Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.
In order to analyze the respiratory, cardiovascular, and ECG responses to acute hypoxic hypoxia, three experimental series were carried out in a randomized manner on 11 healthy, unacclimatized volunteers at rest during standardized stepwise exposure to 6000 m (PAO2 35.2 +/- 2.9 mmHg/4.7 +/- 0.4 kPa) in a low-pressure chamber a) without (control), b) with propranolol, and c) with atropine combined with propranolol. The results show that hypoxic hyperventilation and alveolar gases are not affected by activation of the sympatho-adrenal axis or by parasympathetic withdrawal. Sympathetic activity, however, increases heart rate, stroke volume (pulse pressure), estimated cardiac output and systolic blood pressure, whereas decreased parasympathetic activity increases heart rate and estimated cardiac output, but lowers stroke volume. The fall in peripheral resistance, observed during progressive hypoxia in all three groups, is thought to be due to hypoxia-induced depression of the vasomotor center. At altitude catecholamine secretion and vagal withdrawal synergistically account in the ECG for the R-R shortening, the relative Q-T lengthening, the elevation of the P wave and the ST-T flattening. Probable direct hypoxic effects on the heart are the increase in P-Q duration and the minor but still significant depression of the T wave. It is concluded that at altitude increased sympatho-adrenal and decreased parasympathetic activity is without effect on hypoxic hyperventilation, but accounts for most of the cardiovascular and ECG changes. Diminution of sympathetic activity and imminent vagotonia arising after acute ascent to 6000 m probably reflect hypoxia of the central nervous system.
The effect of glyburide on coronary reactive hyperemia and dilator responses to adenosine was evaluated in isolated perfused guinea pig hearts and anesthetized dogs. In isolated guinea pig hearts, changes in flow due to increasing concentrations of adenosine were measured, followed by 2 min of global ischemia to produce reactive hyperemia. This procedure was repeated after glyburide treatment. A similar study was performed in anesthetized open chest dogs. In isolated guinea pig hearts, 1 µM glyburide reduced reactive hyperemia with a peak flow reduction of 30.7% and debt repayment reduction of 78.0%, relative to vehicle-treated hearts. The adenosine dose-response curve in these hearts was shifted 20-fold to the right by 1 µM glyburide. Glyburide (3 mg/kg + 0.01 mg/kg/min) in dogs inhibited both the peak flow (from 154 ± 26 to 105 ± 22 ml/min) and the percentage of debt repayment (from 756 ± 243 to 336 ± 88%) of reactive hyperemia. Additionally, the canine intracoronary adenosine response curve was shifted rightward 100-fold by glyburide. Thus, there is a glyburide-sensitive component influencing the magnitude of both the adenosine and the reactive hyperemia response, suggesting that some of this response involves ATP-sensitive potassium channels.
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