Cardiac Surgery in Patients With Liver Cirrhosis (CASTER) Study: Early and Long-Term Outcomes

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Ultrasound-guided supraclavicular cannulation of left brachiocephalic versus right internal jugular vein: Comparative analysis of central venous catheter-associated complications

Aims

Central venous catheters are essential for the management of pediatric cardiac surgery patients. Recently, an ultrasound-guided access via a supraclavicular approach to the brachiocephalic vein has been described. Central venous catheters are associated with a relevant number of complications in pediatric patients. In this study, we evaluated the frequency of complications of left brachiocephalic vein access compared with right internal jugular vein standard access in children undergoing cardiac surgery.

Methods

Retrospective analysis of all pediatric cases at our tertiary care university hospital over a two-year period receiving central venous catheters for cardiac surgery. Primary endpoint: Frequency of complications associated with central venous catheters inserted via the left brachiocephalic vein vs. right internal jugular vein. Complications were defined as: chylothorax, deep vein thrombosis, sepsis, or delayed chest closure. Secondary endpoints: Evaluation of the insertion depth of the catheter using a height-based formula without adjustment for side used.

Results

Initially, 504 placed catheters were identified. Following inclusion and exclusion criteria, 480 placed catheters remained for final analysis. Overall complications were reported in 68/480 (14.2%) cases. There was no difference in the frequency of all complications in the left brachiocephalic vein vs. the right internal jugular vein group (15.49% vs. 13.65%; OR = 1.16 [0.64; 2.07]), nor was there any difference considering the most relevant complications chylothorax (7.7% vs. 8.6%; OR = 0.89 [0.39; 1.91]) and thrombosis (5.6% vs. 4.5%; OR = 1.28 [0.46; 3.31]). The mean deviation from the optimal insertion depth was left brachiocephalic vein vs. right internal jugular vein 5.38 ± 13.6 mm and 4.94 ± 15.1 mm, respectively.

Conclusions

Among children undergoing cardiac surgery, there is no significant difference between the supraclavicular approach to the left brachiocephalic vein and the right internal jugular vein regarding complications. For both approaches, a universal formula can be used to determine the correct insertion depth.     

Germicide wound pad with active, <Emphasis Type="Italic">in situ</Emphasis>, electrolytically produced hypochlorous acid

We describe a new wound dressing technology that can actively generate an inorganic germicide agent, in situ, within the wound pad. The technology provides real time control over the quantitative, spatial and temporal delivery of the germicide. The identity of the germicide is hypochlorous acid (HClO). The HClO is produced in a flexible wound pad, made of a composite of thin (micrometer scale) layers of various materials, with different electrochemical properties that enhance HClO production. Active control over the production of HClO is achieved by control of the pH and of the electric potential across the layers. The effectiveness of the Active HClO Pad (AHClOP) concept is demonstrated in a study on sterilization of E. coli in a deep wound contamination simulating gel. The performance of the AHClOP is compared with that of four commercial wound dressings. Results show that the AHClOP can sterilize throughout the gel, while the commercial dressings cannot.     

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH

Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min^–1; S 379 ml·min^–1) than in EMs (R 783 ml·min^–1; S 828 ml·min^–1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min^–1; S 201 ml·min^–1) relative to extensive metabolisers (R 533 ml·min^–1; S 586 ml·min^–1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min^–1) than extensive (267 ml·min^–1) metabolisers.The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml^–1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.Presented in part at the 23rd Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Sydney, 4–6 December, 1989     

Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of <Emphasis Type="Italic">PIK3CA</Emphasis> mutations in breast cancer

Background

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PIK3CA, is one of the most frequently mutated genes in breast cancer, and the mutation status of PIK3CA has clinical relevance related to response to therapy.The aim of our study was to investigate the mutation status of PIK3CA gene and to evaluate the concordance between NGS and SGS for the most important hotspot regions in exon 9 and 20, to investigate additional hotspots outside of these exons using NGS, and to correlate the PIK3CA mutation status with the clinicopathological characteristics of the cohort.

Methods

In the current study, next-generation sequencing (NGS) and Sanger Sequencing (SGS) was used for the mutational analysis of PIK3CA in 186 breast carcinomas.

Results

Altogether, 64 tumors had PIK3CA mutations, 55 of these mutations occurred in exons 9 and 20. Out of these 55 mutations, 52 could also be detected by Sanger sequencing resulting in a concordance of 98.4 % between the two sequencing methods. The three mutations missed by SGS had low variant frequencies below 10 %. Additionally, 4.8 % of the tumors had mutations in exons 1, 4, 7, and 13 of PIK3CA that were not detected by SGS. PIK3CA mutation status was significantly associated with hormone receptor-positivity, HER2-negativity, tumor grade, and lymph node involvement. However, there was no statistically significant association between the PIK3CA mutation status and overall survival.

Conclusions

Based on our study, NGS is recommended as follows: 1) for correctly assessing the mutation status of PIK3CA in breast cancer, especially for cases with low tumor content, 2) for the detection of subclonal mutations, and 3) for simultaneous mutation detection in multiple exons.

     

Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring

Very low voriconazole concentrations are commonly observed during therapeutic drug monitoring. Possible mechanisms include inappropriate dose selection, rapid metabolism (as a result of genetic polymorphisms or enzyme induction), and also nonadherence. We aimed to develop a method to distinguish between rapid metabolism of and nonadherence to voriconazole by quantification of voriconazole metabolites. In addition, the relevance of common genetic polymorphisms of CYP2C19 was assessed. In a retrospective study, samples with voriconazole concentrations 0.2 μg/mL or less in routine therapeutic drug monitoring (as quantified by high-performance liquid chromatography) were evaluated. Voriconazole and its N-oxide metabolite were quantified in residual blood using a highly sensitive liquid chromatography-tandem mass spectroscopy method (lower limit of quantitation = 0.03 μg/mL). Genetic polymorphisms of CYP2C19 were determined by real-time polymerase chain reaction using the hybridization probe format and the polymerase chain reaction-random fragment length polymorphism format. A total of 747 routine therapeutic drug monitoring plasma/blood samples of 335 patients treated with systemic voriconazole were analyzed and in 18.7% of all samples, voriconazole concentrations 0.2 μg/mL or less were found. In 32 samples (30 patients) with adequate dosage and timing of blood withdrawal, nonadherence was strongly suspected in seven patients because voriconazole-N-oxide concentrations were below 0.03 μg/mL, which was not observed in a reference group of 51 healthy volunteers with controlled drug intake. In 10 patients, of whom EDTA blood was available, the ultrarapid metabolizer genotype (CYP2C19*1\*17, CYP2C19*17\*17) was found in 80% and its prevalence was significantly higher as compared to a reference group (P = 0.02). In conclusion, quantification of voriconazole-N-oxide allowed for detection of suspected nonadherence in one of four patients with very low voriconazole concentrations. In the remaining patients, ultrarapid metabolism resulting from the CYP2C19*17 polymorphism appears to play a major role. Thus, in the case of voriconazole therapy failure, both nonadherence and genetic factors have to be considered.     

Quantitative low-volume assay for simultaneous determination of fentanyl,norfentanyl, and minor metabolites in human plasma and urine by liquid chromatography—tandem mass spectrometry (LC-MS/MS)

A rapid and sensitive liquid chromatography/tandem mass spectrometric (LC-MS/MS) method for simultaneous quantification of fentanyl (F), norfentanyl (NF), despropionylfentanyl (DPF), and hydroxynorfentanyl (OHNF) in human plasma and urine specimens has been developed and validated according to international guidelines. Analytes were extracted from 250-μL plasma or urine by liquid–liquid extraction. OHNF in urine affords a second extraction step and analysis with a different column. Calibration curves in plasma were linear from 0.05–10 ng/mL for F, 0.07–0.5 ng/mL for NF, 0.02–1.0 ng/ml for DPF, and 0.67–3.0 ng/mL for OHNF; in urine, from 0.09–10.0, 0.17–50, 0.08–1.0, and 1.0–5.0 ng/mL for F, NF, DPF, and OHNF, respectively. Analytical bias and intra- and inter-assay imprecision were within ±15 % of target, except for OHNF in plasma and DPF in urine at the respective lower quality control level. All analytes were stable in processed samples when stored for 24 h at room temperature. Recoveries and process efficiencies were above 82.9 and 75.1 % for all analytes in plasma and urine. The low level of DPF in plasma indicated with a matrix effect of 71.3 % moderate ion suppression, all other analytes in plasma and urine showed no matrix effects. The lower limit of quantification (LOQ) in plasma was 0.05, 0.07, 0.02 and 0.67 ng/mL for F, NF, DPF, and OHNF, respectively. In urine, the LOQ of F, NF, DPF, and OHNF were 0.09, 0.17, 0.08, and 1.28 ng/mL, respectively. This assay has been applied to human specimens collected during a clinical drug–drug interaction study.