Pharmacokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function.

The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 +/- 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 +/- 0.22 mg/L and 0.36 +/- 0.21 mg/L, respectively). Using 14C-labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration-time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate-induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen-induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three- to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.

The correlation between protein catabolic rate and Kt/V in hemodialysis is not a mathematical artifact.

To test whether the demonstrated correlation between Kt/V urea and normalised protein catabolic rate (NPCR) is caused by a mathematical artifact, we examined 12 adult and 8 paediatric haemodialysis patients. Kt/V was determined by the classical method. As an equivalent of NPCR we measured normalised urea generation rate (NUGR) by a one-week collection of dialysate and urine using total body water estimated by bioelectrical impedance for normalisation. The correlation between Kt/V and NUGR was 0.58 (all), 0.55 (adults), and 0.62 (children). Since the determination of Kt/V and NUGR are not interdependent, we conclude that the correlation between Kt/V and protein catabolism is not artifactual.

Two-sample hemodialysis urea kinetic modeling: validation of the method.

Urea kinetic modeling (UKM) by a two-sample method (UKM2) was compared with the classical three-sample method (UKM3) and direct quantification. Assuming the patient to be in a weekly steady state and using an approximate treatment schedule, UKM2 can compute urea generation rate (G), distribution volume (V), Kt/V, and normalized protein catabolic rate (NPCR). Twenty-three stable patients were examined. The results obtained by UKM2 and UKM3 differed little (G -4.2%, V -1.0%, Kt/V 0.9%, NPCR -2.7%), and the correlations between them were high (r > or = 0.96). The differences between UKM2 and direct quantification were greater, but also highly correlated. G determined midweekly by UKM2 was highly correlated with G found directly from 1-week collection of dialysate and urine (r = 0.96). Repeating analysis over a 5-week period, the results obtained by UKM2 varied no more than those obtained by UKM3 (around 8% for all four kinetic variables). In conclusion, UKM2 produces reliable results requiring less data to be entered than using UKM3.

Reliability of haemodialysis urea kinetic modelling in children.

The reliability of urea kinetic modelling (UKM) in paediatric haemodialysis was tested by comparing results of the classic variable volume model (UKM3), a recently introduced two-sample modification of this (UKM2) and direct quantification by a partial dialysate collection method (PDC). Urea generation rate (G) was also found from a 1-week collection of dialysate and urine (OWC). Nine children aged 2-18 years and weighing 10.6-39.9 kg were examined over 1 week (25 treatments). UKM3 and UKM2 gave almost identical results, but deviated from PDC and OWC. The two indirect methods overestimated G by 24% and 18%. However, the correlations between the results were very high for all variables and all methods (r > or = 0.96). Repeating UKM3 and UKM2 mid-week for 5 consecutive weeks, the following coefficients of variation were found: for the normalised whole body urea clearance (Kt/V) 10% and 11%, respectively; for normalised protein catabolic rate 17% and 14%. It is concluded that all tested methods can be used, but each method requires its own reference interval. Results of UKM seem to vary somewhat more than in adults. This should be considered when assessing children by such methods.

Comparison of extra-cellular fluid volume measurement in children by 99Tcm-DPTA clearance and multi-frequency impedance techniques.

Comparisons of extra-cellular fluid (ECF) volume estimates made by isotope dilution and electrical impedance techniques have been made in a group of 16 children. For each patient an estimate of ECF volume (Vt) was obtained from measurements of the blood clearance of 99Tcm-diethylene triamine penta-acetate (DPTA) which was compared with two estimates (Vi1 and Vi2) of ECF volume obtained from measurements of the whole-body electrical impedance at 50 frequencies in the range 1 kHz to 1.348 MHz and a third estimate Vh based on patient height, L, alone. The observed frequency response of the impedance measurements was fitted to a three-element equivalent-circuit model of whole-body impedance and gave a value of the ECF resistance R. Vi1 was obtained from Vi1 = a (L2/R) + b. Vi2 was given by c(W1/2L2/R)2/3 where W is the patient weight, and Vh was given by dL2 + e. The constants a, b, c, d, e were determined by comparison with Vt and were equal to 0.335 l omega m-2 (standard error = 0.01 1 omega m-2), 0.42 l (0.25 l), 0.33 l (omega 2kg-1m-4)1/2 0.007 l (omega 2kg-1m-4)1/3, 4.92 l m-2 (2.8 x 10(-5) lm-2), 0.13 l (0.41 l), respectively. Vi1, Vi2, Vh were linearly correlated with Vt (r2 = 0.98, 0.99, 0.95, respectively, p < 0.001), and upper and lower levels of agreement were given by +/- 0.95 l (Vt and Vi1), 1.44 l and -1.12 l (Vt and Vi2), +/- 1.5 l (Vt and Vh), respectively. Thus inclusion of the impedance data accounted for greater volume variation, but differences between the techniques were not significant (paired t-test and Mann-Whitney analysis) suggesting that more accurate and detailed measurements are required.

Haemodialysis recirculation measured using a femoral artery sample.

The traditional method for measuring vascular access recirculation has been questioned. We have compared methods based on samples from the femoral artery, a peripheral vein, and a slow flow technique. Seventeen patients on high-flux haemodialysis with blood flow 355 +/- 42 ml/min were examined after 60 min of treatment. Using urea as the marker solute, recirculation was 0.0 +/- 1.8% (femoral artery), 6.7 +/- 2.7% (peripheral vein), and 4.7 +/- 1.6% (slow flow), and using creatinine 0.1 +/- 1.4% (femoral artery), 7.8 +/- 3.0% (peripheral vein) and 2.9 +/- 1.2 (slow flow). Access recirculation was non-existent among these patients when using the femoral artery sample: maximum 3.1%. In contrast, the traditional method (peripheral vein) produced values up to 13.5%. The observed differences can be explained by cardiopulmonary recirculation. Blood returning from the periphery mixes with blood returning from the dialyser, so that solute concentration will be less in femoral artery than in peripheral vein. In conclusion, neither the traditional method nor slow-flow techniques accurately quantify access recirculation. Cardiopulmonary recirculation must be considered in kinetic studies, including routine dialysis prescription, where samples should be taken at least 2 min after termination of dialysis.

Medical reasoning and patient requests in decision-making for female genitourinary infections.

The aim of this study was to investigate General Practitioners' (GPs') collection and analysis of data on women presenting with lower genitourinary (GU) complaints, also taking into account patient preferences. For 135 patients seen after nurse triage, eleven GPs recorded the clinical data they had explored, an evaluation of the patient's desire (or not) for medical interventions, a preliminary diagnosis with certainty estimate, and management actions. Whether a clinical data item was explored varied between 97% of the patients for fever to 15% for pelvic examination. Decisions regarding diagnosis followed to a large extent results from screening laboratory tests. For prescription of antibiotics the patient's desire (or not) for medical interventions was a significant discriminant. The GPs reported the lowest diagnostic certainty for diagnosis of urethritis, the highest for cystitis. Factors contributing to physicians' uncertainty in their decision-making were assumed patient reluctance for medical interventions and negative screening tests. In conclusion, patient requests and preferences significantly influenced the GPs, even though results from screening laboratory tests were mainly used as the basis for decisions. The high reliance on screening tests may often cause other clinical information to be neglected. Thus, the uncertainty regarding patients with negative laboratory test results may reflect that important information is not included in the clinical analysis.

Pharmacokinetics of felodipine in chronic hemodialysis patients.

Five chronic hemodialysis patients (1 woman and 4 men, aged, 46-68 yr) were given an oral dose of 10 mg felodipine followed by 0.057 mg [3H] felodipine IV. After 5 hours, a hemodialysis treatment lasting 4 hours was performed. Blood and dialysate flows were 200 mL/min and 500 mL/min, respectively. Capillary dialyzers with 1.3 m2 cellulose acetate membrane were used. The pharmacokinetic characteristics and reduction in diastolic BP were similar to those in hypertensive patients with normal renal function and in uremic patients who were not treated with dialysis. There was no measurable removal of felodipine by hemodialysis. Dialyzer clearance of radioactive metabolites was about 10 mL/min, and only 8.9% of the dose was eliminated by the treatment. The half-life of radioactive metabolites was 10 days (6-14 days) in three patients dialyzed thrice weekly. Since the metabolites are biologically inactive, no adjustment of dose is required in hemodialysis patients.

Precision of hemodialysis urea kinetic modeling: empirical data and Monte Carlo simulation.

To examine the precision of variable volume urea kinetic modeling (UKMv) 15 stable hemodialysis patients were followed with repeated sampling for 5 weeks. Samples were frozen and later submitted to careful batch analysis. On average, the index for dialysis adequacy (Kt/V) varied 6.1% and normalized protein catabolic rate (pcr) varied 10.5%. Immediate routine analysis correspondingly rendered 8.6% and 13.2%. A simpler, fixed volume model (UKMf) had an almost similar variation and results correlated highly with UKMv. The duration of the preceding interval does not affect Kt/V, but per is lower during longer intervals. Computer simulation demonstrated that most of the variation of calculated pcr could be explained by fluctuations of urea generation, i.e., secondary to dietary changes. Fluctuations in the efficiency of dialysis may cause most variation of Kt/V, but the imprecision of the urea analysis also contributes. Precise knowledge of effective dialyzer clearance is not important for the calculation of Kt/V and pcr. It is concluded that calculating these variables with a simple model, employing a reasonable estimate of dialyzer clearance will suffice for routine use. The slightly higher accuracy of a more sophisticated model is overshadowed by day-to-day variations.

Accuracy of hemodialysis urea kinetic modeling. Comparison of different models.

To test the accuracy of urea kinetic modeling (UKM), the classic fixed-volume model UKMf, two variable-volume models (UKMvb and UKMvd), direct dialysis quantification (DDQ) and a partial dialysate collection method (PDC) were evaluated in 15 stable, high-hematocrit patients. Urea generation rate (G) was also determined from a 1-week collection of total dialysate and urine (OWC). The results, except distribution volumes, were highly correlated. However, Kt/V, the normalized whole-body urea clearance, was about 8% higher with UKMvb and UKMvd. Two of three simple equations for Kt/V rendered grossly deviating, but highly correlating, results. The normalized protein catabolic rate was 8% higher with UKMvd. With OWC as reference, UKMvb and UKMvd overestimated G by 19 and 15%, respectively. All results of PDC closely followed those of DDQ. This method may be an alternative for exact quantification. Before using a new UKM method it should be compared to an established reference method.

Secondary effects of erythropoietin treatment on metabolism and dialysis efficiency in stable hemodialysis patients.

To test the possible effect of erythropoietin (EPO) induced higher hematocrit on dialysis efficacy and metabolism, 14 metabolically stable hemodialysis patients were evaluated with various kinetic methods, including total dialysate collection. Tests were performed twice before EPO treatment and twice when hemoglobin had stabilized in the targeted range. Samples were frozen and batch analyzed for each patient after completion of the study. During this period, dialysis regimens were fixed. EPO treatment caused several significant changes. Hematocrit increased from 21.5% to 34.3%. Pre- and postdialysis serum potassium increased 0.3-0.4 mmol/l, and 56% more potassium binder was given. Serum phosphate concentrations were unchanged, but the aluminum hydroxide dose had been raised 44%. Dialyzer clearance decreased for urea (4.8%), creatinine (14.7%), phosphate (16.5%) and potassium (8.6%). The ratio of postdialysis/predialysis measurements changed for calcium, creatinine and uric acid. Five patients experienced enhanced appetite, but average dry weight did not change, nor could changes be demonstrated for protein catabolism, generation rate of urea and creatinine, or their distribution volumes. Estimated sodium intake remained unchanged. The findings indicate that EPO treatment reduces dialysis efficiency slightly for a number of substances, but in the metabolically stable patient there are no impressive dietary changes. Problems can be overcome by appropriate changes of dialysis regimen and medication.

Improvement of decisions regarding hemodialysis patients by urea kinetic modeling.

The potentials for improving decisions about adequacy of dialysis (AD) and daily protein intake (DPI) by urea kinetic modeling (UKM) were examined. Four nephrologists evaluated AD, DPI, and metabolic stability in 62 patients. UKM was done three times; but the results were not revealed. Clinicians' decisions were then compared with UKM measures of effective dialysis (Kt/V) and protein catabolic rate (pcr). Detection of inadequately treated patients by the clinicians was poor (28%, Kt/V less than 1.0; and 40%, Kt/V less than 0.9). Specificities of the clinicians' decisions were 0.96 and 0.92, respectively. Combining pcr and consensus decisions, 59 patients could be assigned a probable DPI. Using this as "gold standard," the average clinician detected 77% of 13 low DPIs. Single or triple pcr determinations alone detected 77% or 62%, respectively. Specificities were 0.91, 0.85, and 1.0. Simulated decision making suggested that combining pcr with clinical evaluation in a logical way would lead to detection of most patients with low DPI. Qualitative data from individual patient cases causing controversies are presented and discussed. It is concluded the UKM should be used routinely to assess the adequacy of dialysis and daily protein intake.

Inter-observer variation in decision-making regarding patients on chronic hemodialysis: a study using the kappa index.

To examine inter-observer variation in the monitoring of patients with chronic disease, four nephrologists independently assessed 62 patients on maintenance hemodialysis. Deviation from normal was determined for adequacy of dialysis, protein intake, and metabolic state. The kappa-index, which allows to adjust for chance agreement, was used to analyze each monitoring diagnosis. Low agreement was found on decisions concerning adequacy of dialysis (kappa 0.12-0.26), while agreement was higher about protein intake (kappa 0.21-0.46), and metabolic state (kappa 0.24-0.52). Two physicians classified no patient as overdialyzed, while 16-18% were thus categorized by the other two. Routines for review of recent medical history also differed significantly between the physicians. Measures are needed to increase the reliability of decisions regarding the monitoring of chronic hemodialysis. A long lasting physician-patient relationship is not a sufficient prerequisite for diminishing decision variation. Medical audit as part of the clinical routine, and use of additional sources of information, exemplified by urea kinetic modeling, are discussed.

DiaKin: an integrated program package for hemodialysis kinetics.

A flexible program for the IBM PC performing a number of calculations of relevance for the prescription of hemodialysis treatment has been developed. The program has a 'spreadsheet'-like user-friendly interface, and results may be presented graphically. The present implementation covers 89 algorithms/equations, all based on the assumption of single-pool kinetics. Some of these are detailed for the first time, including considerations on their implementation using a generalizing, structured approach.

Audit of decision-making regarding female genitourinary infections in outpatient practice.

Patient data, diagnosis, work-up measures, and prescriptions were collected from 63 consultations by general practitioners (GPs) to study day-to-day management of women with complaints suggestive of genitourinary (GU) infections. The collected patient data were thereafter presented to a panel of 9 specialist physicians for their individual recommendations. On drug prescriptions, the panel supported 81% of the decisions, did not support 14%, and remained undecided on 5% of the cases. In all but one of the unsupported cases, the GP had prescribed antibiotics. On diagnoses, the panel supported 62% of the decisions, did not support 13%, and was undecided on 25% of the cases. The most frequent discordance concerned diagnosis of urethritis. On collection of medical data by history and physical examination, the panel found 22% of the consultations unsatisfactory. Discordance in both diagnosis and drug prescription were related to remarks about data collection. The results suggest that the body of knowledge available for GPs for management of female GU infections in outpatient practice is incomplete.

Urea kinetics and clinical evaluation of the haemodialysis patient.

Urea kinetic modelling (UKM) was performed on 62 patients in a haemodialysis unit not normally using kinetic methods. Without knowledge of the results, four nephrologists, four nurses and the patients themselves evaluated adequacy of dialysis (eAD) and daily protein intake (eDPI). Thirty-two patients had Kt/V less than 1.0, and 17 patients had Kt/V less than 0.9. Estimated improvement of the efficacy of treatment after the intervention of a physician was minor. Seven patients had a protein catabolic rate (pcr) at less than 0.8 g/kg per day. On average physicians identified five of these. Both nurses and doctors exhibited highly significant correlations between Kt/V and eAD, and between pcr and eDPI, but the correlation coefficients were generally modest (typically below 0.4). When patients evaluated themselves, no significant correlations were found. Examined individually, all four physicians' decisions about eAD correlated better with model-generated decisions than with eAD stated by their colleagues. It is concluded that UKM should be used to secure adequate and more uniform treatment prescription. There is no 'clinical standard' competing with UKM. Nurses make satisfactory evaluations compared to doctors, but the patients are unable to assess the adequacy of their dialysis or diet.

Pharmacokinetics of chloral hydrate poisoning treated with hemodialysis and hemoperfusion.

In a severe case of chloral hydrate intoxication treated with combined hemodialysis and hemoperfusion the pharmacokinetics of the metabolites trichloroethanol (TCE), trichloroethanol glucuronide (TCE-Glu) and trichloroacetic acid (TCA) were studied. Indications of delayed absorption and some slowing of metabolism were found. At a blood flow rate of 200 ml/min clearances by hemodialysis and hemoperfusion, respectively, in ml/min were estimated to be 188 and 156 for TCE, 184 and 181 for TCE-Glu, 142 and 91 for TCA. Clearance by hemoperfusion declined with time. The half-lives of TCE and TCA were 3.2 and 4.3 hours during combined hemodialysis and hemoperfusion. After termination of treatment the half-life of TCE was 12.8 hours, whereas TCA was metabolized so slowly, that no reliable calculation could be performed. We conclude that hemodialysis and hemoperfusion are equally and highly efficient in the treatment of chloral hydrate poisoning, but hemoperfusion may increase the risk of gastric bleeding more than hemodialysis. Hemodialysis may therefore be preferable and should be tried in spite of low blood pressure.