Biomedical subjects
Publications and source records attributed to P C Farrell.
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The protein binding of 14C-hippurate has been measured by conventional ultrafiltration techniques in the plasma of normal subjects and in uremic subjects pre- and postdialysis. In addition, the clearance of 14C-hippurate was determined in vitro in both isotonic saline and plasma to assess binding limitations on hippurate removal during dialysis. Binding levels of hippurate in normal subjects of 68+/-1.8% (n = 5) were significantly higher than either postdialysis (48.3+/-15.4%; n = 7) or predialysis (36.6+/-11.7%; n = 7) levels in the same uremic subjects. Actual levels of plasma hippurate were, however, considerably greater in uremics (24.7+/-11.2 mg/dl' n = 7) than in normal subjects (congruent to 0.5 mg%). The difference in hippurate binding between pre- and postdialysis samples in uremics was significantly different from zero (p less than 0.01, t = 5.36), indicating depletion of competitive site-binding species during dialysis. The saline clearance of hippuric acid (99.1 +/-0.5 ml/min; n = 6) under standard conditions in a capillary dialyzer (CDAK-4) was consistent with the expected clearance of a solute of its molecular weight. Hippurate clearance in citrated plasma, where binding was determined as 50+/-3%, was 65+/-0.7 ml/min (n = 6), in good agreement with a theoretically predicted clearance of 60 ml/min for this level of binding. High serum levels of hippurate and its derivatives, may depress effective function of various organs. In addition to the normal dietary intake of hippurate and its precursors, patients on dialysis receive a further burden of hippurate precursor in the form of benzyl alcohol, the common preservative in heparin solutions. The large body burdens of hippurate in dialysis patients, coupled with its impaired removal on dialysis due to binding, point to the necessity for a through investigation of the potential toxicity of this compound.
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A pharmacokinetic model for minimal dose heparinization for chornic hemodialysis patients was recently described by Gotch and Keen. The model requires the determination of two parameters: dose sensitivity (computed for a given heparin dose from increase in WBPTT above a baseline value) and the heparin elimination constant. This study describes the extension of this model to the more precise control of anticoagulation during routine dialysis. S and K were measured in 30 stable chronic dialysis patients and were found to differ markedly (0.015 less than or equal to S 0.08 sec/unit; 0.04 less than or equal to K less than or equal to 1.7 hr-1). The mean S value was 0.041 +/- 0.002 sec/unit (N = 30) and the mean K value was 0.90 +/- 0.06 hr-1 (N = 30). In addition, the mean t 1/2 of heparin obtained in the group of 30 patients from individual rate constants was 0.86 +/- 0.06 hr, in excellent agreement with values obtained in normal subjects given similar doses of the drug. Variations in sensitivity during dialysis were minimal, but variations in elimination rate of up to 50% were encountered during modeling. However, the large variations in K did not affect the applicability of the model of control clotting times during dialysis when infusion requirements were based on mean values of S and K taken over four to five dialyses. In an initial group of five patients, whose heparin requirements were reduced by an average of 38% +/- 20 (range 13% to 65%), there was no significant change in the degree of dialyzer clotting in comparing premodeling and postmodeling heparin therapy. In most of the remaining patients (N = 22) the pattern was similar: a reduction in total heparin administration without increased dialyzer clotting. In three patients (10%) over-all heparin dose had to be moderately increased (3% to 13%). Heparin modeling has been successfully applied to routine anticoahe technique cannot be extended to other clinical procedures involving either intermittent or continuous infusion of heparin. To assist in the application of heparin modeling, nomograms have been developed.
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The performance characteristics of nine currently available disposable parallel-flow dialyzers were assessed, both before and immediately following dialysis, by measuring: (i) in vitro clearances of C14 labeled urea, creatinine, and sucrose and H3 labeled vitamin B12 at standard conditions, (ii) ultrafiltration rates in saline at 37C, and (iii) loss in the mass transfer coefficient-membrane area product (hoA), following a single dialysis. Parallel-plate dialyzers underwent considerable membrane stretching during dialysis and exhibited greater variability, particularly regarding vitamin B12 clearance and ultrafiltration ability, than did capillary dialyzers. The variability in plate units was greater for large-area dialyzers where there were 25 to 26 blood channels. However, despite considerable differences in performance characteristics, all dialyzers were judged to be clinically acceptable in terms of both solute clearance and ultrafiltration characteristics.
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For patients with chronic renal disease, haemodialysis can provide reasonable rehabilitation and, in most cases, a life expectancy in excess of 10 years. However, dialysis is unable to provide for any loss of the kidneys' endocrine or metabolic activities and the kidneys' excretory capacity is only replaced suboptimally. Recent well controlled studies on the frequency, time and techniques of dialysis, instigated mostly as a consequence of recent hypotheses, such as the "middle molecule" theory and consideration of the potential importance of residual renal function, have resulted in a complete reassessment of the nature of adequate dialysis. Developments such as sorbent-based dialysis are leading to a wearable dialyser. Theoretical and hardware developments are providing not only more adequate treatment, but improved rehabilitation for those patients on chronic dialysis therapy.
A large-area short-time (LAST) haemodialysis regimen (three hours by three times per week on a 2-5 M2 haemodialyser) has been compared with conventional haemodialysis (six hours by three times per week on a 1-3 M2 haemodialyser) on four patients over a period of eight months. Parameters monitored throughout the study included: Serum biochemistries, haematocrit, extra-cellular fluid space, platelet function, granulocyte kinetics, immunological status and neurological status. All patients showed weight increases (3--12%) during the LAST dialysis period. These increases were related to problems of intradialytic hypotension which resulted from the increased rate of fluid removal required during the LAST dialysis period. Hypotension was not a problem during routine dialysis all patients showed an increase of 10--20% (P less than 0-05) in predialysis serum urea and creatinine and a moderate decrease in predialysis serum bicarbonate (from 24-8 +/- 2-2 to 21-4 +/- 2-6 mM/I, P less than 0-005). This study indicates that, providing fluid balance can be controlled, a LAST dialysis regimen provides comparable therapy to conventional haemodialysis. However, recent studies have suggested that short-time dialysis may be possible with conventional 1-0 to 1-3 M2 haemodialysers, indicating that short-time haemodialysis may not need to involve more costly large-area haemodialysers.
A commercially available sorbent-based dialysate regeneration system has been compared to conventional single-pass dialysate delivery systems for treatment periods of six weeks in 13 patients on maintenance dialysis. The results of treatment were virtually identical in comparing sorbent and conventional systems except that seven of the eight patients using 2-5 M2 dialysers for 3--4 hours thrice per week developed asymptomatic metabolic acidosis with the dialysate regeneration system. This complication was not seen in the five patients using 1-3 M2 dialysers and having a 6--7 hour treatment thrice weekly. Dialysate regeneration systems are particularly suited for use when water supplies are limited or of insufficient purity for single-pass dialysis, and when a portable artificial kidney is required. To avoid metabolic acidosis with this system, using currently available disposable cartridges, each dialysis treatment should be of at least 4-5 hours duration.
Relative thrombogenicities of several brands of intravascular catheters were measured in the saphenous and cephalic veins of sheep. Differences in thrombogenicity between brands of up to eleven fold were found. At least one brand contained an ingredient which was locally toxic to sheep and which caused phlebitis in cannulated vessels. The brands tested were made from six types of plastics. It is suggested that differences in manufacturing technique may be more important than the type of plastic in determining the thrombogenicity of catheters.
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Aspirin, a drug known to inhibit the platelet release reaction, was evaluated for its potential in reducing platelet/fibrin deposition in hollow fibre dialysers. Twelve patients with endstage renal failure were given the drug under controlled conditions while being treated by regular maintenance haemodialysis. After base-line data were collected during a mean number of 11.7 dialysers per study, observations were repeated for a mean of 9.3 dialysers, during which time each patient took 600 mg of aspirin by mouth every morning. Thrombus deposition, measured by volume loss of the blood compartment of the dialyser fibre bundle, was significantly reduced (P less than 0.05) during aspirin administration in six of the 12 studies. The mean volume loss of the fibre bundle in these six studies (responders) was 25% per dialysis during the control period, and 13% with aspirin; in the other six studies (non-responders), the mean values were 8% and 6% respectively. Aspirin prolonged the bleeding time in all patients, and significantly (p less than 0.05) impaired platelet aggregation in both responders and non-responders.
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