Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Later management of documented ischaemic heart disease: secondary prevention and rehabilitation.

Patients may present with a variety of syndromes related to ischaemic heart disease. These include unstable or stable angina pectoris, acute myocardial infarction, and occasionally cardiac failure without prior anginal pain or infarction. For the purposes of this review, it will generally be assumed that the condition has been stabilised, though one important aspect of the rehabilitation process is the recognition of continuing or recurrent problems such as angina pectoris and cardiac decompensation. This should then be followed by appropriate intervention. The key components of post-hospital management of such patients are: (i) support; (ii) education; (iii) assessment; (iv) intervention (if necessary); (v) therapy; and (vi) lifestyle modification.

Chronic non-neurological toxicity from volatile substance abuse.

1. Most of the evidence for chronic non-neurological toxicity from volatile substance abuse is derived from case reports. 2. Factors important in assessing these reports are the marked variations in exposure conditions and in the composition of the products abused. 3. In a young and otherwise healthy population, any chronic organ toxicity arising from VSA has to be gross in order to become clinically apparent. This may partially explain the relatively low incidence of reporting. 4. Toluene and the chlorinated hydrocarbons 1,1,1-trichloroethane and trichloroethylene can cause permanent damage to the kidney, liver, heart and lung, in certain volatile substance abusers.

Cardiac hypertrophy in diabetic nephropathy: an echocardiographic study.

Echocardiography was used to study the prevalence and severity of left ventricular hypertrophy in patients with established diabetic nephropathy (persistent proteinuria for at least 2 y plus severe retinopathy). Fifteen patients had mild renal impairment (serum creatinine less than 150 mumol l-1), 14 patients had moderate renal impairment (serum creatinine 150-400 mumol l-1), and 20 patients had severe renal impairment (serum creatinine greater than 400 mumol l-1). Thirty-six of the 49 (73%) were on anti-hypertensive treatment, despite which mean blood pressure was 161 +/- 25/89 +/- 9 (+/- SD) mmHg. Left ventricular hypertrophy was demonstrated in 42 of the 49 patients (85%), and increased in severity with increasing renal impairment. Interventricular septal + left ventricular posterior wall thickness was 25 +/- 3 mm in those with mild renal impairment, 28 +/- 6 mm in those with moderate renal impairment and 30 +/- 4 mm in those with severe renal impairment. The most severe left ventricular hypertrophy was seen in the Afro-Caribbean patients. Left ventricular hypertrophy was present even in those with marginally raised blood pressure and was related to age and serum creatinine but not to present blood pressure or duration of proteinuria.

Chronic cardiac toxicity after inhalation of 1,1,1-trichloroethane.

Two patients showed evidence of chronic cardiac toxicity after repeated exposure to 1,1,1-trichloroethane. In both cases there was circumstantial evidence of a deterioration after routine anaesthetic use of the related compound halothane. An adolescent boy who sniffed trichloroethane presented with multiple ventricular arrhythmias during tonsillectomy. Follow up showed mild chronic left ventricular impairment. A 54 year old man had repeated industrial exposure to trichloroethane and deteriorated from mild stable cardiac failure to end stage cardiac failure after halothane anaesthesia for herniorrhaphy. Chronic cardiac toxicity is a previously unreported feature of this type of solvent exposure. Related compounds such as halothane may have a toxic interaction after exposure to trichloroethane.

In support of cardiac chronotropic beta 2 adrenoceptors.

The effects of atenolol (50 mg) and propranolol (40 mg) on exercise- and isoproterenol-induced heart rate increments were studied in 9 male volunteers. Propranolol reduced maximal heart rate from 187 +/- 4 to 146 +/- 7 beats/min and atenolol reduced it to 138 +/- 6 beats/min. There was no difference between the drugs at any point during exercise. Isoproterenol sensitivity was measured as the dose of isoproterenol required to increase resting heart rate by 25 beats/min (CD-25). Propranolol increased the CD-25 from 1.8 +/- 0.3 micrograms after placebo to 39 +/- 8 micrograms and atenolol increased the CD-25 to 8 +/- 2 micrograms. The increase by propranolol was significantly greater than that of atenolol. Intravenous atropine (0.04 mg/kg) did not alter the isoproterenol CD-25 during placebo or atenolol. The CD-25 with propranolol decreased after atropine (39 +/- 8 versus 25 +/- 5 micrograms) and was due to diminished plasma propranolol concentrations as the drug sensitivity (measured by Ka) was unchanged before (12 +/- 2 ml/ng) and after (10 +/- 3 ml/ng) atropine. These data support the hypothesis that moderate exercise is primarily a beta 1-mediated response and therefore equally antagonized by cardioselective and nonselective blockers, but that isoproterenol stimulates both beta 1 and beta 2 receptors. The greater ability of the nonselective agent to antagonize isoproterenol tachycardia with no significant change after atropine suggests the presence of cardiac beta 2 chronotropic receptors. The physiologic and pathologic importance of these receptors has yet to be determined.

Drug treatment of primary pulmonary hypertension.

Primary pulmonary hypertension is a rare but difficult-to-manage condition. Adequate clinical trials of agents used in its treatment have not been performed. A variety of drugs have been reported to provide benefit in patients with primary pulmonary hypertension, including beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, and vasodilators such as isosorbide dinitrate, diazoxide, hydralazine, angiotensin converting enzyme inhibitors, prostaglandins and calcium antagonists. Calcium antagonists appear to offer the most promise, although treatment failures have occurred with them as well as with all other drugs used in this condition. In the absence of a specific treatment for primary pulmonary hypertension, several of the agents listed above should be tried before accepting therapeutic failure. Invasive investigation is necessary to adequately monitor the acute response to therapy. Whether combination therapy with 2 or more drugs might improve the response to treatment is an area worthy of further research.

Milrinone in heart failure. Acute effects on left ventricular systolic function and myocardial metabolism.

Milrinone, a new bipyridine compound related to amrinone, is a potent non-adrenergic inotrope in experimental preparations and also shows vasodilator activity. In the present study the haemodynamic and metabolic effects of milrinone were evaluated in 12 patients with congestive heart failure. Milrinone 5 mg given orally produced a sharp reduction in left ventricular end diastolic pressure without significantly affecting stroke volume. The improvement in left ventricular function was due to a combination of vasodilation and positive inotropism. Thus small reductions in blood pressure and systemic vascular resistance were associated with increments in the isovolumic indices of left ventricular function. The relation between left ventricular end systolic pressure and dimension was displaced leftwards and downwards. Only reductions in left ventricular cavity dimension were statistically significant, however. Though myocardial oxygen consumption did not change significantly, it tended to increase whereas lactate consumption tended to decrease. This trend towards oxygen imbalance suggests the need for caution in the use of milrinone in patients with severe coronary artery disease.

Beta 1-selective and non-selective beta-adrenoceptor blockade, anaerobic threshold and respiratory gas exchange during exercise.

The effect of oral doses of the beta 1-selective adrenoceptor antagonist atenolol (50 mg), the non-selective antagonist propranolol (40 mg) and placebo was investigated during exercise in a crossover comparison in six healthy but untrained subjects. Descriptors of ventilation, respiratory gas exchange, and arterialized blood lactate and glucose were obtained during steady state bicycle ergometric exercise at 20% and 60% of the subjects' previously determined maximal oxygen uptake (VO2 max). At these work intensities, the previously reported increase of respiratory exchange ratio (RER) during non-selective beta-adrenoceptor blockade was found to be trivial (placebo = 0.96 +/- 0.03 s.e. mean; propranolol = 0.97 +/- 0.01; atenolol = 0.97 +/- 0.04; 60% VO2 max, 10 min exercise) and only present during the early minutes of effort. Oxygen uptake and carbon dioxide production did not differ between treatments. Both drugs produced highly significant falls in peak expiratory flow (PEF) rates and tidal volume (VT) which were compensated by an increase in respiratory rate. PEF, 60% VO2 max: placebo = 3.8 +/- 0.3 l/s; propranolol 3.6 +/- 0.3 l/s (P less than 0.03); atenolol 3.1 +/- 0.3 l/s (P less than 0.01). VT, 60% VO2 max: placebo 2.0 +/- 0.1 l; propranolol 1.8 +/- 0.21 (P less than 0.05); atenolol 1.7 +/- 0.1 1 (P less than 0.01). Arterialized lactate was significantly elevated during work at 20% and 60% VO2 max, but rose progressively at the 60% VO2 max load. Ventilation, oxygen uptake and ventilatory equivalent for carbon dioxide also rose progressively at this workload. Ventilatory equivalent for oxygen showed no significant rise.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta 1-selective and nonselective beta-adrenoceptor blockade during exercise conditioning in healthy adults.

The interaction of beta 1-selective (cardioselective) and nonselective beta-adrenoceptor blockade with exercise conditioning was investigated in 30 healthy adult persons. A double-blind protocol was used and the effects of atenolol (100 mg/day), propranolol (80 mg twice daily), and placebo were studied by treadmill testing (Bruce protocol) before and after a 2-month supervised program of dynamic exercise. Exercise tolerance was assessed by time and work performed to exhaustion. Subjects who received propranolol, but not those who received atenolol or placebo, showed an acutely impaired exercise tolerance after drug administration but before training (-8 +/- 4%, p less than 0.05). All 3 groups showed significantly improved exercise capacity following training after drug treatment had been discontinued (atenolol, 22 +/- 6% improvement; propranolol, 13 +/- 6%; placebo, 10 +/- 3%). However, when tested while still receiving medication, subjects who received propranolol failed to show significant improvement in exercise capacity. In contrast, patients who received atenolol and placebo improved significantly. The data indicate that enhancement of maximal work capacity by exercise conditioning can occur despite administration of either beta 1-selective or nonselective beta-adrenoceptor antagonists. However, the fatiguing effects of propranolol that were evident when work performance during propranolol therapy was compared with work performance while not receiving propranolol before the training program persists after training and may limit the net improvement in work capacity induced by exercise conditioning compared with the pretraining state.

Hemodynamic and metabolic responses to exercise after adrenoceptor blockade in humans.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metabolic responses to acute exercise 2 h after prolonged prior exercise to induce skeletal muscle glycogen depletion, enhancing the dependence on hepatic glucose output and circulating free fatty acids (FFA). Plasma catecholamines were higher during exercise after, as opposed to before, glycogen depletion and were elevated further by all three drugs. Propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. Atenolol reduced systolic blood pressure and did not change diastolic blood pressure. Both beta-blockers reduced FFA levels, but only propranolol lowered plasma glucose relative to placebo during exercise after glycogen depletion. In contrast, prazosin reduced systolic and diastolic blood pressures and resulted in elevated FFA and glucose levels. The results indicate important differences in the hemodynamic effects of beta 1-selective vs. nonselective beta-blockade during exercise after skeletal muscle glycogen depletion. Furthermore they confirm the importance of beta 2-mediated hepatic glucose production in maintaining plasma glucose levels during exercise. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamines, which in the absence of blockade of hepatic beta 2-receptors produces elevation of plasma glucose. The results suggest there is little role for alpha 1-mediated hepatic glucose production during exercise in humans.

Demonstration of beta adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic, radioligand binding and adenylate cyclase activation studies.

The postulated beta adrenoceptor blocking properties of the new antiarrhythmic drug propafenone were studied by in vivo comparison against placebo and propranolol in the antagonism of both exercise- and isoproterenol-induced tachycardia and by in vitro radioligand binding studies of animal and human left ventricular muscle membrane preparations. Interaction with frog erythrocyte membrane adenylate cyclase was also investigated. In the clinical studies, a double blind crossover comparison of oral propafenone (300 mg), propranolol (40 mg) and placebo indicated significant antagonism of chronotropic response to isoproterenol 2 hr postdose with dose ratios of 4.1 +/- 1.3 (mean +/- S.E.M.) for propafenone and 16.8 +/- 5.1 for propranolol. Chronotropic response to exercise was modestly reduced by propafenone. Analysis of the binding of [125I]iodocyanopindolol to human left ventricular membranes revealed specific beta adrenoceptor competition by propafenone with an EC50 of 111 +/- 13 nM. Propranolol EC50 was 2.4 +/- 0.2 nM in this system. Competitive inhibition of isoproterenol-stimulated frog erythrocyte membrane adenylate cyclase activity was also obtained with propafenone. The ratio of affinities (calculated from the apparent dissociation constant; KD) for propranolol-propafenone was 1:40 for the in vivo study and 1:50 for the in vitro system. Propafenone is a specific antagonist of the human beta adrenoceptor and this action can be demonstrated during in vivo study in human subjects. At clinical dosages it appears likely that it will achieve a modest degree of beta blockade which may contribute to its antiarrhythmic effect.

Hemodynamic and metabolic responses to exercise after alpha 1-, beta 1-, and nonselective beta-adrenoceptor blockade in man.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study. The study involved measurement of the hemodynamic and metabolic responses to exercise after heavy exercise in order to induce skeletal muscle glycogen depletion and thus enhance the dependence on hepatic glucose output and circulating free fatty acids. Catecholamine responses to exercise were enhanced by glycogen depletion and by both beta-blocking drugs. Catecholamine levels were highest with propranolol; as a consequence, at high work loads, propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. At high work loads, atenolol reduced systolic blood pressure but did not change diastolic blood pressure. Both beta blockers reduced free fatty acid levels, but only propranolol accelerated the fall of plasma glucose levels during "glycogen-depleted" exercise. In contrast, during exercise prazosin reduced systolic and diastolic blood pressures, and elevated heart rate and plasma catecholamines, particularly noradrenaline. Concomitantly, prazosin raised free fatty acid and lactate levels, and increased the plasma glucose level at a time when placebo therapy resulted in a steady fall in glucose levels. The results indicate important differences in the hemodynamic effects of cardioselective versus nonselective beta-blockade during long-term (or glycogen-depleted) exercise. The importance of beta 2-mediated hepatic glycogenolysis in man is confirmed. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamine levels. There is no indication of an important role for an alpha 1-mediated mechanism in hepatic glucose production in man.

Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.

The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and beta 1-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of beta 1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 +/- 162, 640 +/- 190 and 584 +/- 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 +/- 2.1 to 97.7 +/- 2.7 mg/dl) and on atenolol (from 99.7 +/- 2.2 to 102.1 +/- 4.8 mg/dl), but fell on propranolol (from 96.4 +/- 1.9 mg/dl to 87.2 +/- 2.5 mg/dl, p less than 0.01). These results indicate that blockade of vascular smooth muscle beta 2 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through beta 1-adrenoceptor mechanisms, whereas beta 2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.

Evidence for cardiac beta 2-adrenoceptors in man.

We compared the effects of single doses of 50 mg atenolol (cardioselective), 40 mg propranolol (nonselective), and placebo on both exercise- and isoproterenol-induced tachycardia in two experiments involving nine normal subjects. Maximal exercise heart rate was reduced from 187 +/- 4(SEM) after placebo to 146 +/- 7 bpm after atenolol and 138 +/- 6 bpm after propranolol, but there were no differences between the drugs. The effects on isoproterenol tachycardia were determined before and after atropine (0.04 mg/kg IV). Isoproterenol sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm (CD25) and this was increased from 1.8 +/- 0.3 micrograms after placebo to 38.9 +/- 8.3 micrograms after propranolol and 8.3 +/- 1.7 micrograms after atenolol. The difference in the effects of the two was significant. After atropine the CD25 was unchanged after placebo (2.3 +/- 0.3 micrograms) and atenolol (7.7 +/- 1.3 micrograms); it was reduced after propranolol (24.8 +/- 5.0 micrograms), but remained different from atenolol. This change with propranolol sensitivity was calculated as the apparent Ka, this was unchanged by atropine (11.7 +/- 2.1 and 10.1 +/- 2.5 ml/ng). These data are consistent with the hypothesis that exercise-induced tachycardia results largely from beta 1-receptor activation that is blocked by both cardioselective and nonselective drugs, whereas isoproterenol activates both beta 1- and beta 2-receptors so that after cardioselective blockade there remains a beta 2-component that can be blocked with a nonselective drug. While there appear to be beta 2-receptors in the human heart, their physiologic or pathologic roles remain to be defined.

Diagnosis of acute aortic dissection by M-mode and cross-sectional echocardiography: a five-year experience.

During a five-year period, 26 cases of acute thoracic aortic dissection were studied by M-mode and cross-sectional echocardiography prior to cardiac catheterization and aortography. The diagnosis could be made non-invasively in 20 patients. Important information concerning the extent of the dissection, and the presence or absence of aortic regurgitation or a pericardial effusion could be obtained. Negative examinations were largely confined to cases where the distal thoracic aorta alone was involved. In a further 30 cases admitted to the coronary care unit during this period in which echocardiography was performed to rule out aortic dissection, two false-positive examinations led to aortography which demonstrated aortic dilatation and aortic regurgitation only. In the remaining 28 cases, echocardiographic examination was negative and none of these patients subsequently evidenced aortic dissection. Echocardiography using both M-mode and cross-sectional techniques is a rapid and highly effective method of making an early diagnosis of thoracic aortic dissection. Cross-sectional echocardiography is complementary to the M-mode technique, enhancing diagnostic accuracy by improving structural recognition in a condition where the normal anatomy is often severely distorted.

The influence of hemodialysis fistulas on circulatory dynamics and left ventricular function.

This study was designed to examine the influence of arteriovenous (A-V) fistulas on cardiac output and left ventricular performance in 13 uremic patients on regular hemodialysis. M-mode echocardiography and systolic time intervals were used to derive indices of left ventricular function, and cardiac output was measured by thermodilution. Measurements were performed before and after acute digital occlusion of the A-V fistulas. Occlusion of a single fistula caused systemic vascular resistance and the systolic diameter of the left ventricle to increase from 9.6 +/- 1 to 13.5 +/- 2 units (p less than 0.001) and from 3.2 +/- .3 to 3.4 +/- .4 (p less than 0.05) respectively. The increase in afterload caused a reduction in cardiac output from 11.0 +/- 1 to 9.6 +/- 1 l/min (p less than 0.001) and probably accounted for the minor, though not significant, "deterioration" in the indices of left ventricular function. Bilateral fistula occlusion in 8 patients exaggerated these changes, and the reduction in fractional shortening from 43 +/- 4 to 37 +/- 4% was significant at the 5% level. In two patients with severe left ventricular failure, fistula occlusion caused a more pronounced deterioration in cardiac performance. These results show that acute A-V fistula occlusion effectively lowers cardiac output and is, therefore, likely to be beneficial in the management of high output failure. However, when intrinsic left ventricular disease is the primary etiological factor in heart failure, fistula occlusion is unlikely to be helpful, and may worsen the hemodynamic derangement.