Studies on the biochemical basis of oxygen toxicity.
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Biomedical subjects
Publications and source records attributed to A Besarab.
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Eighteen patients with known past occupational lead exposure underwent parenteral diagnostic chelation with ethylenediaminetetraacetic acid and x-ray fluorescent determination of in vivo skeletal lead stores at the distal styloid process of the ulna and at the temporal base bone using a cobalt 57 source and measuring lead Ka x-rays. X-ray fluorescent lead measurements in both locations correlated with results of diagnostic chelation. Using a post-chelation urinary excretion of greater than 600 micrograms lead/24 h as the definition of "high-" lead stores, sensitivity of x-ray fluorescence at the wrist and temple was 56% and 39%, respectively.
Venous pressure measured by the dialyzer is an unreliable measure of intra-access venous pressure. During dialysis and zero extracorporeal blood flow, intra-access venous limb pressure (VPd) was measured directly 401 times in 133 subjects using a high flow "in-line" three-way stopcock adjacent to the venous return needle. Subjects with systolic VPd/systolic blood pressure (BP) > or = 0.4, inadequate blood flow, or edema in the access extremity were referred for angiography. Percent diameter lumen reduction by a stenosis (%D) > 50% was considered hemodynamically significant. The authors did 138 angiograms. It was found that VPd/BP increased with %D in both ePTFE bridge grafts and native fistulae. Measurements of venous limb VP/BP taken at the time of dialysis and at the time of angiography did not differ (n = 55). On 80 occasions, accesses had significant stenoses. The overall sensitivity of VPd/BP in ePTFE bridge grafts was 91% and specificity 91%. False negative results occurred in seven of 24 native and eight of 114 ePTFE graft studies; 14 of 15 patients had arm swelling caused by central stenosis. Recirculation > 15% was more sensitive (71%) in detecting stenosis in native accesses than was intra-access pressure. It was concluded that VPd/BP > 0.4 is a useful, sensitive, and specific criteria for detecting synthetic bridge graft accesses at risk for thrombosis.
In anemic non-renal and hemodialysis (HD) patients, erythropoietin (EPO) levels vary > 10 fold at any hematocrit (Hct), suggesting marked variation in endogenous EPO production among individuals. We hypothesized that this intrinsic variation that reflects differences in bone marrow sensitivity to circulating EPO could account for the > 10 fold variability in recombinant human erythropoietin (rHuEPO) requirements of HD patients to correct their anemia, and could be evaluated by examining the response to blood loss and measurement of red blood cell (RBC) survival (tau). The renal response to blood loss was studied in normal patients (N = 14) and in non-rHuEPO treated HD (n = 12) patients by measuring the increase in EPO (delta EPO) above basal level. Serum samples were obtained before and after the blood loss event. Delta EPO after a one-unit phlebotomy was larger in normal patients than in HD patients, although delta Hct was larger in HD. Regression of delta EPO against Hct/erythropoietin basal level, an index of bone marrow sensitivity, indicated parallel responses in normal and HD subjects, with the magnitude of response decreased in HD. To exclude an effect of a difference in RBC survival between control and end-stage renal disease (ESRD) patients, we measured more than 16 other patients (Hct 24.1) that averaged 107 days (range 70-140) and were independent of Kt/V (mean 1.01; range 0.67-1.38). Intersubject differences in bone marrow sensitivity to EPO exist and are detected by delta EPO after blood loss. Response of delta EPO to blood loss is diminished, but not abrogated, by renal disease.
Normalized intra-access pressure (PIA), expressed as the access pressure/systemic blood pressure, detects venous outlet stenosis and correlates with access blood flow. General use of (PIA) is limited by time, special equipment needs, and cost. We therefore correlated pressure measurements from the venous drip chamber (PDC of Fresenius H-machines and from an external transducer, P tau, for blood flows (BFR) of 0 to 400-500 ml/min. Measurements were conducted 2-3 weeks apart in a cohort of 33 patients. PDC = -21 + 1.28 P tau; PDC = P tau = 75 mmHg at BFR = 146 ml/min. The major determinant of P tau at BFR = 0 was access type and venous outflow problems. The difference between P tau and PDC (delta = offset) was 17 +/- 1 mmHg (range, 2-43); delta correlated with the height difference between the two sites. Differences in systemic blood pressure, zero calibration, and hydrostatic pressure accounted for 90% of the variance between replicate measurements of PDC. Detection of outlet stenosis was compared by using PIA calculated from P tau and from PDC + 17. Only three of 66 measurements using the latter produced misclassification, and never on replicate measurements. P tau and PDC measurements in 62 additional patients showed a persistent offset of 17 mmHg. The authors conclude that PDC at BFR = 0 can be used to monitor prospectively prosthetic bridge grafts for stenosis as long as the offset for a particular dialysis machine is determined.
The presence of access recirculation reduces delivered urea clearance and produces an increased volume/weight (V/M) ratio in three-point kinetic modeling. We measured R in 20 patients receiving conventional hemodialysis and correlated results with normalized intra-access venous pressure (PIA) and with angiographic or color-flow Doppler studies. Twenty patients were equally divided into those with and without persistently elevated modeled V/W ratios (0.64 vs 0.53), and subdivided into those with native and synthetic bridge graft accesses. Kinetic modeling parameters (Kt/V) and P1A did not differ between the two V/W groups. Modeled volume was quite accurately predicted by the equations in the normal group but deviated by 7.3 +/- 2.1 L in the high V/W ratio group. Three of 10 native and 4 of 10 graft accesses had trivial and hemodynamically insignificant abnormalities by color-flow Doppler or angiography. Recirculation was independent of V/W group and when measured by the slow flow/clamp technique was negligible (< 2.0%). Access flow always exceeded prescribed dialyzer blood flow by more than 300 ml/ min. Therefore, access recirculation was unlikely. In many of the high V/W patients, alternative explanations for falsely high modeled volume were found on follow-up modeling. Only one patient appeared to have a true high volume. The authors conclude that high urea volumes during kinetic modeling are unlikely to occur from access recirculation, but arise from other factors affecting the delivered urea clearance.
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Absolute value of access flow (QA) and change in flow (deltaQA) over time are major determinants of access patency. However, QA may change in response to variation in systemic hemodynamics among dialysis sessions. We examined the effect of mean arterial pressure (MAP), cardiac output (CO), and segmental resistances (R) on QA. Access flow and CO (L/min) were determined by Transonic ultrasound dilution. Static intra-access pressures (mm Hg) at the arterial segment (AS) and venous segment (VS) were determined with the access unoccluded. During access occlusion (O), the AS pressure was equated to arterial pressure (MAPo), whereas the VS pressure reflected venous pressure (VP). Total and segmental vascular resistances (mm Hg-min/L) were calculated as deltaP/Q. We studied 58 arteriovenous (AV) grafts and 35 autologous AV fistulae (AVF) with measurements on two or more occasions in 43 grafts and 25 AVF. MAPC differed from MAPo by >20 mm Hg in 22% of patients. AS (58 +/- 2 vs. 31 +/- 2) and VS (40 +/- 1 vs. 25 +/- 2) were greater in grafts than in AVF, whereas VP was equal. Access flow (0.91 +/- 0.03 vs. 0.91 +/- 0.05 L/min), cardiac output (5.1 +/- 0.1 vs. 5.5 +/- 0.2 L/min), and total access resistance (115 +/- 5 vs. 11 +/- 6) were equal in grafts and AVF, but non-access systemic R was lower in patients with AVF that those with grafts (26 +/- 1 vs. 30 +/- 1). AS and VS resistances were greater in AVF than grafts (87 +/- 6 vs. 54 +/- 3 and 37 +/- 3 vs. 16 +/- 3). Multivariate analysis indicated that CO and ipsilateral MAPo affected flow in both access types. In grafts, all three access resistance elements, AS, VS, and total independently influenced flow, whereas in AVF, the VS did not. Unexpectedly, the ratio of systemic to access resistance also influenced access flow. The pressure in the venous system draining the access affected access flow in AVF but not grafts. We conclude that the hemodynamics of grafts and AVF differ. Cardiac output, MAP, and the arterial segment resistance influence QA in both access types and need to be considered when evaluating QA as part of the trend analysis for detecting access dysfunction.
Data on the use of recombinant human erythropoietin (rHuEPO) were obtained from 25 hemodialysis centers to determine whether route of administration (intravenous [i.v.] vs. subcutaneous [s.c.]) or various dialysis factors influenced the response to rHuEPO; 844 of 958 patients had sufficient data for evaluation. Hematocrit (HCT) increased from 23.8 to 29.1% after a mean rHuEPO treatment period of 202 days; 48.4% of all patients did not reach a HCT greater than or equal to 29%. The s.c. route increased HCT more than the i.v. route. Multivariate analysis of the response (i.e., increase in HCT from baseline) showed a positive correlation with more rapid dialysis but a negative correlation with reuse, baseline HCT, transfusion dependence, and frequency of administration. The effects of dialysis and reuse were not present when the response was normalized by weekly dose. It was concluded that one half of all patients treated did not attain the recommended target HCT, perhaps due to economic constraints or resetting of goals. The s.c. route may be preferable to optimize response.
Venous pressure measured at the venous bubble trap (VPdm) is a complex function of true intra-access pressure (VP0), hematocrit, needle gauge, and blood flow. In a patient free circuit, needle gauge, hematocrit, and blood flow influenced the pressure drop through the venous return needle. Measured intra-access pressure (VPm) and VPdm also were determined 149 times in 83 subjects. The increase in VPdm above VP0 under conditions of flow through 16 gauge needles was affected by blood flow rate, hematocrit, and VP0 with coefficients similar to those found in vitro. Calculation of VP0 from VPdm produced an absolute difference greater than 20 mmHg in 35-40% of cases. Mean VP0 was significantly lower in subjects with native compared with expanded polytetrafluorethylene accesses. It was concluded that VP0 is influenced by access type and can be estimated but that direct measurement is preferred. Direct measurement of VP0 may be a sensitive test to screen for venous outlet stenosis because it should vary with access flow and outlet geometry.
The hematologic response of 65 continuous ambulatory peritoneal dialysis (CAPD) patients to subcutaneous recombinant human erythropoietin (rHuEPO) was compared with that of 369 hemodialysis patients (HD). Pretherapy transfusions were more common in HD than CAPD. The response was measured as the change in hematocrit after 70 or more days of therapy (or as the hematocrit change normalized by a weekly dose) in CAPD patients. The weekly rHuEPO dose did not differ, but the dosing frequency was less in CAPD than in HD patients. Hematologic response parameters were greater in CAPD. Multivariate analysis showed that the response in both groups varied inversely with the frequency of dosing and with pretherapy baseline hematocrit. In HD subjects, the response also varied inversely with previous transfusion history. The authors concluded that CAPD patients responded better to rHuEPO than HD patients. This may be a result, in part, of lower ongoing blood losses. Patients with more severe anemias responded less well, whereas more sensitive patients were dosed less frequently.
The incidence of vascular access clotting was evaluated over 5.25 years. The first 32 months served as a control period. During the second period of 31 months, recombinant human erythropoietin (epoetin) was used for an average duration of 13 months (range, 2-32 months) in 79 patients. The overall incidence of vascular access clotting decreased from a monthly rate of 0.06 to 0.03 events per patient-month over the 5 year period. Distribution of the number of events per patient did not differ between the two periods, with 55% to 60% of patients having no clotting episode. Patients with recurrent clotting (two or more events) accounted for 68% of episodes. During the second period, there were no differences in the incidence of vascular access clotting in epoetin treated patients vs untreated patients (0.38 events per patient-year vs. 0.46 events per patient-year, both slightly lower than in period 1 [0.52 events per patient-year]). It is concluded that epoetin does not increase vascular access clotting.
Sterilants are used to disinfect reverse osmosis (RO) thin film composite membranes or peripheral loop water delivery systems. Formaldehyde (4.0% weight/volume) and metabisulphite (1.0%) were used to sterilize the RO and peripheral loop, and sodium hypochlorite (0.5%) was used to sterilize the peripheral loop with only acid/alkaline treatment of the RO; each sterilant was evaluated for 4 months. Sanitization at the machine was with sodium hypochlorite or glutaraldehyde. Quantitative RO processed water (weekly) and dialysate (4-6 from each station during the period of each sterilant) cultures were obtained. AAMI standards were used (< 200 CFU/ml RO water; < 2,000 CFU/ml dialysate). Bacterial growth exceeded Association for the Advancement of Medical Instrumentation (AAMI) limits in 16% of RO water and 4.7% of dialysate samples, but repeat cultures invariably failed to confirm initial abnormal results. Chi-square analysis showed no differences among sterilants. No difference among sterilants was noted in arithmetic or log10 mean colony counts. Sporadic low level gram positive and gram negative organism growth occurred with all sterilants. Continued "sterility" that met AAMI standards was obtained for 1 year, first with metabisulphite and then with acid/alkaline RO and sodium hypochlorite loop treatment. It is concluded that all three sterilants are effective for disinfection of hemodialysis delivery systems. Sodium hypochlorite is recommended because of its safety advantages and readily available test of adequate removal.
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