Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10 000 IU/m² at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin^TM from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac^TM under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m² of Asparaginase medac^TM. Another 15 children were given 2500 IU/m² of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m² every third day) showed complete L-asparagine depletion (<0.1 μM ), the median trough enzyme acitivity was 265 IU/l. At the second step of dose reduction (2500 IU/m²) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme acitivity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac^TM dose reduced from the usual 10000 IU/m² down to 5000 IU/m² or 2500 IU/m², applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.     

Silent Cerebral Events/Lesions Related to Atrial Fibrillation Ablation: A Clinical Review

Brain magnetic resonance imaging (MRI) has identified a high incidence of cerebral ischemia in asymptomatic patients after atrial fibrillation (AF) ablation (silent). Detection of cerebral ischemic events on MRI is based on acute hyperintense lesions on diffusion‐weighted imaging. In the literature, the incidence is related to specifications of MRI and depends on the definition applied. In comparative studies, silent cerebral events (SCE, diffusion‐weighted MRI [DWI] positive only) appear to be approximately 3 times more common compared to using a definition of silent cerebral lesions (SCL; without fluid attenuated inverse recovery sequence [FLAIR] positivity). Whereas the FLAIR sequence may turn positive within days after the ischemic event, SCE definition is highly sensitive for early phases of ischemic brain damage. SCE/SCL appear to represent cerebral ischemic infarcts and determine the “embolic fingerprint” of a specific ablation technology and strategy used. The optimum time point for detecting SCE is early after AF ablation (24–72 hours), whereas detection of SCL can only be performed within the first 2–7 days (due to delay of FLAIR positivity). Different technology‐, procedure‐, and patient‐related parameters have been identified to play a role in the multifactorial genesis of SCE/SCL. In recent years, evidence has been gathered that there may be differences of SCE/SCL rates depending upon the ablation technology used, but small patient numbers and a large number of potential confounders hamper all studies. As major findings of recent studies, mode of periprocedural and intraprocedural anticoagulation has been identified as a major predictor for incidences of SCE/SCL. Whereas procedural characteristics related to higher SCE/SCL‐rates may be modified, unchangeable patient‐related factors should be taken into account for future individualized risk assessment. Novel ablation devices introduced into the market should be tested for their potential embolic fingerprint and refinements of ablation procedures to reduce their embolic potential should be prompted. The knowledge of “best practice” in terms of low SCE/SCL rates has prompted changes in work‐flow, which have been implemented into ablation procedures using novel ablation devices. So far, no study has linked SCE/SCL to neuropsychological decline and the low number of AF‐ablation‐associated events needs to be weighted against the multitude of preexisting asymptomatic MRI‐detected brain lesions related to the course of AF itself. Future studies are needed to evaluate if more white matter hyperintensities due to AF may be prevented by AF ablation (producing only a small number of SCE/SCL).     

The Use of Impella 2.5 in Severe Refractory Cardiogenic Shock Complicating an Acute Myocardial Infarction

Objectives

To investigate the outcome of patients with acute myocardial infarction (AMI) complicated by refractory cardiogenic shock (CS) who underwent mechanical circulatory support with Impella 2.5.

Background

AMI complicated by CS remains a highly fatal condition. A potent and minimally invasive left ventricular assist device might improve patient outcomes.

Methods

We analyzed the procedural characteristics and outcomes of 22 consecutive patients who underwent, between July 2008 and December 2012, a percutaneous coronary intervention and Impella 2.5 support for AMI complicated by CS refractory to first‐line therapy with inotropes and/or Intra‐aortic balloon pump.

Results

In this analysis, patients were relatively young with a mean age of 57.9 ± 11.6 year old and 59.1% were male. The majority of patients (77.3%) were admitted in CS and 40.9% sustained cardiac arrest prior to admission. Hemodynamics improved significantly upon initiation of support, end‐organ and tissue perfusion improved subsequently demonstrated by a significant decrease in lactate levels from 6.37 ± 5.3 mmol/L to 2.41 ± 2.1 mmo/L, (P = 0.008) after 2 days of support. Thirteen (59.1%) patients were successfully weaned‐off Impella 2.5 and 4 (18.2%) were transitioned to another device. We observed a functional recovery of the left ventricle when compared to baseline (43 ± 10% vs. 27 ± 9%, P < 0.0001). The survival rate at 6 months and 1 year was 59.1% and 54.5%, respectively.

Conclusion

Impella 2.5 was initiated as a last resort therapy to support very sick patients with refractory CS after failed conventional therapy. The use of the device yielded favorable short and mid‐term survival results with recovery being the most frequently observed outcome. (J Interven Cardiol 2015;28:41–50)

     

Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation

Monocarboxylate transporter 8 ( MCT8 or SLC16A2) is important for the neuronal uptake of triiodothyronine (T3) in its function as a specific and active transporter of thyroid hormones across the cell membrane, thus being essential for human brain development. We report on a German male with Allan–Herndon–Dudley syndrome presenting with severe intellectual and motor disability, paroxysmal dyskinesia combined with truncal muscular hypotonia, and peripheral muscular hypertonia at his current age of 9 years. Additionally, the patient has a lesion in the left putamen region revealed by magnetic resonance imaging and elevated serum T3 levels. The male appeared to have a hemizygous mutation (R271H) in the MCT8 gene that was sequenced directly from genomic DNA and occurred de novo in the maternal germline, as both his mother and his sister were not carriers of the mutation. Ruling out a common polymorphism, 50 normal individuals of the same ethnic background did not harbour the mutation. The identified MCT8 gene mutation (R271H) is very likely to be the genetic cause for neuronal hypothyroidism despite elevated serum T3 levels.     

Clinical Significance of Sleep-Related Breathing Disorders in Patients with Implantable Cardioverter Defibrillators

The prevalence and clinical significance of sleep-related breathing disorders (SRBDs) in patients with cardiac disease and a history of life-threatening ventricular tachyarrhythmias is unclear. Forty consecutive recipients of implantable cardioverter defibrillators (ICDs) with cardiac disease and a documented history of spontaneous, life-threatening, ventricular tachyarrhythmias underwent full night polysomnography. SRBDs were diagnosed if the apnea/hypopnea index was > 10. SRBD were diagnosed in 16 of 40 patients (40%): central sleep apnea (CSA) was present in 9 of these 16 patients (56%), 8 of whom had associated Cheyne-Stoke respiration. Seven of the 16 patients with SRBD (44%) had obstructive sleep apnea (OSA). Patients with and without SRBDs were comparable with respect to left ventricular ejection fraction, NYHA classification, underlying heart disease, ICD indications, and concomitant antiarrhythmic drug and beta-blocker therapy. Patients were followed prospectively for 2 years. ICD-treated ventricular tachyarrhythmias occurred in 10 of 24 patients (42%) without SRBD, in 4 of 9 patients (44%) with CSA, and in 3 of 7 patients (44%) with OSA (NS). The numbers and circadian distributions of episodes recorded during follow-up in patients without SRBD versus with CSA or OSA were not significantly different (14 ± 25, median = 4 vs 4 ± 5, median = 2.5 vs 15 ± 15, median = 7, respectively). The 2-year mortality, which was entirely attributable to nonsudden cardiac events, was highest in patients with CSA (4/9 [44%], vs 0/7 [0%] with OSA, vs 3/24 patients (12.5%) without SRBD; P < 0.05).     

Female executives are particularly prone to the sleep-disturbing effect of isolated high-strain jobs: a cross-sectional study in German-speaking executives

This study assessed the main, curvilinear, interactive and gender-dependent effects of job demands, job control and social support in the prediction of sleep quality. Participants were 348 male and 76 female executives and managers from Germany, Austria and Switzerland. A multiple regression controlling for age, occupational hierarchy and various health behaviors was computed. On the level of the main effects of the Job–Demand–Control–Support (JDCS) model, the results indicate a sleep-promoting effect of social support. A significant three-way interaction of job demands, job control and social support was observed. This interaction confirms the buffering effect of high job control and high social support on high job demands. Further, this three-way interaction of the JDCS dimensions is moderated by gender as indicated by a significant four-way interaction. The directions of the significant interactions suggest that female executives are especially prone to react with impaired sleep quality when exposed to isolated high-strain jobs. The study seems to imply that the JDCS model is a suitable framework for the prediction of sleep quality among executives and managers. The results suggest that the JDCS model might contribute to a better understanding of the higher prevalence of poor sleep amongst female executives. Further, the results imply that high job control and high social support might help executives to maintain good sleep quality despite experiencing high job demands.     

Response to sodium benzoate treatment in non-ketotic hyperglycinaemia

Therapy with benzoic acid in a case of classic neonatal non-ketotic hyperglycinaemia (NKH) was successful in stopping seizures but not in promoting mental development. Serum glycine levels were normalizable even by administering low doses of 53 mg sodium benzoate/kg body mass (BM) per day. Despite giving a higher dosage (240 mg/kg BM per day) normalization of glycine concentration in cerebrospinal fluid (CSF) was not achieved. However, seizures ceased. Restriction of protein intake (≤2 g/kg BM per day) seemed to be profitable. CSF glycine concentrations below 100 μmol/L may be sufficient to prevent seizures in older infants who have adapted to neuronal glycine exposure. No toxicity of sodium benzoate treatment was detected when administering doses of up to 470 mg/kg BM per day but side effects such as itching and hyperactivity were obvious.