Contrast medium-removing effect of hemofiltration and hemodiafiltration
Toshiya Okahisa, Masahiro Sogabe, Shigehito Hayashi, Hiroshi Shibata, and Susumu Ito

Second Department of Internal Medicine, The University of Tokushima School of Medicine, Tokushima, Japan

Abstract:The contrast medium-removing effect of hemofiltration (HF) and hemodiafiltration (HDF) was experimentally investigated using a bovine blood tank model. HF and HDF were performed at a blood flow rate of 100ml/min with a polysulfone hemofilter (PS filter-CF;membrane area:0.7m2). Two hundred milliliters of iomeprol (300mgI/ml) was administered by a single injection into4liters of bovine blood. The blood half-lives of iomeprol were 1.0hr for the high flow rate HDF group [replacement fluid flow rate (QF):10ml/min and dialysate flow rate (QD):40ml/min], 1.8hr for the HDF group (QF:10ml/min and QD:10ml/min), and 3.8hr for the HF group (QF:10ml/min). The mean clearance rates were 39.7ml/min for the high flow rate HDF group, 21.4ml/min for the HDF group, and 12.0ml/min for the HF group. Iomeprol was mostly excreted in the waste fluid. It is concluded that HDF can remove contrast media more effectively than HF. J. Med. Invest. 45:87-93, 1998

Keywords:contrast medium, iomeprol, hemofiltration, hemodiafiltration

In recent years, opportunities to use contrast media have increased with improvements in various diagnostic imaging methods, including CT and angiography, as well as in intra-arterial therapy. Non-ionic contrast media with low osmotic pressure, including iomeprol, have been developed and come into use because they have less pronounced biolog-ical effects than conventional ionic contrast media with high osmotic pressure(1-4). All contrast media, however, are foreign matter to patients and experimental animals, and their use involves the risk of provoking adverse reactions, such as iododerma and nephrotoxicity (5,6). Since contrast media are mostly excreted in urine via the kidneys, they may accumulate in patients with renal failure (7,8). Furthermore, it has been reported that necrosis of the pancreas in the acute necrotic pancreatitis rat model exacerbated following the administration of a contrast medium (9) and that a patient with severe acute necrotic pancreatitis who underwent contrasted CT showed worsened prognosis (10). Therefore, contrast media should be used very carefully in patients with renal function disorders or necrotic lesions. Taking these findings into consideration, the supplementary removal of contrast media in blood appears to be highly desirable. Various blood purification therapies, such as hemodialysis (HD), hemofiltration (HF), and hemodiafiltration (HDF), are currently performed for patients with renal failure (11-13). HD, which may result in a decrease in blood pressure due to the rapid removal of solutes, is difficult to perform for seriously ill patients with multiple organ failure who frequently present with unstable hemodynamics (14). By contrast, HF has less effect on hemodynamics than HD (11). However, HF alone is not sufficient for removing substances of low molecular weight. For this reason, HDF, a method by which the dialysate circulates outside the HF filter and which has the advantages of both HD and HF, has been introduced (12, 13). HF and HDF are usualy performed for several hours at high flow rates with a large membrane area hemofilter. For critically ill patients with unstable hemodynamics, HF and HDF are often performed continuously at low flow rates with a small membrane area hemofilter [continuous hemofiltration (CHF) and continuous hemodiafiltration (CHDF)] to prevent a decrease in blood pressure and to continuously correct the water and electrolyte balance (15, 16). Contrast media with a molecular weight of less than1,300daltons have very low protein binding rates and are regarded as substances which are removable by HD (17-20). However, no in-depth studies have been made to date on the contrast medium-removing ability of blood purification therapies other than HD. In this study we investigate the efficacy of HF and HDF, at low flow rates with a small membrane area hemofilter, to remove iomeprol, a non-ionic contrast medium with low osmotic pressure. In addition, we studied the mechanism by which these therapies remove iomeprol.

A solution containing 140 milliliters of citrate-phosphate-dextrose (CPD) (21) was added to 1 liter of bovine blood immediately after collection, and the hematocrit and total protein of the mixture were adjusted to 38% and 6.0 g/dl, respectively, before the start of the present study. Four liters of the adjusted bovine blood was poured into a tank and warmed at 36°C while being stirred with a stirrer (Figure 1). The console used for HF and HDF was a KM-8800(Kuraray Co., Ltd., Osaka, Japan), and the filter:a polysulfone hemofilter (PS filter-CF;membrane area:0.7〓;Kuraray). The replacement fluid and dialysate consisted of commercial replacement fluid which had previously been mixed with the CPD solution to obtain a concentration which was comparable to actual blood concentration. The bulk of the nafamostat mesilate (Torii Pharmaceutical Co., Ltd., Tokyo, Japan) was dissolved in the 5% glucose solution to obtain a concentration of10mg/ml, and the material was administered as an anticoagulant at a dose of 3ml/hr (30mg/hr) before filtration.
The test materials were divided into the following four groups:Group I (high flow rate HDF group, n=4) which underwent HDF at a blood flow rate (QB) of 100ml/min, a replacement fluid flow rate (QF) of 10ml/min, and a dialysate flow rate (QD) of 40ml/min ; Group II (HDF group, n=4) which under-went HDF at a QB of 100ml/min, a QF of10ml/min, and a QD of 10ml/min;Group III (HF group, n=4) which underwent HF at a QB of 100ml/min, and a QF of 10 ml/min ; and Group IV (control group, n=4) for which no blood purification method was used, and the blood in the tank was only stirred.
A non-ionic contrast medium with low osmotic pressure, iomeprol (612.4mg/ml;iodine content:300mgI/ml ; molecular weight : 777 ; protein binding rate:0%;Eisai Co., Ltd., Tokyo, Japan) was used in the present study. Iomeprol was administered by one injection into the tank at 30min after the start of HF and HDF. A 5-ml blood sample was collected in the afferent and efferent tubes, and a5-ml waste fluid sample was collected in the drainage tube on a time-course basis (at 5 and 30 min, as well as at 1, 2, 4, and 6hr after administration). These samples were centrifuged at 3,000rpm for10min, and the isolated plasma and waste fluid were stored at -20°C until the determination of iomeprol concen-trations by high-performance liquid chromatography (HPLC).
The pharmacokinetic parameters were calculated, and data were analyzed with the least square method. Blood half-lives and elimination rates of iomeprol were calculated according to the following formulas:
Half-life (hr) = Ke / AUC;
Elimination rate (%) = [Ca(t5)-Ca(t)]/Ca(t5)×100,
where Ke is the elimination rate constant, AUC is the area under the curve, Ca (t5) is the blood iomeprol concentration in the afferent tube5min after administration, and Ca(t) is the same concen-tration at t hours.
To investigate the elimination rate of iomeprol into the waste fluid and the adsorption rate on the HDF filter, the sieve coefficients, clearance rates, and adsorption rates of iomeprol were calculated according to the following formulas:
Sieve coefficient = Cd(t)/Ca(t);
Clearance rate (ml/min) = [Ca(t)-Cv(t)]/Ca(t)×QB;
Adsorption rate (%) = {[Ca(t)-Cv(t)]/Ca(t)-Cd(t) ×(QF+QD)/Ca(t)/QB}×100,
where Cd(t) is the iomeprol concentration in the waste fluid in the drainage tube at t hr after administration, Ca(t) is the iomeprol concentration in blood in the afferent tube at t hr after administration, Cv(t) is the iomeprol concentration in blood in the efferent tube at t hr after administration, QB is the blood flow rate, QF is the replacement fluid flow rate, and QD is the dialysate fluid flow rate.
For statistical analysis, blood iomeprol concentrations were expressed as the geometric mean±geometric SE, and other data were expressed as the mean or the mean±SD. Blood concentrations and parameters obtained for each model were com-pared by analysis of variance (repeated ANOVA) and Wilcoxon's rank sum test. A difference was considered statistically significant at a P value <0.05.

Five minutes after administration, the blood iomeprol concentration for Group IV (control group) was41.0±0.2mg/ml and no significant change was seen in this level. A semilogarithmic fit made of the concentration versus time data yielded a linear elim-ination curve for iomeprol in the blood purification groups (Figure2). The blood purification groups showed a decrease in blood iomeprol concentrations, yielding the following half-lives:1.0±0.04hr for Group I (high flow rate HDF group) ; 1.8±0.1hr for Group II (HDF group);and 3.8±0.1hr for Group III (HF group). Significant differences were seen in the kinetics of iomeprol concentration in the 4groups (p<0.001). Four hours after admin-istration, the blood iomeprol concentrations were2.8±0.4mg/ml for Group I, 9.7±1.2mg/ml for Group II, and 17.9±0.4mg/ml for Group III and, 6hrs after administration, the corresponding concentrations were 0.7±0.1mg/ml, 4.3±0.8mg/ml, and12.3±0.6mg/ml, respectively.
Four hours after administration, the elimination rates were 93.1±1.2% for Group I, 75.4±2.8% for Group II, and 51.1±1.0% for Group III and, 6hrs after administration, the corresponding rates were98.4±0.4%, 88.1±1.6%, and 66.3±1.8% respectively (Figure 3). Significant differences were seen in the elimination rates of iomeprol from the blood in the4groups (p<0.001). The elimination rates were sig-nificantly higher in Group I than in Groups II and III (p<0.001), and in Group II than in Group III (p<0.001).
No changes were observed in sieve coefficient, clearance rate, or adsorption rate. The mean sieve coefficients were 0.73±0.07 for Group I, 0.90±0.10 for Group II, and 1.04±0.05 for Group III. The corresponding mean clearance rates were 39.7±2.8ml/min, 21.4±4.0ml/min, and 12.0±1.1ml/min, respectively. As shown in Table1, the clearance rates were significantly higher in Group I than in Groups II and III, and in Group II than in Group III. The adsorption rate accounted for 1.5 to 6.9%,and no significant differences were seen among the 3groups.

CHF and CHDF have been used for critically ill patients with unstable hemodynamics to correct the imbalance of water and electrolytes (15, 16) and, in some reports, these therapies have been described as effective in removing chemical mediators related to the development of multiple organ failure (22, 23). HD removes substances of low molecular weight from blood by diffusion, and the clearance rate by HD is inversely proportional to the square root of the molecular weight of the substance in question(24). HF, on the other hand, filtrates substances of medium molecular weight (MW:<30,000daltons) from blood by negative pressure (25). Thus, HF is generally more effective than HD in removing sub-stances of medium molecular weight (MW:≥300 to 30,000 daltons) (26). However, the recent development of dialyzers with a high performance membrane has enabled substances of medium molecular weight (MW:<10,000) to be removed by HD as well (27). Iomeprol is a substance of medium molecular weight (MW:777), with a very low protein binding rate, and a very low accumulation rate in tissue (8). Therefore, it has been reported that iomeprol can be removed from blood to the same extent in critically ill patients as in healthy subjects by HD, a method which utilizes a new type of dialyzer with a large membrane area consisting of a high perfor-mance membrane which can remove substances of medium molecular weight (MW:<10,000) (17).
HDF has the advantages of both HD and HF, and has greater ability to remove substances of low molecular weight than HF (12,13). In the present study, HDF removed iomeprol more effectively than HF at the same blood and replacement fluid flow rates (QB : 100ml/min ; and QF : 10ml/min). In blood purification therapy, the removal of a substance in blood is achieved not only by excretion in waste fluid but also by adsorption to membranes. However, the percentage of iomeprol removed by adsorption to membranes was less than 7%. Clearly, iomeprol was mostly excreted in waste fluid. The sieve coefficient, the ratio of the waste fluid iomeprol level to that of the blood, was 1.0 for the HF group. Therefore, it was considered that the efficacy of HF in the removal of iomeprol could be improved by increasing QB and QF, the latter nearly to QF max. Although the sieve coefficient is lowered by an increase in the QD of HDF, the clearance of iomeprol by HDF should be further enhanced by an increase in the QD since the volume of iomeprol excreted in the waste fluid will increase.
Contrast media administered to patients are mostly excreted in unchanged form in urine via the kidneys (7). Following the intravenous administration of 40and 80ml of iomeprol (816.5mg/ml;iodine content, 400mgI/ml) to healthy volunteers at a dose of 10ml/min, the blood half-life of iomeprol was 1.95hr. Two hours after administration, about 50% of the iomeprol administered was excreted in urine and, at 4hr, about 80% (8). In the present study, the blood half-life of iomeprol was 1.0 hr for the high flow rate HDF group and 1.8hr for the HF group. The elimination rate of blood iomeprol, 4hrs after administration, was93.1% for the high flow rate HDF group, and 75.4%for the HDF group. It is predicted that the blood half-life and the elimination rate of HDF (QB:100ml/min;QF:10ml/min;and QD:10ml/min) would be comparable to that of healthy adults, and those of high flow rate HDF (QB:100ml/min;QF:10ml/min ; and QD : 40ml/min) superior to that of healthy adults (8). A small volume (4liters) of blood and a tank model were used in the present study, and the efficacy of iomeprol removal from blood only was assessed using a one-compartment model. As such, the effect of the distribution of iomeprol into extracellular fluids could not be taken into consideration. Consequently, it can be assumed that the half-lives and decreases in iomeprol following HF and HDF in clinical cases would be lower than the results obtained in the present study.
While the contrast medium-removing ability of HF or HDF in clinical cases has not been reported to date, several reports have described the efficacy of HD in the removal of contrast media. Generally, it can be predicted that more than 80% of a contrast medium administered is eliminated by HD which uses a dialyzer with a large membrane area at a blood flow rate of 200ml/min. Ueda et al. have reported the efficacy of HD (QB:200ml/min and QD:500ml/min) using a hollow fiber dialyzer with an acetate cellulose diacetate membrane (membrane area : 2.1〓) in the removal of iomeprol (714.4mg/ml ;iodine content:350mgI/ml) from patients with chronic renal failure (17). The clearance rate of iomeprol for the high flow rate HDF group was about 40ml/min, i.e., about one-third the clearance rate (130ml/min) of iomeprol by HD reported by Ueda et al (17). The clearance rate of a contrast medium is dependent upon its quality (molecular weight and protein binding rate), filter (material, type, and membrane area), and flow rate parameters (QB, QF, and QD). In the present study, the rate of iomeprol clearance by HF and by HDF was inferior to that by HD. This result was attributed to the following:1) QB, QD, and QF of HF and HDF were set at low levels similar to CHF and CHDF cases;and 2) a hemofilter with a smaller membrane area was used.
Despite the fact that newly developed low-osmolar and non-ionic contrast media affect renal function to a lesser extent and are better tolerated than con-ventional media (1-4), acute renal failure caused by these new contrast media has been reported (28, 29). The incidence of renal damage after angiographic procedures was reported to be over20% in patients with a serum creatinin above 2mg/dl (30-32) and over 70% in diabetes mellitus patients with an abnormal renal function (33, 34). For this renal damage, stan-dard conservative prophylactic therapies are not effective (32, 33, 35). Moon et al. reported that no further impairment of renal function was observed following the use of HD in any of 7 high-risk patients of developing contrast media nephropathy:serum creatinin above 4.5mg/dl in 7patients, diabetes mellitus in 5 patients, hypertension in 6 patients (36). They suggested that accelerated elimination of contrast media by prophylactic HD can be benefical in preventing further reduction in renal function after angiographic procedures in high-risk patients. On the other hand, Younathan et al. reported that after examinations with contrast media performed between regular HD in end-stage renal disease, there was no significant change in blood pressure, ECG, total serum protein, osmolarity, extracellular fluid volume, or body weight (37). They concluded that immediate dialysis after administration of non-ionic contrast agents is not necessary.
Continuous intra-arterial administration of a protease inhibitor to patients with severe acute necrotic pancreatitis has been used as an effective therapy(38, 39). However, it is necessary to confirm the necrotic area of the pancreas with contrasted CT before conducting this therapy, and the use of a contrast medium carries the risk of exacerbating renal function and necrosis of the pancreas (9, 10).The effects of contrast media on patients and exper-imental animals have not been examined in sufficient detail. The effects of accelerated elimination of contrast media by prophylactic blood purification therapies on necrotic lesions have not been examined. It is, therefore, necessary not only to investigate the effects of contrast media on patients and experimental animals but also to determine the time points and rates at which they should be removed from blood after administration. Furthermore, randomized control studies should be performed to evaluate the benefical effects of early contrast media removal in preventing side effects of contrast media .
We consider that HDF, at low flow rates with a small membrane area hemofilter, is a method which has less effect on hemodynamics and, as such, can remove contrast media more safely in patients with unstable hemodynamics than HD and more effectively than HF. We found that the contrast medium-removing ability of HF and HDF, at low flow rates with a small membrane area hemofilter, is never superior to that of HD. However, the contrast medium-removing ability of HF and HDF would probably be improved, as compared with the result of the present study, by setting the blood flow rate, dialysate flow rate, and replacement fluid flow rate higher and by using a hemofilter with a larger mem-brane area. It is generally felt that opportunities to use contrast media for patients with renal function disorders or necrotic lesions will increase and that contrast media will be used more frequently for patients with unstable hemodynamics. We consider that it is possible to remove contrast media more safely and effectively by selecting the blood purification therapy most suited to a particular pathological process.

We sincerely thank Eisai Co., Ltd., Kuraray Co., Ltd., and Torii Pharmaceutical Co., Ltd. for their cooperation in this study.

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Received for publication June 12, 1998 ; accepted July 24, 1998.

1 Address correspondence and reprint requests to Toshiya Okahisa, M.D., Second Department of Internal Medicine, The University of Tokushima School of Medicine, Tokushima, Kuramoto-cho, 770-8503, Japan and Fax:+81-886-33-9235.