Dialysate Concentrations Research Articles

Pharmacokinetics of Intraperitoneal Gentamicin in Peritoneal Dialysis Patients with Peritonitis (GIPD Study)

Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate samples were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%-82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status (P=0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4-29.9) hours, terminal volume of distribution of 0.30 (0.20-0.36) L/kg, observed peak plasma concentration of 3.1 (2.4-3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4-2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity.

Effects of hemodialysis on serum fetuin-A levels

Fetuin-A is a calcification inhibitor, negative acute phase response marker and cardiovascular mortality predictor in hemodialysis patients. Low levels of fetuin-A are associated with malnutrition, inflammation, decreased bone mass density, low-turnover bone and use of high calcium concentration dialysate. Hemodialysis procedure (HD) has been shown to decrease fetuin-A levels by 20%, probably due to HD-induced inflammation or acute changes in calcium metabolism. The aim of our study was to investigate effects of HD on serum fetuin-A levels. Forty clinically and hemodynamically stable hemodialysis patients (21 females, 68 (38-85) years) underwent routine bicarbonate hemodialysis or hemodiafiltration with polysulfone dialyzer. On consecutive HD dialysis solution with different calcium concentration with/without citric acid was used to assess influence of calcium shifts and parathyroid activity on fetuin-A changes during HD. All other parameters of HD were kept constant. Serum fetuin-A, calcium, phosphorus, iPTH, CRP and other biochemical parameters were measured before and after each HD. Our data show that predialysis serum fetuin-A levels have positive correlation with iPTH levels (p

On-site production of a dialysis bath from dry salts. Results of solute concentration control by routine clinical chemistry

Background.Dialysis bath production, at least in Europe, is currently based on pre-produced aqueous solutions of dialysis salts (concentrate), which are re-handled by dialysis machines to deliver the final dialysate concentrations. Because of the logistics of aqueous solution creation, a large amount of transportation capacity is needed. Therefore, we changed this process to use pre-produced dry salt containers and to undertake in-clinic dissolution of salts and concentration production. Because no preclinical control for solute concentrations is available so far using this new process, we employed routine clinical chemistry analytics.Methods.We report the controls of solute concentrations created by these methods for 746 samples of concentrates and 151 dissolution processes. For analysis, absolute and relative deviations from prescriptions and associations between the solute concentrations and the density controls of the concentrates were computed.Results.A total of 98% of all the concentrates were found to be within a 10% margin of error from the prescriptions. The mean relative deviation of the solute concentrations from the prescriptions was −0.635 ± 3.83%. Among particular solutes, sodium had the highest maximum deviation of 26 mmol/L from the prescription. Calcium and magnesium (small concentration solutes) exhibited small systematic errors of 1.37 and 1.22%, respectively. Other solute concentrations showed random errors only and no associations with the mean relative deviations of all the solutes within a production batch or with the density controls.Conclusions.Single solute concentration control by routine clinical chemistry after dry salt production of concentrates is a valuable additional tool for monitoring clinical risk with dialysate concentrates. The analytical random error of clinical chemistry exceeds the weight tolerance of production; therefore, such analytics cannot be used for precision production and control of dry salt containers.

Pharmacokinetics of Intraperitoneal and Intravenous Fosfomycin in Automated Peritoneal Dialysis Patients without Peritonitis

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose.

High Correlation Between Clearance of Renal Protein‐Bound Uremic Toxins (Indoxyl Sulfate and p‐Cresyl Sulfate) and Renal Water‐Soluble Toxins in Peritoneal Dialysis Patients

Peritoneal dialysis (PD) is characterized by a slow continuous removal of solutes. Traditionally, dialysis adequacy is quantified by referring to the kinetics of urea nitrogen (UN) and creatinine (Cr) clearance. The efficacy of middle molecular substances and protein-bound solutes as markers for peritoneal dialysis adequacy is not clear. The aim of this cross-sectional study was to investigate correlations between the clearance of indoxyl sulfate (IS), p-cresyl sulfate (PCS), UN, and Cr in the peritoneum and kidneys and to compare the overall clearances of IS and PCS between non-anuric and anuric groups in PD patients. We recruited a total of 175 patients who had been undergoing continuous ambulatory PD (CAPD) or automated PD (APD) for at least 4 months. We measured total IS and PCS concentrations in serum, dialysate, and urine samples. Free IS and PCS concentrations were measured in all serum samples. IS and PCS clearances via both kidney and peritoneum were measured. The mean concentration of IS in the urine samples was 9.2-fold higher than that in the dialysate samples, and concentration of PCS in the urine samples was 8.5-fold higher than that in the dialysate samples. Peritoneal UN and Cr clearances were not correlated with peritoneal PCS clearance (P > 0.05) but were mildly correlated with peritoneal IS clearance. The peritoneal IS and PCS clearances in the different peritoneal equilibration test groups were similar. The renal UN and Cr clearances were strongly correlated with renal PCS and IS clearances (P > 0.89, P < 0.001). In addition, non-anuric patients showed better elimination of total PCS (10.3 mg/day [range, 1.6-19.8] vs. 5.2 mg/day [range, 0-14]; P < 0.001] and IS (37.9 mg/day [range, 25.6-56.7] vs. 24.8 mg/day [range, 17.1-41.6]; P < 0.001) than anuric patients. This cross-sectional study showed that peritoneal clearance of water-soluble solutes is not correlated with that of PCS but is mildly correlated with that of IS. However, the renal clearances of IS and PCS show strong positive correlation with the renal clearances of UN and Cr. This study confirms the important role of residual renal function in the removal of protein-bound uremic toxins.

Development of a novel method for monitoring the antioxidative effect of ascorbic acid in rat blood

► A semi-micro flow injection analysis–chemiluminescence detection hyphenated with microdialysis method was established. ► This method can evaluate in vivo antioxidative effect of ascorbic acid (ASA) after its administration. ► The antioxidative effect in dialysate was identified to be ASA by diminishing its effect with ascorbic acid oxidase. ► ASA concentration in dialysate indicates a good correlation with the antioxidative effect. A real time evaluation method for the ex vivo antioxidative effect in rat blood after administration of ascorbic acid (ASA) is described. The antioxidative effect in small amounts of samples (0.5 μL) could be measured by hyphenated semi-micro flow injection analysis–chemiluminescence detection and microdialysis methods. Antioxidative effects of blood microdialysates obtained from rats administered 50 mg/kg ASA through different routes (intravein: i.v., intraperitoneal: i.p. and per os : p.o.) were evaluated. The increased effects were maintained up to 360 min after administration. The AUC 0–360 (antioxidative effect % × min) were 16,260 ± 1739 (i.v.), 12,873 ± 2152 (i.p.) and 6668 ± 2251 (p.o.). Additionally, ASA was determined to be the source of the microdialysate antioxidative effect by diminishing its effect with ascorbic acid oxidase. Furthermore, the concentration of ASA in the microdialysate was correlated with the antioxidative effect ( r = 0.915).

Fluid State and Blood Pressure Control

The aim of this study was to compare fluid state, ambulatory blood pressure, and sodium removal in automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). This observational, cross-sectional study comprised 20 APD and 24 CAPD patients with a mean duration on peritoneal dialysis of 30 ± 26 and 21 ± 23 months, respectively. Sixty-four percent of the patients were treated with icodextrin. The methods used were 24 hr dialysate and urine collections, standardized 3.86% glucose peritoneal equilibration test (PET), bioimpedance analysis, and 24 hr ambulatory blood pressure monitoring. Extracellular water (ECW) corrected for body weight was 0.23 6 0.03 L/kg both in APD and CAPD patients. The slope normovolemia value according to Chamney was 0.0 6 0.2 L/kg in APD patients and 0.0 6 0.05 L/kg in CAPD patients (not significant [NS]). Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were respectively, 132 ± 25 and 79 ± 8 mm Hg in APD and 129 ± 16 and 76 ± 11 mm Hg in CAPD patients (NS). Sodium concentration in dialysate was respectively, 129.5 ± 3.5 mmol/L in APD and 132.4 ± 4.1 mmol/L in CAPD (p= 0.017). Dialysate sodium removal was 80.6 ± 78.4 mmol/24 hr in APD and 108.7 ± 96.8 mmol/24 hr in CAPD patients (NS). Natriuresis was respectively, in APD 76.6 ± 65.5 mmol/24 hr and in CAPD 93.5 ± 61.7 mmol/24 hr (NS). Total sodium removal was 149.5 ± 76.6 mmol/24 hr in APD and 198.4 ± 75.0 mmol/24 hr in CAPD (p= .039). Despite a higher daily sodium removal in CAPD patients, fluid state and blood pressure were not different between APD and CAPD. In general, volume status and blood pressure appeared to be reasonably controlled in this unselected population.

Transcranial Focused Ultrasound to the Thalamus Is Associated with Reduced Extracellular GABA Levels in Rats

Objective: Transcranial focused ultrasound (FUS), with its ability to non-invasively modulate the excitability of region-specific brain areas, is gaining attention as a potential neurotherapeutic modality. The aim of this study was to examine whether or not FUS administered to the brain could alter the extracellular levels of glutamate and γ-aminobutyric acid (GABA), which are representative excitatory and inhibitory amino acid neurotransmitters, respectively. Methods: FUS, delivered in the form of a train of pulses, was applied to the thalamus of Sprague-Dawley rats transcranially. Glutamate and GABA were directly sampled from the frontal lobe of the rat brain via a direct microdialysis technique before, during, and after the sonication. The dialysate concentrations were determined by high-performance liquid chromatography. Results: The individual levels of the neurotransmitters sampled were normalized to the baseline level for each rat. In terms of the changes in extracellular glutamate levels, there was no difference between the FUS-treated group and the unsonicated control group. However, extracellular GABA levels started to decrease upon sonication and remained reduced (approximately 20% below baseline; repeated-measures ANOVA, p < 0.05, adjusted for multiple comparisons) compared to the control group. Conclusion: The ability to modulate region-specific brain activity, along with the present evidence of the ability to modulate neurotransmission, demonstrates the potential utility of FUS as a completely new non-invasive therapeutic modality.

Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients.

The kidney has a vital role in magnesium homeostasis and, although the renal handling of magnesium is highly adaptable, this ability deteriorates when renal function declines significantly. In moderate chronic kidney disease (CKD), increases in the fractional excretion of magnesium largely compensate for the loss of glomerular filtration rate to maintain normal serum magnesium levels. However, in more advanced CKD (as creatinine clearance falls <30 mL/min), this compensatory mechanism becomes inadequate such that overt hypermagnesaemia develops frequently in patients with creatinine clearances <10 mL/min. Dietary calcium and magnesium may affect the intestinal uptake of each other, though results are conflicting, and likewise the role of vitamin D on intestinal magnesium absorption is somewhat uncertain. In patients undergoing dialysis, the effect of various magnesium and calcium dialysate concentrations has been investigated in haemodialysis (HD) and peritoneal dialysis (PD). Results generally show that dialysate magnesium, at 0.75 mmol/L, is likely to cause mild hypermagnesaemia, results for a magnesium dialysate concentration of 0.5 mmol/L were less consistent, whereas serum magnesium levels were mostly normal to hypomagnesaemic when 0.2 and 0.25 mmol/L were used. While dialysate magnesium concentration is a major determinant of HD or PD patients’ magnesium balance, other factors such as nutrition and medications (e.g. laxatives or antacids) also play an important role. Also examined in this review is the role of magnesium on parathyroid hormone (PTH) levels in dialysis patients. Although various studies have shown that patients with higher serum magnesium tend to have lower PTH levels, many of these suffer from methodological limitations. Finally, we examine the complex and often conflicting results concerning the interplay between magnesium and bone in uraemic patients. Although the exact role of magnesium in bone metabolism is unclear, it may have both positive and negative effects, and it is uncertain what the optimal magnesium levels are in uraemic patients.

Sodium balance in maintenance hemodialysis.

Sodium is the principal solute in the extracellular compartment and the major component of serum osmolality. In normal persons in the steady state, sodium homeostasis is achieved by a balance between the dietary intake and the urinary output of sodium, whereas in intermittent hemodialysis patients, sodium balance depends on dietary intake and sodium removal during hemodialysis. Thus, the main goal of hemodialysis is to remove precisely the amount of sodium that has accumulated during the interdialytic period. Sodium removal during hemodialysis occurs via convective (~78%) and diffusive losses (~22%) between dialysate and plasma sodium concentration. The latter (the sodium gradient) is an important factor in the 'fine tuning' of sodium balance during intermittent hemodialysis. Most use fixed dialysate sodium concentrations, but each patient has his/her own plasma sodium concentrations pre-hemodialysis, which are quite reproducible and stable in the long-term. Thus, in many patients, a fixed dialysate sodium concentration will cause a persistent positive sodium balance during dialysis, which could possibly cause increased thirst, interdialytic weight gain, and mortality. Several methods will be discussed to reduce positive sodium balance, including sodium alignment.

Achievements in CKD-MBD guidelines targets: is there a progress in the implementation practice?

Guidelines should help the practicing nephrologists to reduce the variability in diagnostic and treatment strategies, and achieve the best possible patients' outcomes. The aim of our study was to look at the treatment strategies and the shortcomings in the implementation of the chronic kidney disease mineral and bone disorder (CKD-MBD) KDOQI guidelines in dialysis units across the Republic of Macedonia in 2009, and to analyze trends with regard to our previous analysis from 2005. A questionnaire was sent in 2009 to all dialysis units in our country for data concerning CKD-MBD in dialysis patients. This study included 742 patients, comparable with the reply we got on the same our 2005 survey, with a total of 588 patients. We collected the last 6 months mean values of biochemical parameters [calcium (Ca), phosphate (P), and intact parathyroid hormone (iPTH)], as well as treatment data including dialysate Ca concentration, phosphate binding agents, and vitamin D doses. The majority of patients in both surveys had values within the target ranges for all parameters, except for iPTH, which was <150 pg/ml in most patients, in both reports. Compared to the 2005 study, in 2009 we found a significantly improved control of all four biochemical parameters, but a greater proportion of patients within guidelines targets was found only for serum Ca (79 vs. 67.4%, P<0.05). Treatment with low Ca dialysate concentration of 1.25 mmol/L continued to be an underused option (3.7 vs. 6.1%), while the 1.75 mmol/L was still the standard dialysate in the majority of patients (57.7 vs. 64.2%). The dose of calcium carbonate was significantly reduced (2.77±1.71 vs. 3.06±1.54, P<0.01) in 2009 compared to 2005. The mean of the achieved targets increased significantly in 2009 (2.33±1.05 vs. 2.13±1.03, P<0.01). There was an improved control of all bone and mineral parameters in our dialysis units, following the publication of the CKD-MBD KDOQI guidelines. In order to improve the iPTH values, a more frequent use of low Ca dialysate (1.25 mmol/L) and of non-calcium-based phosphate binders in this small subset of patients should be implemented, as recommended by the guidelines. Individualization of the CKD-MBD management may be successful, even when newer treatment options are not available. Finally, the guidelines implementation process should be a continuous and self-monitored process, with the help of periodic surveys.

Orally administered l-ornithine reduces restraint stress-induced activation of the hypothalamic-pituitary-adrenal axis in mice

In a previous study, we confirmed that orally administered l-ornithine can be transported into the brain of mice. In addition, orally administered l-ornithine, within a limited dose range, had an anxiolytic-like effect in the elevated plus-maze test. However, the mechanism by which orally administered l-ornithine reduced the stress response in mice is still unclear. Experiment 1 determined whether orally administered l-ornithine could reduce the stress-induced activation of hypothalamic-pituitary-adrenal axis. Mice were orally administered l-ornithine (0, 0.75, 1.5 and 3mmol/10ml/kg, p.o.), and restrained for 30min from 30min post administration. There was a significant decrease in the corticosterone levels in the group receiving 0.75mmol of l-ornithine compared to the control group. In Experiment 2, the effect of orally administered l-ornithine (0 and 0.75mmol/10ml/kg, p.o.) on endogenous monoamine release was investigated using in vivo microdialysis. Only the monoamines metabolites 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC) and homovallinic acids (HVA) were detected in the present study. Dialysate concentrations of 5-HIAA, DOPAC and HVA were not significantly changed immediately after administration of l-ornithine and restraint stress. In conclusion, changes of corticosterone concentrations by orally administered l-ornithine were not related to alterations in brain monoamine metabolisms.

Feasibility of Using Dialysis for Determining Calcium Ion Concentration and pH in Calcium‐Fortified Soymilk at High Temperature

Dialysis was performed to examine some of the properties of the soluble phase of calcium (Ca) fortified soymilk at high temperatures. Dialysates were obtained while heating soymilk at temperatures of 80 and 100 °C for 1 h and 121 °C for 15 min. It was found that the pH, total Ca, and ionic Ca of dialysates obtained at high temperature were all lower than in their corresponding nonheated Ca-fortified soymilk. Increasing temperature from 80 to 100 °C hardly affected Ca ion concentration ([Ca²⁺]) of dialysate obtained from Ca chloride-fortified soymilk, but it increased [Ca²⁺] in dialysates of Ca gluconate-fortified soymilk and Ca lactate-fortified soymilk fortified with 5 to 6 mM Ca. Dialysates obtained at 100 °C had lower pH than dialysate prepared at 80 °C. Higher Ca additions to soymilk caused a significant (P≤ 0.05) reduction in pH and an increase in [Ca²⁺] of these dialysates. When soymilk was dialyzed at 121 °C, pH, total Ca, and ionic Ca were further reduced. Freezing point depression (FPD) of dialysates increased as temperature increased but were lower than corresponding soymilk samples. This approach provides a means of estimating pH and ionic Ca in soymilks at high temperatures, in order to better understand their combined role on soymilk coagulation.

Solute transport in dialyzer : A law existing among the solute concentrations in inlet blood, inlet dialysate, and outlet blood.

Solute transport in dialyzer : A law existing among the solute concentrations in inlet blood, inlet dialysate, and outlet blood.

Dialysate bath and QTc interval in patients on chronic maintenance hemodialysis: pilot study of single dialysis effects

Serum concentrations of potassium (K) and calcium (Ca) influence ionic currents and play an important role in the duration of ventricular action potential. Further, the influence of alkalosis in reducing ionized calcium has been well known for a long time. The aim of this study was to assess the effects of different dialysate electrolytes and bicarbonate concentrations on changes of QTc interval in patients on chronic hemodialysis. The study hemodialysis sessions were performed in 22 patients, with different electrolyte and bicarbonate concentrations in dialysate. Tested dialysate concentrations were K of 2 and 3 mmol/L; Ca 1.25, 1.5 and 1.75 mmol/L; and bicarbonate 30 and 34 mmol/L. An electrocardiogram (ECG) was recorded 1 hour before, at the end and every hour for 4 hours after each study dialysis session. QTc interval was measured from the beginning of the QRS complex to the end of a T wave on a 12-lead ECG. Blood was collected and K, total Ca, ionic Ca and pH evaluated. At the end of the study hemodialysis session with dialysate containing low K (2 mmol/L), low Ca (1.25 mmol/L) and high bicarbonate concentration (34 mmol), mean QTc interval was significantly prolonged compared with that recorded with dialysate containing high K (3 mmol/L), high Ca (1.75 mmol/L) and bicarbonate (30 mmol) (40 ± 10 milliseconds vs. 2 ± 2 milliseconds; p<0.01). Dialysate with low concentration of low Ca, K and high concentration of bicarbonate was an independent predictor of QTc; the combination of low Ca and K and high bicarbonate strongly increased the risk of prolonged QTc interval. The present pilot study shows that changes in QTc interval during hemodialysis depend on both electrolyte and bicarbonate concentrations in dialysate.

Dialysate sodium, serum sodium and mortality in maintenance hemodialysis

Individuals with end-stage kidney disease appear to have stable pre-dialysis serum sodium concentrations over time, with lower values associating with increased mortality. Dialysate sodium concentrations have increased over many years in response to shorter treatments, but the relationship between serum sodium, dialysate sodium and outcomes in chronic hemodialysis patients has not yet been systematically examined. We studied a cohort of 2272 individuals receiving thrice-weekly hemodialysis treatment. Available data included demographics, laboratory and clinical measures, details of the dialysis prescription and 30-month follow-up. We examined the distribution of serum and dialysate sodium among subjects and compared mortality according to dialysate and serum sodium concentrations using Cox regression models. Dialysate sodium concentration varied within and among dialysis centers. The pre-dialysis serum sodium concentration (mean 136.1 mmol/L) did not differ across dialysate sodium concentrations. There was evidence for effect modification for mortality according to differing serum sodium and dialysate sodium concentrations (P=0.05). For each 4 mmol/L increment in serum sodium, the hazard ratio for death was 0.72 [95% confidence interval (CI) 0.63-0.81] with lower dialysate sodium compared to 0.86 (95% CI 0.75-0.99) for higher dialysate sodium. Higher dialysate sodium concentration was associated with mortality at higher, but not lower, pre-dialysis serum sodium concentrations. The pre-dialysis serum sodium concentration appears to be unaffected by the dialysate sodium concentration. The relationship between serum and dialysate sodium and mortality appears to be variable. Further research is warranted to determine the biological mechanisms of these associations and to re-examine total body sodium handling in hemodialysis.

Effects of acute ethanol on corticotropin-releasing hormone and β-endorphin systems at the level of the rat central amygdala

The endogenous opioid and corticotropin-releasing hormone (CRH) systems, present in the central amygdala (CeA), are implicated in alcohol consumption. The purpose of this study is to investigate the hypothesis that, in CeA, alcohol stimulates CRH release, which then stimulates β-endorphin release. Rats were unilaterally implanted with a guide cannula to aim microdialysis probes in CeA. Experiment 1: rats received an intraperitoneal (IP) injection of various ethanol doses (0.0, 2.0, 2.4, or 2.8 g ethanol/kg body weight) and microdialysates were sampled at 30-min intervals to determine the effects over time of acute alcohol on the extracellular CRH concentrations in CeA. Experiment 2: phosphate-buffered saline, CRH, or CRH receptor (CRHR) antagonists (antalarmin or anti-sauvagine-30) was microinjected into CeA followed by a saline or 2.8 g/kg ethanol IP injection to determine the effects of CRHR activation or blockade in CeA on the basal and alcohol-stimulated release of β-endorphin. CRH and β-endorphin dialysate contents were determined using specific radioimmunoassays. Acute alcohol induced a delayed increase in the extracellular CRH levels in CeA. Behavioural data showed no difference in locomotion between alcohol- and saline-treated rats. However, a transient increase in grooming was observed which did not correspond with alcohol-induced changes in CRH. Local CRH microinjections increased the extracellular β-endorphin concentrations in CeA. CRHR1 and CRHR2 blockade with microinjections of antalarmin and anti-sauvagine-30, respectively, attenuated the alcohol-induced increase of extracellular β-endorphin in CeA. Acute alcohol exerts indirect actions on CRH release and induced interactions of the CRH and β-endorphin systems in CeA.

In-vivo calibration of microdialysis probe by use of endogenous glucose as an internal recovery marker: measurement of skin distribution of tranilast in rats.

To estimate the absolute concentration of substrates surrounding a microdialysis probe in-vivo, we developed a simple calibration method using endogenous glucose as an internal recovery marker and determined the skin distribution of tranilast (N-(3,4-dimethoxy-cinnamoyl)anthranic acid), an anti-allergic agent, in rats. This calibration method was based on the assumption that the concentration of glucose in the extracellular fluid of skin tissues is the same as that in plasma and that the in-vivo recovery ratio of glucose to tranilast by microdialysis is the same as that estimated in-vitro. Based on these assumptions, the dialysate concentrations of tranilast and glucose recovered from cutaneous microdialysis, glucose concentration in plasma, and in-vitro recovery ratio of tranilast to glucose by microdialysis were determined for the estimation of absolute unbound concentration of tranilast in the extracellular fluid of skin tissues. In an in-vitro study employing plasma containing tranilast, the unbound concentration of tranilast in plasma estimated from the dialysate concentration was just comparable with that determined by ultrafiltration methods. Also in an in-vivo study under steady-state plasma concentration of tranilast in rats, the estimated concentration of tranilast in the skin extracellular fluid was the same level as the unbound concentration of tranilast in plasma. Using the present calibration method, the skin distribution of tranilast administered into the intestinal loop or transdermally was continuously monitored in a quantitative manner.

17 The Polyethersulfone Membrane “Express” Has a Higher Piperacillin/Tazobactam Clearance Independant of the Dialysis Dose

THE POLYETHERSULFONE MEMBRANE “EXPRESS” HAS A HIGHER PIPERACILLIN/TAZOBACTAM CLEARANCE INDEPENDANT OF THE DIALYSIS DOSE. Milen Amde, Charbel Salem, Joseph Groszek, Michael Connor, Seth Bauer, William Fissell; Cleveland Clinic Foundation, Cleveland, Ohio. In the intensive care setting, infection remains the leading cause of death in AKI. The goal of our study is to assess the impact of membrane types and continuous veno-venous hemodialysis (CVVHD) dose on the clearance and serum levels of piperacillin-tazobactam (piptazo). Using high-performance liquid chromatography (HPLC), we measured the serum and dialysate concentrations of pip-tazo. We then calculated the total clearance and area under the curve (AUC) of the drug in 28 anuric ICU patients who were on CVVHD for uninterrupted 24 hours and received 3.375 g Pip-Tazo q 8 hours (n=21) or q 12 hours (n=7). The 15 patients on the polyacrylnitrile M100 had a total pip clearance of 50.3±17.56 ml/min compared to 64.28±25.77 ml/min in the 13 patients on the polyethersulfone membrane Express. We used regression analysis to examine the association between total clearance, trough level, AUC and the variables; filter type, CVVHD dose and dosing interval (the latter was included in the trough level and AUC analysis only). We showed a trend towards lower total clearance with the M100 membrane compared to the Express membrane (coefficient of -11.62, p=0.0203). There was a trend towards lower AUC with higher CVVHD dose (coefficient of -83.2, p=0.0281) and less frequent dosing (-3.8 coefficient for q12 vs q8, p=0.0322) independent of membrane type. In conclusion, the membrane type and the CVVHD dose should be considered when deciding on antibiotics dosage in the critically ill patient. Larger studies are needed to study the impact of CRRT on antibiotics target pharmacokinetic levels and whether more frequent dosing of antibiotics would affect outcomes.

Pharmacokinetic Profiles of Ceftazidime after Intravenous Administration in Patients Undergoing Automated Peritoneal Dialysis

The pharmacokinetics (PK) of ceftazidime after intravenous (i.v.) administration during automated peritoneal dialysis (APD) and their dependence on peritoneal membrane transport are the targets of the present study. Eleven patients receiving a single i.v. dose of ceftazidime (15 mg/kg of body weight) (seven males, median [interquatile] age, 59 [36 to 62]) were recruited. Serum and dialysate samples were collected at the beginning, middle, and end of each of the five dwells during a 24-h period, with dwells 1, 2, and 3 using an automated cycler (designated on-cycler) and dwells 4 and 5 being manual exchanges (designated off-cycler), together with urine collection during the same period. Population PK analysis was employed to estimate the PK parameters. Peritoneal equilibration tests were performed for all patients, and correlations between peritoneal clearance (CL(PD)) for ceftazidime and dialysate-to-plasma ratios for creatinine (D/P(cr)) were obtained using the Spearman's product correlation coefficient (ρ). Ceftazidime renal clearance (CL(renal)) was 0.052 ml/min/kg, and CL(PD) was 0.063 ± 0.050 ml/min/kg. CL(PD) for on- and off-cycler were 0.071 and 0.058 ml/min/kg (P = 0.164), respectively. A significant correlation between CL(PD) and D/P(cr) was observed, with one outlier excluded, suggesting that CL(PD) for ceftazidime during APD is dependent upon the peritoneal small-solute transport rate. A model prediction yielded adequate serum and dialysate concentrations of ceftazidime throughout a 24-h period for sensitive organisms (MIC, 8 μg/ml) by either i.v. (at 15 mg/kg) or intraperitoneal (i.p.; at 20 mg/kg) administration during off-cycler dwells. The present study suggests that the i.v. administration of ceftazidime at 15 mg/kg or i.p. administration of ceftazidime at 20 mg/kg during a long dwell every 24 h can be recommended for treating systemic or intraperitoneal infections of APD patients.