not correlate with physiologic conditions such as physical exercise.

Applying brakes to the runaway American health care system. A proposed agenda.

The American health care system, and especially its cost, is out of control, inhibiting access to care for many, lessening quality of care for some, and creating an almost palpable angst among physicians and others concerned with this enormous national problem. Increased health care rationing in the next decade is inevitable, yet it must not be done with quick fixes, short-term solutions, and patchwork reform of our present system. That would create worse problems for health care in the 21 st century and is clearly unacceptable. We recommend that President Bush appoint a blue-ribbon commission to study our present system in depth, then offer alternative solutions for its many problems. He should look closely at at least the following nine issues: controlling medical technology, instituting a resource-based relative value system for physician reimbursement, establishing an ongoing national medical ethics commission, instituting national malpractice reform, implementing universal medical coverage with Medicare/Medicaid reform, establishing a national health services research and planning institute, reducing the nation's health care facilities, reducing physician supply, and improving health promotion/disease prevention education.

KIE: Two physicians propose an approach to what they see as the inevitable increase in health care rationing in the United States. Davies and Felder recommend that the President appoint a commission to study in depth the current health care system and to offer solutions for its problems. They suggest nine issues that they believe the commission should address: (1) controlling medical technology; (2) developing a resource-based relative value system for reimbursing physicians; (3) establishing a national medical ethics commission; (4) reforming malpractice laws; (5) instituting universal health care coverage and reforming Medicare and Medicaid; (6) establishing a national health services research and planning institute; (7) regulating health care facilities; (8) reducing the supply of physicians; and (9) educating the public about health and disease.

Diastolic function in valvular heart disease.

Diastolic dysfunction in patients with valvular heart disease is characterized by an impaired isovolumic relaxation, a normal or even enhanced early diastolic filling rate and an increased myocardial stiffness. These abnormalities do not depend on coexisting systolic dysfunction but are often combined. Several mechanisms are responsible for the occurrence of diastolic dysfunction, such as increased wall stress, altered myocardial structure, subendocardial hypoperfusion and/or diastolic calcium overload. Postoperative regression of myocardial hypertrophy is beneficial in regard to wall stress, subendocardial hypoperfusion and calcium overload but diastolic dysfunction might become worse after valve replacement due to a relative increase in interstitial fibrosis consequent to the decrease in myocyte mass (= myocardial remodeling). Persisting diastolic dysfunction with a substantial rise in left ventricular filling pressure can be observed during dynamic exercise in postoperative patients with preoperative severe pressure overload hypertrophy. Thus, diastolic dysfunction can be present as a primary derangement of cardiac function and can be unmasked as an abnormal response of diastolic filling pressure during exercise.

Altitude diuresis: endocrine and renal responses to acute hypoxia of acclimatized and non-acclimatized subjects.

As a result of our recently published studies we have thought that altitude diuresis resulting from hypoxic stimulation of the arterial chemoreceptors reduces the cardiac volume overload. To test this hypothesis, cardiovascular, endocrine and renal responses to stepwise acute exposure to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers a mean of 24 days, SD 11, after descending from Himalayan altitudes of at least 4,000 m, with those found in ten non-acclimatized recumbent volunteers. The results showed that natriuresis and diuresis typified the renal responses to altitude exposure of both the acclimatized as well as non-acclimatized subjects, as long as altitude was well tolerated. It was concluded that the renal effects were mediated by atrial natriuretic peptide release and slight suppression of arginine-vasopressin (AVP) secretion, that the increased urine flow at altitude offset the cardiac (volume) overload resulting from hypoxic stimulation of the arterial chemoreceptors, and that enhanced AVP secretion, as found in the non-acclimatized subjects at and above 4,000 m, coincided with subjective and objective distress, i.e. with inadequate altitude adjustment owing to insufficient chemoreflex effects and central hypoxia.

Respiratory, circulatory and neuropsychological responses to acute hypoxia in acclimatized and non-acclimatized subjects.

Respiratory, circulatory and neuropsychological responses to stepwise, acute exposure at rest to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers 24 days, SD 11 after descending from Himalayan altitudes of at least 4,000 m with those found in ten non-acclimatized recumbent volunteers. The results showed that hypoxic hyperpnoea and O2 consumption at high altitudes were significantly lower in the mountaineers, their alveolar gases being, however, similar to those of the control group. In the acclimatized subjects the activation of the cardiovascular system was less marked, systolic blood pressure, pulse pressure, heart rate and thus (calculated) cardiac output being always lower than in the controls; diastolic blood pressure and peripheral vascular resistance, however, were maintained throughout in contrast to the vasomotor depression induced by central hypoxia which occurred in the non-acclimatized subjects at and above 4,000 m [alveolar partial pressure of O2 less than 55-50 mmHg (7.3-6.6 kPa)]. It was concluded that in the acclimatized subjects at high altitude arterial vasodilatation and neurobehavioural impairment, which in the non-acclimatized subjects reflect hypoxia of the central nervous system, were prevented; that acclimatization to high altitude resulted in a significant improvement of respiratory efficiency and cardiac economy, and that maintaining diastolic blood pressure (arterial resistance) at and above 4,000 m may represent a useful criterion for assessing hypoxia acclimatization.

Coronary vasomotion and coronary flow reserve during exercise.

Coronary vasomotion and coronary blood flow are important determinants of myocardial perfusion in patients with coronary artery disease. New digital angiographic techniques allow to study, not only the dimensions of a stenotic lesion (quantitative coronary arteriography), but also coronary flow reserve (parametric imaging). In a preliminary study both techniques were combined and coronary dimensions, as well as coronary flow reserve were determined in 15 patients (seven normals and eight patients with coronary artery disease) at rest, 45 s after 10 mg i.c. papaverine, during two levels of supine bicycle exercise, as well as 5 min after 1.6 mg sublingual nitroglycerin. Our results show that with modern digital subtraction techniques, not only stenosis geometry, but also coronary flow reserve can be determined at rest and during exercise conditions.