A Comparison of Metabolic Control by Continuous and Intermittent Therapies in Acute Renal Failure1 2

Transcription

1 A Comparison of Metabolic Control by Continuous and Intermittent Therapies in Acute Renal Failure1 2 William R. Clark,3 Bruce A. Mueller, Karla J. Alaka, and William L. Macias WA?. Clark, K.J. Alaka, W.L. Macias, Department of Medicine, Nephrology Section. Indiana University School of Medicine, Indianapolis, IN BA. Mueller, Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN (J. Am. Soc. Nephrol. 1994; 4: ) ABSTRACT Azotemia control provided by blood pump-assisted continuous hemofiltration has not been rigorously compared with that provided by intermittent hemodialysis (IHD) for critically ill patients with acute renal failure (ARF). The metabolic control achieved by continuous venovenous hemofiltration (CVVH) and IHD was compared. In ARF patients treated with CVVH (N = I 1), the normalized daily dose of therapy was.59 ±.23 (mean ± SD) and the normalized protein catabolic rate was 1.82 ±.95 g/kg per day. The serum urea nitrogen concentration (SUN) declined with CVVH from an initial value of I 14 ± 32 to 79 ± I 7 mg/dl at steady state (SUNS). The initial analysis was a theoretical comparison between CVVH azotemia control and the control that would have been provided by IHD. Simulated IHD data were generated by conventional urea kinetic methods. The peak concentration hypothesis was invoked to compare CVVH SUN5 and the peak IHD SUN (SUNg). A simulated IHD frequency of five times or more weekly was required to achieve a SUN that did not differ from the CVVH SUN5. A similar comparison between the CVVH group and a separate group of ARF patients (N = I 1) who received IHD was also performed. In the latter I Received February Accepted July 21, Presented In part at the annual meetings of the National Kidney Foundation. Baltimore, MD, November and the American Society for Artificial Internal Organs, New Orleans, LA. April 29, Correspondence to Dr. w. R. CarI, Nephrology Section, Department of Medlclne, Indiana University School of Medicine. I 12 South Drive. Room 18, Indianapolis, IN / $3./ Journal of the American Society of Nephrology Copyright C 1994 by the American society of Nephrology group, the normalized protein catabolic rate and the normalized daily dose of therapy were similar to those of the CVVH group. The SUN (11 ± 12 mg/dl) in the IHD group was significantly higher than the mean CVVH SUNS (P<.5). These data suggest that intensive hemodialysis is required to provide azotemia control similar to that provided by CVVH. In addition, for equivalent amounts of therapy, CVVH achieves better azotemia control than IHD. Key Words: Hemofiltration, hemodialysis. azotemi ure kinetics C ontinuous extracorporeal therapies have assumed increasingly greater importance as alternatives to intermittent hemodialysis (IHD) in the management of critically ill patients with acute renal failure (ARF) (1-8). One limitation of these convective-based therapies has been their inability to provide adequate control of azotemia in patients with severe hypercatabohism due to sepsis, surgery. or trauma (9). The incorporation of blood pump-assisted techniques into these therapies, such as in continuous venovenous hemofiltration (CVVH). has ameliorated this problem by increasing small solute clearances and improving the control of azotemia even in highly catabolic patients. These blood pumpassisted continuous renal replacement therapies may offer an additional advantage in their ability to avoid the repeated serum urea nitrogen (SUN) peaks that are characteristic of IHD and that may mediate uremic toxicity independent of the time-averaged SUN (1 ). However, the degree to which azotemia is controlled by blood pump-assisted hemofiltration versus IHD in critically ill patients with ARF has not been rigorously compared. To determine which therapy offers the best metabolic control, we investigated the adequacy of azotemia control achieved by either CVVH or IHD in patients with ARF. The investigation was performed in two stages. The first was a theoretical comparison between the degree of azotemia control provided to a series of highly catabolic patients treated with CVVH and the control that would have been achieved had these same patients been treated with IHD. To confirm this theoretical analysis, we subsequently per- Journal of the American Society of Nephrology 1413

2 Metabolic Control in Acute Penal Failure formed a similar comparison of metabolic control achieved in the CVVH patient group with that in a separate group of patients with ARF who received IHD. Our analysis suggests that, for the same amount of therapy, CVVH provides better control of metabolic waste products than does IHD. METHODS Patient Populations CVVH Patient Group. Ohiguric patients with ARF who received CVVH at Indiana University Hospital were eligible for inclusion. The exclusion criteria were (1 ) inadequate data acquisition; (2) insufficient treatment time on CVVH to allow a steady-state SUN to be reached; and (3) urine output of more than 4 ml/day. DID Patient Group. This group was obtained by a retrospective review of hospital charts from patients with ARF who required IHD at our institution. The inclusion criteria for these patients were ( 1 ) ohiguric or anuric ARF; (2) a minimum of six hemodialysis treatments during the course of their ARF; (3) adequate documentation of body weights, blood pump speeds, and dialysis times in the hospital chart; and (4) a minimum of two time intervals in which successive SUN values were available for three-point urea kinetic modeling. Patients treated most recently (September 1 992) were included first, and sufficient records before this were reviewed to provide an equal number of patients in the IHD group as were in the CVVH group. Renal Replacement Protocols The standard CVVH operating protocol at our institution was observed for all patients (5). Patients receiving CVVH were monitored in an intensive care unit. The extracorporeal circuit included an Amicon- 2 polysulfone hemofilter (Amicon Division of W.R. Grace & Co., Danvers, MA). Bicarbonate-based replacement fluids were administered in a prefilter mode. Blood flow was generated by a roller blood pump (RS-78; Renal Systems, Minneapolis, MN) that was set at a rate of 1 5 to 2 ml/min. An infusion pump (Flo-gard; Baxter-Healthcare, Deerfield, IL), set at 1, ml/h, was attached to the ultrafiltrate port of the hemofilter to ensure a constant ultrafihtrate production rate. Hemofilters were routinely replaced every 48 h, a period over which Gohper et at. (1 1) have demonstrated that urea sieving coefficient values do not deteriorate appreciably. IHD was performed either in the acute hemodialysis unit or in an intensive care unit with Centrysystem 2 machines (CGH Medical, Lakewood, CO) and a bicarbonate-based dialysate. Hemodialyzers with cuprophane (Baxter-Heahthcare), cellulose acetate (Baxter-Healthcare), or saponified cellulose ester (Althin CD Medical, Miami Lakes, FL) membranes were used. Manufacturers in vitro data, reduced by 1% for in vtvo purposes, were used to estimate blood urea clearances, based on blood and dialysate flow rates. Data Acquisition Immediately before the initiation of CVVH, clinical, hematologic, and biochemical data were collected. Additional biochemical data, including SUN values, were obtained every 6 h throughout the CVVH procedure. The 24-h ultrafiltrate production rates, as well as complete fluid intake and output data, were recorded daily. For the IHD group, a urea kinetic modeling interval consisted of a particular hemodiahysis session and the subsequent interdialytic period. The three SUN determinations were made before and after the hemodialysis session and before the subsequent treatment. Body weight was measured at these times in each patient. For each modeling interval, the intradialytic time, the interdialytic time, and the blood flow rate were recorded. CVVH Urea Kinetic Analysis On the basis of serial SUN determinations, each patient s CVVH treatment course was divided into a steady-state and a non-steady-state period. The steady-state period was defined as the first 24-h period during CVVH therapy in which the SUN varied by less than 5%. The 24- to 48-h period immediately preceding the steady-state period was defined as the non-steady-state period. Separate analyses of steadystate and non-steady-state data allowed the determination of the urea generation rate (G) and distribution volume (V), respectively, as we have described previously (1 2). Blood urea clearance (K) values were obtained from an expression for predilutlonal hemofiltration derived by Ofsthun et at. (1 3). This expresslon uses the blood flow, replacement fluid, and ultrafiltration rates along with the urea sieving coefficient to determine K. A sieving coefficient of 1. was assumed for the 48-h life of each hemofilter used. The protein catabolic rate (PCR) was determined from the total daily nitrogen appearance rate as a function of G and the non-urea nitrogen generation rate (14). The normalized PCR (NPCR) was calculated by the method described by Gotch (15). A quantitative assessment of the degree of azotemia control delivered by CVVH was expressed as the relationship between the steady-state SUN (SUN.) and the ratio NPCR/(KT/V)d (1 6). In this relationship, T was the treatment duration and the fraction (KT/ V)d was the normalized daily dose of therapy. This analysis was similar to that performed by Gotch and Sargent in their description of steady-state azotemia control in the National Cooperative Dialysis Study (16) Volume 4 Number

3 Clark et al Comparison of Azotemia Control CVVH versus Simulated IHD. The degree of azotemia control achieved by CVVH, in a series of patients with ARF, was compared with the control that would have been achieved in the same patients had they been treated with IHD. Several assumptions were made for the IHD simulations: ( 1 ) a single pool, constant-volume urea kinetic model was used; (2) steady state with respect to both NPCR and V was present during a 1 -wk simulation period; (3) the values of G, V. and NPCR calculated by CVVH urea kinetic data for each patient did not change with a change of therapy to IHD; (4) treatment duration was 4 h in all simulations; (5) a symmetric dialysis schedule was used; and (6) the relationship between SUN and NPCR/(KT/V)d, obtained from the CVVH data, also existed at steady state in the IHD simulations. That is, a certain value of NPCR/(KT/V)d yielded equivalent values for the CVVH SUNS and the IHD time-averaged SUN (SUNa). Varying dialyzer blood urea clearances (1 6 or 2 ml/min) and dialytic frequencies (three, five, or seven times per week), along with the values for NPCR and V obtained for the CVVH patients, were used to calculate (KT/V)d for the simulated IHD regimens. The SUNa was determined from the SUN versus NPCR/(KT/V)d curve. From these determinations, SUN versus time profiles over the 1 -wk simulation period were generated by the use of the analyses described below. The kinetic equation relating the peak SUN (SUN) to the trough SUN (SUN) was expressed as (15): SUNS SUNe T (G/K)(1 - e T ) (1) For a symmetric dialysis schedule, the peak, trough, and time-averaged SUN were related by: SUNa (SUNg + SUN)/2 The combination and rearrangement of Equations 1 and 2 allowed the SUN to be expressed as a function of SUNa and the various kinetic parameters: SUN = [2(SUNa) (G/K)( 1 - e_kr!)j/( 1 + e T ) (3) The mean SUN generated from each simulated IHD regimen for each patient was compared with that patient s mean SUN. obtained from the CVVH analysis by use of one-way analysis of variance at the.5 significance level. CVVH versus Actual IHD. To confirm this theoretical analysis, similar comparisons were made between these same CVVH patients and a separate group of patients with ARF who actually received IHD. In the latter set of patients, three-point urea kinetic modeling was used multiple times during the course of their ARF. Because steady state with respect to V did not exist in this group, a variablevolume model was used. For this model, the urea nitrogen mass balance during the intradialytic period was given by (15): SUN = SUN[(V + flt)/v1ik $ + [G/(K + /3)J 1 - [(V + T)/V)_ In this equation, f3 represents the rate of intradialytic weight loss, which was assumed to be the result of net fluid loss. During each modeling interval, the application of the mass balance equation to both the intradialytic and interdialytic periods and the subsequent simultaneous solution of the two equations in an iterative fashion produced values of G and V for each patient. NPCR and KT/V were then determined for each modeling interval, and the mean values for all of the analyzed intervals were calculated. The mean SUN from the IHD group was compared with the mean SUN, from the CVVH group by unpaired t test at the.5 significance level. The mean kinetic parameters G, NPCR, and (KT/V)d in each group were compared in a similar manner. RESULTS Patient Characteristics Eleven patients, age 52 ± 2 1 (mean ± SD) yr. comprised the CVVH group. Thirteen data sets were gencrated in these 1 1 patients, who were treated for a mean duration of 9.5 ± 7.5 days. In the two patients who were studied twice, the mean duration between study periods was 1 3 days. The primary indication for CVVH was ohiguric ARF complicated by volume overload and acidemi All but one patient required both mechanical ventilation and vasopressor sup- (2) port. Hypotension precluded the use of hemodialysis in most of these patients. An equal number of patients were obtained for the IHD group by a review of the records of patients with ARF who were treated with this therapy at our institution. Beginning with those patients who were treated in September and then progressing backwards in time, 64 hospital charts had to be reviewed before 1 1 patients who met all of the inclusion criteria could be identified. These patients, age 54 ± 1 8 yr, received 1 3 ± 6 dialysis treatments over a period of 24 ± 1 2 days. The mean IHD frequency was 3.9 times per week, whereas the mean duration of therapy was 3.7 ±.5 h per treatment. The average blood flow rate was 313 ± 33 ml/min. Urea Kinetic Analyses Results of the urea kinetic analyses for both the CVVH and actual IHD groups are shown in Table 1. (4) Journal of the American Society of Nephrology 1415

4 Metabolic Control in Acute Penal Failure TABLE I. Results of the urea kinetic analyses for the two patient groups#{176} 11 Parameter CVVH Group 1HD Group Blood Urea Clearance (K, ml/ 15.2 ± ± 16 mm) SUN (mg/dl) I 1 ± I 2b SUNS (mg/dl) 79 ± 17 Urea Generation Rate (G, mg I I.7 ± ± 3.4 of urea N/mm) NPCR (g of protein/kg per 1.82 ± ±.48 day) (KT/V)d.59 ± ±.2 -I C, z C/) w I- I- 1/) I- C/) a Note: values are reported as mean ± SD. b p<.5 versus VVH mean SUN,. 3 In the patients treated with CVVH, the ultrafiltrate production rate was 941 ± 46 ml/h, resulting in a blood urea clearance of ±.9 ml/min. The average daily dose of therapy, (KT/V)d, was.59 ±.23. Despite the high mean NPCR (1.82 g/kg per day) in these patients, the SUN fell from an initial value of 1 14 ± 32 mg/dl to 79 ± 17 mg/dl at steady state. The time required to reach steady state was 6.5 ± 4.7 days (range, 3 to 1 7 days). The duration of steady state was quite variable, lasting from the mmimum of 24 h to several days. In the IHD group, an average of 3.6 kinetic modeling intervals were analyzed per patient. The mean blood urea clearance was 1 97 ± 1 6 ml/min per treatment period. The daily dose of therapy (.59 ±.2) was the same as in the CVVH group. The mean NPCR (1.48 ±.48 g/kg per day) also was not significantly different from that of the CVVH group. These (KT/ V)d and NPCR values resulted in a mean SUN of 11 ± 12 mg/dl. Comparison of Azotemia Control: CVVH Versus Simulated IHD Figure 1 is a graphical representation of CVVH azotemia control as a function of both patient-related NPCR/(KT/V)d Figure 1. Graphical representation of CVVH azotemia control as a function of both patient-related (NPCR, V) and treatment-related (K, T) parameters. A linear relationship (r =.92) exists between SUN, and the ratio NPCR/(KT/V)d. (NPCR and V) and treatment-related (K and T) parameters. In these patients with ARF, a linear relationship (r =.92) existed between the SUNS and the ratio NPCR/(KT/V)d. This relationship is similar to that described by Gotch and Sargent in patients with ESRD treated with chronic hemodialysis (16). Results of the IHD simulations appear in Table 2. Values for (KT/V)d, SUNa and SUN are given for varying blood urea clearances (either 1 6 or 2 ml/ mm) and different treatment frequencies (three, five, or seven times per week). The hypothetical urea clearance was assumed to be achievable throughout the entire 4-h treatment sessions. To assess azotemia control, the mean SUN from each IHD regimen was compared with the mean CVVH SUN,. For K = 16 ml/min, the mean SUN was not significantly different (P >.5) from the mean CVVH SUN, with the daily IHD regimen only. Similar analysis for K = 2 ml/min demonstrated that IHD performed five times or more per week was required to control azotemia to TABLE 2. IHD simulation results#{176} Dialysis Sessions (KT/V)d SUNO (mg/dl) SUNG (mg/dl) Per K=16 K=2 K16 K2 K16 K2 Week mi/mm mi/mm mi/mm mi/mm mi/mm mi/mm 3.44±.16.54±.21 14±24 87±18 15±4 13± ±.26.89±.34 65±15 54±11 92±24 8±2b 7 1.2± ±.48 48±1 4±8 67±17b 59±14 a Note: values are reported as mean ± SD. b p>.5 versus VVH mean SUN, Volume 4 Number

5 Clark et al a similar degree as did CVVH at steady state. (All other mean SUN values were statistically different at the.5 significance level from the mean SUN,). For these comparisons, we assumed that the change from CVVH to simulated steady-state IHD did not alter the linear relationship between SUN, and the ratio NPCR/(KT/V)d or the patient-specific parameters, NPCR and V. More precise estimates of the equivalency of azotemia control by the two therapies appear in the subsequent two figures. Figure 2 is a graph of SUN versus (KT/V)d for all of the simulated IHD regimens. The mean steady-state CVVH SUN (79 mg/dl) is represented by the horizontal line. The intersection of this line with the curve produces the dialytic (KT/ V)d required to produce equivalent degrees of azotemia control by CVVH and simulated IHD. This value (.92) is significantly greater than the mean steadystate CVVH (KT/V)d of.59 (Table 1). In Figure 3, the mean SUN is plotted against IHD frequency to determine therapy equivalency. The horizontal line again represents the mean CVVH SUN.. The abscissa value corresponding to each intersection point represents the IHD frequency that results in azotemia control equivalent to that of CVVH. The figure demonstrates that equivalency for K = 16 ml/min and K = 2 ml/min occurs at approximately 5.9 and 5.2 times per week, respectively. Comparison of Azotemia Control: CVVH Versus Actual IHD _1 z U) 4 C.) a The CVVH and IHD patient groups were well matched with respect to (KT/V)d and NPCR (Table 1) SIMULATED (KT/V)d Figure 2. Predicted SUNP versus (KT/V)d for all simulated IHD regimens. The mean steady-state CVVH SUN (79 mg/dl) is represented by the horizontal line. The intersection of this line with the curve produces the dialytic (KT/V)d that results in equivalent degrees of azotemia control by CVVH and IHD J C, z U) 4 I-. C.) K16 ML/MIN 2 4 b 8 SIMULATED IHD FREQUENCY (PER WEEK) Figure 3. Predicted SUN versus simulated IHD frequency for K = 16 mi/mm and 2 mi/mm. The mean steady-state CVVH SUN (79 mg/dl) is represented by the horizontal line. The intersection of this line with each curve produces the simulated IHD frequencies that result in azotemia control equivalent to that of CVVH. The frequencies are 5.9 and 5.2 dialyses per week for K = 16 and 2 mi/mm. respectively. Consequently, a direct comparison of azotemia control by the two therapies could be made. There was no statistical difference between the mean CVVH SUN. and the mean IHD SUNa (71 ± 1 mg/dl). This lack of difference was not unexpected, because the two groups had similar degrees of net protein catabohism and received similar amounts of therapy. However, the mean SUN in the IHD group was significantly higher than the CVVH SUN. (1 1 versus 79 mg/dl; P <.5). To confirm that the modeling techniques applied in the IHD simulations were clinically valid, the mean treatment parameters of the actual IHD group from Table 1 were used to construct a graph of predicted SUN versus actual IHD frequency, which appears in Figure 4. These mean data were used as input parameters for Equation 4 to determine the predicted SUN for actual IHD frequencies ranging from three to seven times per week. Figure 4 shows that, for the mean frequency at which the IHD patient group received therapy (3.9 times per week), the predicted mean SUN was 1 5 mg,/dl. This value closely approximated the actual mean SUN (1 1 mg/dl) that was determined for the IHD group and suggests that the modeling techniques used for the IHD simulations in the initial comparison were valid. DISCUSSION Continuous hemofiltration involves the purely convective removal of both low-molecular-weight solutes Journal of the American Society of Nephrology 1417

6 Metabolic Control in Acute Penal Failure 1 a C, z U) 4 a I- C-) a 1 ACTUAL IHD FREQUENCY (PER WEEK) Figure 4. Predicted SUNG versus IHD frequency for patients who actually received IHD. The mean frequency at which the IHD group received treatment (3.9 times per week) is represented by the vertical line. The intersection of this line with the curve produces the mean SUN (15 mg/dl) predicted by the kinetic analysis, which is not significantly different from the actual mean SUNP (1 1 mg/dl) in the IHD group. and those of larger molecular size. Diffusion-based hemodialysis effectively removes relatively small compounds, but blood clearances significantly decrease with increasing solute molecular weight such that the removal of compounds in the middle molecule range (3 to 5, d) and larger is typically poor (1 7). Previous investigators have suggested that continuous hemofiltration, because of its relatively inefficient convective elimination of small molecules, results in inadequate control of azotemia in hypercatabolic patients with ARF (9). However, this investigation demonstrates that, with the incorporation of a blood pump, continuous hemofiltration controls azotemia very well. Despite the high catabolic rates in our patients (mean NPCR, 1.82 g/kg per day), the blood pump-assisted urea clearances resulted in a mean steady-state SUN of 79 ± 1 7 mg/dl. Continuous arteriovenous and venovenous hemodialysis are additional extracorporeal therapies used for critically ill patients with ARF (6-8). In general, these therapies provide somewhat better small solute clearances than CVVH. However, this improvement comes at the expense of some convective elimination capacity such that CVVH is superior to these treatments in the removal of solutes of increasing molecular weight. The elimination of molecules substantially larger than those primarily removed by dialysisbased therapies may be desirable in patients with ARF. The possible role of middle molecules in the 4 pathogenesis of the uremic syndrome has been postulated by several investigators (1 8-2). In addition, improved survival in patients with septic shock and ARF may be made possible by treatment with hemofiltration (21,22). This improvement in survival may. result from the removal of putative vasoactive mediators of the sepsis syndrome, which may be in the middle molecule range. Thus, superior large molecule removal potential may be another advantage of continuous hemofiltration over dialytic therapies in critically ill patients with ARF. In this study, the comparative analysis between CVVH and IHD was based on the peak concentration hypothesis formulated by Keshavlah et at. (1 ). This hypothesis attempted to explain the similar clinical outcomes observed for patients with ESRD treated with continuous ambulatory peritoneal dialysis and chronic IHD, despite the superior small solute removal capability of the latter. Keshaviah et at. reasoned that the peak SUN during an IHD cycle may be a better reflection of uremic toxicity than the timeaveraged SUN and suggested that a comparison of the IHD peak SUN and the continuous ambulatory peritoneal dialysis steady-state SUN is most valid. Clinical studies will be required to confirm the validity of the peak concentration hypothesis. The investigation presented here invoked this hypothesis to demonstrate that (KT/V)d values of.92 for simulated IHD (Figure 2) and of.59 for CVVH (Table 1 ) provided comparable levels of azotemia control. In addition, these simulations indicated that an intensive IHD regimen would have been required to achieve azotemia control equivalent to that obtained by the CVVH regimen. For a blood urea clearance of 16 ml/min, IHD would have been required approximately six times per week to provide azotemia control comparable to that achieved by CVVH. For a blood urea clearance of 2 ml/min, five dialysis sessions per week would have been necessary. The consistent attainment of a blood urea clearance of 2 ml/min for the entire 4-h duration of repeated IHD sessions in this group of critically ill patients probably represents a best-case scenario. Consequently, in these highly catabolic patients, a dialytic frequency of at least five times per week would have been required to achieve azotemia control comparable to that with CVVH. The average (KT/V)d and NPCR values for the CVVH group and IHD group were not statistically different. Consequently, a valid comparison of azotemia control between the two groups was feasible. The similar mean SUNa and SUN, values for the IHD and CVVH groups, respectively, confirmed the validity of the comparison. As was done in the analysis of simulated IHD, the peak concentration hypothesis was used in the comparison of actual IHD to CVVH. This comparison demonstrated that mean peak azo Volume 4 Number

7 Clark et al temia control in IHD was significantly worse than mean steady-state CVVH azotemia control. In addition, this comparison showed that the modeling methods used in formulating the simulated IHD regimens provided clinically valid predictions of azotemia control. This was documented by the similarity of the SUN value predicted by kinetic modeling to the actual SUN value in the IHD group (1 5 versus 1 1 mg/dl, respectively). A number of potential problems complicated the analysis of both patient groups. First, every dialysis session, which the actual IHD patients underwent in the course of their ARF, was not modeled because of the unavailability of SUN values. However, the mean of 3.6 modeling intervals per patient should have generated valid estimates of NPCR and (KT/V)d. Second, unlike the CVVH group, steady state with respect to SUN was not achieved in all of the patients who received IHD. Consequently, neither NPCR nor (KT/V)d necessarily remained constant in the IHD group. However, because mean NPCR and (KT/V)d were derived from multiple modeling intervals that were temporally dispersed over each patient s course of ARF, we believe that they were representative values for analysis. The method by which blood urea clearances were determined may also have been a limitation in the IHD analysis. Manufacturer-supplied in vitro urea clearance data, derived from aqueous test solutions at varying flow rates, were used in the kinetic analyses. The in viva urea clearance was assumed to be 1% less than the in vitro value at a particular flow rate. Prior studies addressing the difference between in vitro and in viva urea clearances have yielded discordant results. Grossman et at. (23) found the difference between in vitro and in viva values to be 3% for hematocrits ranging between 2 and 3% over a wide range of blood flow rates. However, Barth et at. (24) more recently showed that manufacturer-supplied clearance data overestimate blood urea clearances by approximately 16%. They also demonstrated that the use of both manufacturers data and arteriovenous SUN measurements provided less reliable estimates of blood urea clearance than the direct quantification of dialysate urea method (25). However, this latter method is technically difficult and, consequently, was not performed in this study. Finally, the assumption that the urea sieving coefficient remained constant at 1. during the entire duration of use for a particular filter may have introduced some error. However, we have found that sieving coefficient values remain higher than.95 for the 48-h period of use at our institution (unpublished data). This observation has recently been confirmed by other investigators (1 1). This investigation should eliminate the misconception that continuous renal replacement therapies, in general, are unable to control azotemia in hypercatabohic patients with ARF. However, as is necessary for any therapy. both the risks and benefits of a continuous modality in this setting must be assessed before therapy institution. The benefits of adequate azotemia control and the avoidance of repeated urea nitrogen peaks must be balanced against the potential risks of systemic anticoaguhation, hypotension, and electrolyte abnormalities in all patients for whom treatment is being contemplated. In addition, the actual degree to which azotemia needs to be controlled by any therapy in ARF remains poorly defined (26). CONCSIONS Using urea kinetic modeling, we have established a methodology to compare rigorously the azotemia control provided by continuous and intermittent extracorporeal therapies for patients with ARF. By use of this methodology, we have shown that frequent and intensive hemodialysis would be required to provide azotemia control similar to that provided by CVVH. In addition, this analysis demonstrated that, to provide equivalent metabolic control, the required amount of CVVH therapy would be substantially less than that of IHD therapy. The corollary of this latter finding suggests that, for equivalent amounts of therapy, CVVH provides better azotemic control than that achieved by IHD. We conclude that the adequate clearance of nitrogenous compounds with the avoidance of repeatedly high peak SUN values and a superior large solute clearance combine to make CVVH preferable to IHD in the treatment of critically ill patients with ARF. ACKNOWLEDGMENTS The authors thank Mr. Gary McNally for his assistance in the preparation of the manuscript. REFERENCES 1. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F: Arterlovenous hemofiltration: A new and simple method for treatment of overhydrated patients resistant to diuretics. Khin Wochenschr 1977;55: Paganini E, Nakamoto 5: Continuous show ultrafiltration in ohiguric acute renal failure. Trans Am Soc Artif Intern Organs 1 98;26: Lauer A, Saccaggi A, Ronco C, Belledonne M, Glabman S, Bosch J: Continuous arteriovenous hemofiltration in the critically ill patient. Ann Intern Med 1983;99: Kaplan A, Longnecker R, Volkert V: Continuous arteriovenous hemofiltration: A report of six months experience. Ann Intern Med 1 984; 1: Macias W, Mueller B, Scarim 5, Robinson M, Rudy D: Continuous venovenous hemofihtration: An alternative to continuous arteriovenous he- Journal of the American Society of Nephrology 1419

8 Metabolic Control in Acute Penal Failure mofiltration and hemodiafiltration in acute renal failure. Am J Kidney Dis ; 18: Sigler M, Teehan B: Solute transport in continuous hemodialysis: A new treatment for acute renal failure. Kidney Int 1 987;32: Cottrell A, Mehta R: Cytokmne kinetics in septic ARF patients on continuous venovenous hemodialysis (CVVHD) [Abstracti. J Am Soc Nephroi 1992;3: Relton S, Greenberg A, Palevsky P: Dialysate and blood flow dependence of diffusive solute clearance during CVVHD. Am Soc Artif Intern Organs J 1992;38: Kjellstrand C, Jacobson 5, Lins L. Acute renal failure. In: Maher J, Ed. Replacement of Renal Function by Dialysis. 3rd Ed. Dortdrecht: Kluwer Academic Publishers; 1989: Keshaviah P, Noiph K, Van Stone J: The peak concentration hypothesis: a urea kinetic approach to comparing the adequacy of continuous ambulatory peritoneal dialysis (CAPD) and hemodiahysis. Peritoneal Dial mt i 989;9: Golper T, Erbeck K, Roberts P, Price J: Small solute sieving coefficients using hemodialyzers as filters in continuous venovenous hemofiltration [Abstracti. J Am Soc Nephrol 1992;3: Clark W, Murphy M, Alaka K, Mueller B, Pastan 5, Macias W: Urea kinetics during hemofiltration. Am Soc Artif Intern Organs J 1 992;38: M664-M Ofsthun N, Colton C, Lysauglit M. Determinants of fluid and solute removal rates during hemofiltration. In: Henderson L, Quellhorst E, Baldamus C, Lysaught M, Ecis. Hemofiltration. Berlin: Springer-Veflag: 1986: Sargent 3, Gotch F, Borah M, et al.: Urea kmnetics: A guide to nutritional management of renal failure. Am J Chin Nutr 1 978;3 1: Gotch F. Kinetic modeling in hemodialysis. In: Nissenson A, Fine R, Gentile D, Eds. Clinical Dialysis. 2nd Ed. Norwalk: Appleton and Lange; 199: Gotch F, Sargent J: A mechanistic analysis of the National Cooperative Dialysis Study. Kidney mt 1985;28: Henderson L. Ultrafiltration biophysics. In: Maher J, Ed. Replacement of Renal Function by dialysis. 3rd Ed. Dortdrecht: Kluwer Academic Publishers; 1989: Babb A, Strand M, Uvelli D, Milutinovic J, Scribner B: Quantitative description of dialysis treatment: A dialysis index. Kidney Int 1 975;7:S23-S Furst P, Zimmerman L, Bergstrom J: Determination of endogenous middle molecules in normal and uremic body fluids. Chin Nephrol 1976;5: Vanholder R, Schoots A, Ringoir S. Uremic toxicity. In: Maher J, Ed. Replacement of Renal Function by Dialysis. 3rd Ed. Dortdrecht: Kluwer Academic Publishers; 1989: Macias W, Mueller B, Kraus M, Clark W: Management of refractory septic shock with continuous venovenous hemofiltration [Abstract]. Am Soc Artif Intern Organs J 1993;22: van Bommel E, Grootendorst A, van LeengOed L: Influence of high-volume hemofiltration on hemodynamics in porcine endotoxic shock [Abstract]. Blood Purif 1992;1: Grossman N, Kopp K, Frey J: Transport of urea by erythrocytes during haemodlalysis. Proc Eur Dial Transplant Assoc 1967;4: Barth R, Caruso C, Li J, Berlyne G: Accurate in vivo measurement of diahyzer urea clearance (Ku) and mass transfer coefficient: A daunting task [Abstract]. J Am Soc Nephrol 1992;3: Malchesky P, Ellis P, Nosse C, Lankhorst B, Nakamoto S: Direct quantification of dialysis. Dial Transplant 1982;1 1: Gillum D, Dixon B, Yanover M, et al.: The role of intensive dialysis in acute renal failure. Chin Nephrol 1 986;25: Volume 4. Number