Drug clearance during Continuous Veno-Venous Hemofiltration (CVVH). A mathematical model based on ex-vivo experiments

Introduction:

Continuous veno-venous hemofiltration (CVVH) with an AN69 membrane is used in hemodynamical unstable patients with acute renal failure admitted to the Intensive Care Unit (ICU) of the Catharina Hospital in Eindhoven (CHE), the Netherlands. Literature search revealed that only the clearance and kinetics of some antibiotics during CVVH were studied. Data obtained with different renal replacement techniques and membranes can’t easily be extrapolated to CVVH with an AN69 membrane. (Reetze-Bonorden et al., 1993; Mueller et al., 2003) Due to the lack of clinical research data, dosages in patients treated with CVVH at the ICU of the CHE or are not adjusted or are adjusted on the base of the empirical determined creatinin clearance of 30 ml/min. For aminoglycosides and vancomycin dose adjustment is performed applying therapeutic drug monitoring. Because of this a lot of drugs are possibly suboptimal dosed during CVVH.

Aim:

The aim of this study was to develop a predictive mathematical model based on ex-vivo experiments for the drug clearance by CVVH with an AN69 high-flux membrane.

Methods:

The experimental set-up consisted of a PRISMA CFM hemofiltration machine with a AN69 HF 0,9 m², 500 ml heparinised bovine blood as blood compartment, blood flow rate 150 ml/min and ultrafiltration rate 1500 ml/h. The following drugs were added to the blood compartment in therapeutic concentrations, covering a broad range in molecular weight (Mw), % protein binding (%PB), logP and charge (C): amiodarone, amitriptyline, carbamazepine, cyclosporine, clozapine, digoxin, phenobarbital, phenytoin, gentamycin, midazolam, acetaminophen, theophylline, tobramycin, valproic acid and vancomycin. The sieving coefficient (SC) was calculated by SC=(2x concentration ultrafiltrate) / (concentration post membrane + concentration pre membrane).

Results:

All four parameters; %PB, logP, C and Mw contributed statistically significant (p < 0,05) to the SC. The regression line, explaining 75% of the variance (R²=0,751) is:

Conclusion:

Based on the ex-vivo experiments a mathematical model has been extracted to predict a-priori the sieving coefficient of drugs during CVVH with an AN69 high-flux membrane on the base of protein binding, charge, logP and molecular weight. This model has to be validated in vivo and can then be used, if valid, for drugs which physico-chemical properties in the ranges studied: p%PB 0 − 98%, logP −7,32 – 7, Mw 151 – 1500, C −1 – 3.     

TRPV5: an ingeniously controlled calcium channel

Body Ca(2+) homeostasis is tightly controlled and slight disturbances in renal Ca(2+) reabsorption can lead to excessive urine Ca(2+) excretion and promote kidney stone formation. The epithelial Ca(2+) channel TRPV5 constitutes the rate-limiting step of active Ca(2+) reabsorption in the kidney. Elucidation of the molecular pathways controlling TRPV5 function provides important information for our understanding of renal Ca(2+) handling, since active Ca(2+) reabsorption fine-tunes the final amount of Ca(2+) excreted into the urine. Over the last years, the molecular regulation of TRPV5 has been dismantled in detail. Various calciotropic hormones, known to alter renal Ca(2+) reabsorption, affect the expression of TRPV5. Others stimulate the trafficking of TRPV5 to the plasma membrane, while a number of associated proteins and ions control channel activity at the plasma membrane. Dynamic cell surface presence of TRPV5 is largely mediated by endosomal recycling processes allowing internalized channels to reappear at the plasma membrane. We present recently identified factors shown to modulate TRPV5 activity by diverse mechanisms to ultimately control renal Ca(2+) handling. The selected factors include klotho, tissue kallikrein, pH, Ca(2+), Mg(2+), PIP(2) and WNK4. This review covers the distinctive properties and regulation of the highly Ca(2+)-selective TRPV5 channel and highlights the implications for our understanding of the process of Ca(2+) reabsorption.     

Relationships between volume and pressure measurements and stroke volume in critically ill patients

Objective  

To evaluate the relationships between the changes in stroke volumeindex (SVI), measured in both the aorta and the pulmonary artery, and thechanges in intrathoracic blood volume index (ITBVI), as well as therelationship between changes in aortic SVI and changes in the pulmonary arterywedge pressure (PAWP).     

Effect of a complete nutritional supplement on antibody response to influenza vaccine in elderly people

BACKGROUND: The impact of influenza infection on morbidity and mortality in the elderly population can be severe. Influenza vaccination is not very effective in this age group, which is potentially related to impaired nutritional status. We investigated the effect of a 7-month nutritional supplementation on antibody response to influenza vaccine in elderly people. METHODS: Nineteen subjects aged 65 years and older with a body mass index of 25 kg/m(2) or less were studied. Subjects received a complete liquid nutrition supplement containing energy, vitamins, and minerals, including enhanced levels of antioxidants or noncaloric placebo drink for 7 months. Antibody titers to influenza strains A/Sydney/5/97 (SY), A/Beijing/262/95 (BE), and B/Yamanashi/166/98 (YA) before and 28 days after vaccination were measured. Age, gender, weight, height, serum albumin, serum prealbumin, hemoglobin, and serum vitamin E at baseline were registered. RESULTS: Mean fold increase upon vaccination for SY was significantly larger in the supplement group (2.76 +/- 0.66) compared to the placebo group (1.91 +/- 0.66). These differences were not observed for YA (1.73 +/- 0.31 vs 1.19 +/- 0.18) and BE (4.40 +/- 2.63 vs 5.76 +/- 3.34). For all three strains, there was no significant difference between groups in protective antibody levels (HI titer > or =40) after vaccination. CONCLUSIONS: We conclude that provision of a complete liquid nutrition supplement including enhanced levels of antioxidants may have a beneficial effect on antibody response to influenza vaccination in the elderly population. Further confirmation of these findings and their clinical consequences should be the subject of a larger study.     

Characterization of human skin equivalents developed at body's core and surface temperatures

Human skin equivalents (HSEs) are in vitro developed three‐dimensional models resembling native human skin (NHS) to a high extent. However, the epidermal lipid biosynthesis, barrier lipid composition, and organization are altered, leading to an elevated diffusion rate of therapeutic molecules. The altered lipid barrier formation in HSEs may be induced by standardized culture conditions, including a culture temperature of 37°C, which is dissimilar to skin surface temperature. Therefore, we aim to determine the influence of culture temperature during the generation of full thickness models (FTMs) on epidermal morphogenesis and lipid barrier formation. For this purpose, FTMs were developed at conventional core temperature (37°C) or lower temperatures (35°C and 33°C) and evaluated over a time period of 4 weeks. The stratum corneum (SC) lipid composition was analysed using advanced liquid chromatography coupled to mass spectrometry analysis. Our results show that SC layers accumulated at a similar rate irrespective of culture temperature. At reduced culture temperature, an increased epidermal thickness, a disorganization of the lower epidermal cell layers, a delayed early differentiation, and an enlargement of granular cells were detected. Interestingly, melanogenesis was reduced at lower temperature. The ceramide subclass profile, chain length distribution, and level of unsaturated ceramides were similar in FTMs generated at 37°C and 35°C but changed when generated at 33°C, reducing the resemblance to NHS. Herein, we report that culture temperature affects epidermal morphogenesis substantially and to a lesser extent the lipid barrier formation, highlighting the importance of optimized external parameters during reconstruction of skin.