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Computer program to prescribe acetate-free biofiltration as a continuous renal replacement therapy: theoretical description and in vivo validation

We describe the theoretical features and in vivo assay of an original computer-based program, which describes Na and HCO3 kinetics with acetate-free biofiltration performed as a continuous veno-venous renal replacement therapy (CVVAFB). In 14
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  168 I NTRODUCTION In recent years, bicarbonate (HCO 3 ) has been increasing-ly used as the main buffer with substitution fluids for bloodpurification. Consequently, acetate-buffered fluids havebeen progressively discarded. However, acetate has not been completely abandoned. In substitution fluids con-taining both electrolytes and HCO 3 (usually 32-34mmol/L), 3-4 mmol/L of acetate are still added to prevent calcium salt precipitation. Therefore, due to the negligiblelevels of acetate in blood, there is a dialysate-to-plasma gra-dient of 3-4 mmol/L in patients on bicarbonate hemodial- ysis (HD). Concerning HCO 3 , if a theoretical plasma concentrationof 20 mmol/L is considered, then a dialysate-to-plasmagradient as high as 12-14 mmol/L is expected. Therefore,in bicarbonate HD, about 25% of the net mass balance of buffers can in fact be accounted for by acetate.  Acetate infusion can induce some untoward clinical ef-fects, including cardiovascular instability and increased ni-tric oxide synthesis. A new technique for renal replace-ment therapy (RRT), acetate-free biofiltration (AFB ® ),aimed at obviating the aforementioned problem, was pro-posed about 20 yrs ago (1, 2). With AFB ® , there is no si-multaneous mixing of calcium and HCO 3 . Only HCO 3 isinfused into blood (as NaHCO 3 ), whereas calcium is sup-plied only with the electrolyte-containing, HCO 3 -freedialysate. Consequently, there is no need for acetate. Due to the complex interactions between the convectiveand diffusive fluxes of bicarbonate and sodium during AFB ® , dedicated computer software (Skipper ® ) was neces-sary to predict their kinetics and enable the physician toselect the most suitable working parameters of each ses-sion (3). Some clinical observations reported that AFB ® could im-prove both acid-base control and hemodynamics in pa-tients on regular dialysis treatment for end-stage renal disease(4). Consequently, AFB ® could also be advis-able for critically ill patients with acute renal failure (ARF)in intensive care units (ICUs), in particular those treated with continuous renal replacement therapy (CRRT) be-cause of their poor cardiovascular stability. However, AFB ® JN EPHROL2006; 19: 168-175 O O  RIGINAL RIGINAL  I I  NVESTIGA NVESTIGA TION TION  Computer program to prescribe acetate-freebiofiltration ® as a continuous renal replacement therapy: Theoretical descriptionand  in vivo validation Corrado Vitale, Cristiana Bagnis, Martino Marangella Nephrology and Dialysis Unit, A.S.O. Ordine Mauriziano, Turin - Italy  ABSTRACT:We describe the theoretical features and in vivo  assay of an srcinal computer-based program, which describes Na and HCO 3  kinetics with acetate-free biofiltration ®  performed as a continuous veno-venous renal re- placement therapy (CVVAFB). In 14 patients, CVVAFB sessions were performed as follows. Machine Hospal Prisma  ® ,membrane AN69 0.9 m 2 , blood circuit Hospal M100pre Set, dialysate bags of electrolyte solution with basic composi-tion of: Na 139 mEq/L, K 2 mEq/L, Ca 3.0 mEq/L, Mg 2 mEq/L, Cl 146 mEq/L, and glucose 5.5 mmol/L. Predilu-tional infusion bags of 167 mEq/L of NaHCO 3 solution (Hospal Biosol). To guide the prescription of the dialysate(Q D ) and the infusate (Q Inf  ) flow rates we designed a suitable computer program, which calculated Na and HCO 3  ki-netics and predicted their plasma profiles at equilibrium. Prescribed flow rates were Q B 150 ml/min, Q D 1636 ±42ml/hr, Q Inf  639 ±74 ml/hr and ultrafiltration (UF) rate 110 ±41 ml/hr. During CVVAFB, plasma profiles of HCO 3 and Na became stable after 24 hr. With HCO 3 , the average predicted and observed plasma levels at equilibrium were27.1 ±1.5 and 27.3 ±1.5 mEq/L, respectively (p=ns); with Na, the predicted and observed levels at equilibrium were140.2 ±1.8 and 141.3 ±1.7 mEq/L, respectively (p=ns). There was a good correlation between predicted and ob-served values for both Na (p<0.01, r=0.78) and HCO 3 (p<0.01, r=0.87). These results confirmed the reliability of ourmathematical model for CVVAFB. A Long-term trial is needed to obtain more information on its clinical effects andcompare CVVAFB with other continuous renal replacement therapy techniques. Key words: Continuous renal replacement therapy, Acetate-free biofiltration, Hemodiafiltration, Hemodialysis, Intensive care   Vitale et al  169 has never been switched from an intermittent to a contin-uous technique for blood purification. The solute kinetics with CRRT are different from those oc-curring with intermittent blood purification techniques. With applied flow rates of 2-3 l/hr, the dialysate becomesfully saturated with respect to plasma, i.e. the concentra-tions of diffusible solutes tend to be the same in bothblood and dialysate (5). Similarly to intermittent AFB ® , if CRRT is made by using HCO 3 -free dialysate, a greateramount of HCO 3 moves from the blood to the dialysateand must be carefully compensated by infusing NaHCO 3 .However, just because of the different kinetics of solutes with continuous and intermittent dialysis techniques, Skip-per ® cannot be used to tailor the best dialysate and infusateflow rates with continuous veno-venousAFB ® (CVVAFB).Therefore, a dedicated computer program was necessary for calculating kinetics and mass balances of Na andHCO 3 . The correct management of Na balance is important incritically ill patients, who can both be given Na with par-enteral nutrition, and lose it through drainage and urine.This gain and loss participates with the substitution fluidssupplied during CRRT in determining the final electrolytebalance. In this computer program, additional determi-nants of Na balance are taken into account, thereby help-ing the nephrologist to accomplish and maintain physio-logical plasma levels of Na and HCO 3 during CVVAFB. In this paper, we detail the mathematics of our computerprogram for CVVAFB prescription and report the resultsof its in vivo  assay. M ETHODS The machine  CVVAFB was tailored to the Hospal Prisma ® machine, set on its program for pre-dilution continuous hemodiafiltra-tion. The choice of the pre -  dilution infusion, instead of thepost  -  dilution used for intermittent standard AFB ® , wasaimed at reducing the anticoagulant dose.The standard technical performances of Prisma ® are as fol-lows. Dialysate flow rate (Q  D ), up to 2500 ml/hr; infusion-al flow rate (Q  Inf  ), up to 2000 ml/hr and blood flow rate(Q  B ), up to 180 ml/min. Four rotating pumps control theblood, dialysate, infusate and the effluent (spent dialysate,infusate and net ultra-filtration (UF)) flow rates; a syringepump provides anticoagulant supplementation. The pre-scribed fluid balance is automatically controlled by threegravimetric scales, which are connected to the dialysate, in-fusate and the effluent bags. CVVAFB design  In CVVAFB, Na and HCO 3 are infused pre-dilutionally andmove from the plasma to the dialysate through the filtermembrane. An “equilibrium point” is finally reached, when the gain and loss of these solutes compare and theirplasma concentrations level off over time. Starting from defined values of dialysate and infusate flow rates (the main determinants of solute clearances), it ispossible to predict the “equilibrium points” of Na andHCO 3 concentrations in plasma. Based on these assump-tions, we designed a computer program (running on Mi-crosoft Excel ® ) that estimates the concentrations at whichNa and HCO 3 reach their respective “equilibrium points”,based on the prescribed flow rates of blood and fluids(Tab. I). Computer program: theoretical basis To use the computer program for CVVAFB, some input  variables are required, as follows. Blood flow rate (Q  B ml/min), hematocrit (Hct, %), dialysate flow rate (Q  D ml/hr), dialysate Na concentration (Na D mEq/L), in-fusate flow rate (Q  inf  ml/hr), Na and HCO 3 concentra-tions in infusate (Na inf  and HCO 3inf  mEq/L), prescribedUF rate (Q  uf  ml/hr), Na intake due to total parenteral nu-trition and therapies (Na TPN mEq/24 hr), Na losses withdrainage and/or urine (Na loss mEq/24 hr), estimated en-dogenous acid production (H + mEq/kg bw) and patient body weight (kg) (Tab. I). The input variables depend on both the individual charac-teristics of each patient and the CVVAFB program pre-scribed. Starting from defined values of input variables,the program simulates Na and HCO 3 kinetics during CV- VAFB and predicts the plasma levels at equilibrium, as de-tailed below. In other words, input variables are independent variables  , whereas plasma Na and HCO 3 levels are dependent variables  and are the main output of the program. Dialysate and infusate flow rates of 1.6 and 0.6 L/hr, re-spectively, were routinely prescribed to provide a wholeurea clearance of at least 2 L/hr (6). The equilibriumpoints were set and changes in working parameters weremade if predicted plasma Na and HCO 3 levels at equilibri-um differed from desired physio-logical values (Tab. I). Concerning HCO 3 balance, a daily HCO 3 consumptionroughly equivalent to the daily ash-acid production was as-sumed. While under normal conditions a daily acid pro-duction of about 1 mEq/kg body weight occurs (7), inthese patients increased metabolic production occurs, fix-ing the daily metabolic consumption of HCO 3 at 1.2mEq/kg bw, to be used for calculations.  As far as blood analyses are concerned, Na was reported astotal plasma concentration (NaP) and HCO 3 as totalblood concentration (HCO 3 ). However, because diffusiveand convective kinetics involve only the diffusible or ultra-filterable electrolyte fraction, it was necessary to introducesome correcting factors in the calculations, as follows. The ionic concentration of Na in plasma water (Na + P) wascalculated as NaP divided by 0.935 (correction for pro-tein) and multiplied by 0.96 (8). Then, Na + P was consid-  TABLE I - CVVAFB COMPUTER PROGRAM: A WORKSHEET (4 EXAMPLES)BLOODExample # 122a2bPrescribed flow rate (ml/min)input150150150150Hematocrit (%)input25252525DIALYSATE Prescribed flow rate (ml/hr)input1600200016001600[Na] concentration (mEq/L)input144139144144INFUSATEPrescribed flow rate (ml/hr)input600500500600[Na] concentration (mEq/L)input167167167167[HCO 3 ] concentration (mEq/L)input167167167167Prescribed ultrafiltration (ml/hr)input120150150150Net ultrafiltration (ml/hr)output100505050OTHER METABOLIC PARAMETERSIntravenous infused Na (mEq/24 hr)input75757575Intravenous infusion, flow rate (ml/hr)input20100100100Na output (urine, drainage) (mEq/24 hr)input0000Endogenous fixed acid (mEq/kg bw)input1. weight (kg)input65656565Plasma HCO 3 at equilibrium (mEq/L)output26.416.622.025.6Plasma sodium at equilibrium (mEq/L)output 141135138139 Continuous acetate-free biofiltration  170 ered as a reliable estimate of ultrafilterable Na (ufNa) (8).Diffusible plasma Na (dNa + P) was calculated as Na + P mul-tiplied by 0.97 (Donnan factor) (8). In bicarbonate-freedialysate, Na (Na D ) was considered freely diffusible (8). Due to the diffusibility of CO 2 in whole blood, the measureof its concentration in whole blood was considered as a re-liable estimate of its concentration in plasma water. Conse-quently, the derived value of whole blood HCO 3 concen-tration (HCO 3 ) was also used as ultrafilterable HCO 3 (ufHCO 3 ). Diffusible HCO 3 (dHCO 3 ) was calculated asHCO 3 x 1.15 (9). Other derived variables were obtainedfrom input variables, according to the procedures detailedbelow. Due to the pre-dilution infusion, Na is slightly higher inthe plasma in the filter capillaries than in the plasma that enters the arterial line of the circuit. Therefore, plasma Nain the filter (NaP f  ) was calculated as: [(Na inf  * Q  inf  + NaP *Q  P ) / (Q  inf  + Q  P )], where Q  P stands for plasma flow rate,calculated as Q  B * (100-Hct)/100. The same procedure was made to calculate plasma HCO 3 in the filter (HCO 3f  ). In CRRT, dialysate is fully saturated with diffusible plasmasolutes. Therefore, diffusive balances of Na (NaDB) andHCO 3 (HCO 3 DB) were calculated as the plasma-to-dialysate gradient of their diffusible fractions, times thedialysate flow rate [NaDB = (NaD - dNa  +  P   f  ) * Q   D  ; HCO 3 DB= dHCO   f3  * Q   D  ]. Considering the convective balances of Na (NaCB) andHCO 3 (HCO 3 CB), they were calculated as the ultrafilterable fractions of NaP f  (ufNa f  ) and HCO 3f  (ufH-CO 3f  ) times the whole convective flow (Conv), which is thesum of Q  inf  and Q  uf  . The amount of Na infused in CRRT was calculated as(Na inf  * Q  inf  ); the whole reinfusive balance of Na (NaRB) was calculated as the sum of (Na inf  * Q  inf  ) plus Na TPN . Theamount of HCO 3 reinfused in CRRT was calculated as(HCO 3inf  * Q  inf  ). The estimated metabolic consumptionof HCO 3  was considered equal to the estimated daily gen-eration of endogenous fixed acid, namely, H + x kg of body  weight (GenH + ). Finally, the calculations of the whole bal-ance of Na and HCO 3 (NaWB and HCO 3  WB) were madeas follows. 1) NaWB: NaDB + NaCB + NaRB -Na loss 2) HCO 3  WB: HCO 3 DB + HCO 3 CB + HCO 3 RB - GenH + Input variables were inserted in the MSExcel ® electronicspreadsheet, where the derived variables were calculated,according to the criteria described above. Algebric values(positive or negative) of each balance were taken into ac-count. Finally, equation [1] was solved for NaP whenNaWB = 0 and equation [2] was solved for HCO 3  WB = 0,thereby obtaining an estimate of NaP and HCO 3 at equi-librium. Table II summarizes the mathematical procedures . Patients   After preliminary assays in vitro  , the reliability of our com-puter program for CVVAFB was also tested in vivo  in 20critically ill patients with ARF, admitted to the ICU after  Vitale et al  171 cardiovascular surgery. Of the patients, 14 had been treat-ed continuously for at least 48 hr and were selected for thestudy. All patients were treated using the same machine. The eth-ical committee of our institution approved the study. CVVAFB prescription  The target “equilibrium points” of Na and HCO 3 had beenpredicted from the prescribed dialysate and infusate flow rates. Other water and electrolyte intakes or losses were TABLE II -  VARIABLES USED FOR NaAND HCO 3 MODELING IN CVVAFB a) Input variablesUnit  HctHematocrit% Weight Body weightkgQ  B Blood flow rateml/minQ  D Dialysate flow rateml/hrNa D Dialysate sodium concentration mEq/LQ  Inf  Infusate flow rateml/hrNa Inf  Infusate sodium concentrationmEq/LHCO 3inf  Infusate bicarbonate concentrationmEq/LQ  uf  Prescribed ultrafiltration rateml/hrNa TPN Na intake (parenteral nutrition)mEq/24 hrH + Endogenous acid generationmEq/kgNa loss Sodium losses (urine, drainages)mEq/24 hr b) Basic settingsCalculations NaPSodium concentration in plasmamEq/LNa + PIonized Na in plasma water[NaP * 0.96 / 0.935]mEq/LufNaUltrafilterable plasma Na [Na + P]mEq/LdNa + PDiffusable plasma Na[Na + P * 0.97]mEq/LHCO 3 Plasma HCO 3 [blood HCO 3 ]mEq/LdHCO 3 Diffusable plasma HCO 3 [HCO 3 * 1.15]mEq/L c) Derived variablesCalculations Q  P Plasma flow rate [Q  B * (100-Hct)/100]ml/minNaP f  NaP into the filter[(Na inf  * Q  inf + NaP * Q  P )/(Q  inf  +Q  P )]mEq/LNa + P f  Na+P into the filter[NaP f  * 0.96 / 0.935]mEq/LufNa f  ufNa into the filter[Na + P f  ]mEq/LdNa + P f  dNa+P into the filter[Na + P f  * 0.97]mEq/LHCO 3f  HCO 3 into the filter[(HCO 3inf  * Q  inf  + HCO 3 * Q  P )/(Q  inf  +Q  P )]mEq/LdHCO 3f  dHCO 3 into the filter[HCO 3f  * 1.15]mEq/LConvWhole convection[Q  inf  + Q  uf  ]ml/hrNaDBNa diffusive balance [(Q  D /1000) * (NaD - dNa + P f  ) * 24] mEq/24 hrNaCBNa convective balance [ufNa f  * effUF * 24 / 1000]mEq/24 hrNaRBNa reinfusive balance [(Na inf  * Q  inf  * 24 / 1000) + Na intake ] mEq/24 hrNaWBWhole sodium balance[NaDB + NaCB + NaRB - Na loss ] mEq/24 hrHCO 3 DBBicarbonate diffusive balance [(Q  D /1000) * (- dHCO 3f  ) * 24]mEq/24 hrHCO 3 CBBicarb. convective balance [ - dHCO 3f  * effUF * 24 / 1000] mEq/24 hrHCO 3 InfBBicarbonate infusive balance [HCO 3inf  * Q  inf  * 24 / 1000] mEq/24 hrGenH + Endogenous acid generation [H + * Weight]mEq/24 hrHCO 3  WBWhole bicarbonate balance [HCO 3 DB + HCO 3 CB + HCO 3 InfB - GenH + ]mEq/24 hrNaPat equilibrium point =(((Q  D * Na D + Na inf  * Q  inf  + (Na intake - Na loss ) * 1000/24) * 0.935 * (Q  P * 60 + Q  inf  )) / / ((Q  D * 0.97 + Conv) * 0.96 * Q  P * 60))-( Na inf  * Q  inf  ) / (Q  P * 60)mEq/LHCO 3 at equilibrium point =(((HCO 3inf  * Q  inf  - H + * Weight * 1000/24) / (Conv + Q  D * 1.15) - (HCO 3inf  * Q  inf  ) // (Q  P * 60 + Q  inf  )) * (Q  P * 60 + Q  inf  ) / (Q  P * 60))mEq/L  Continuous acetate-free biofiltration  172 considered as well. Values were entered into the calculator worksheet (Tab. I).The correspondence between the  prescribed  flow rates of dialysate and infusate and the average actual  flow rates sup-plied by the Prisma ® machine was evaluated by random-ized hourly sampling over CVVAFB sessions. With blood,the correspondence between  prescribed  and actual  flow rates was determined in vitro  . Blood circuit  Standard Prisma M100pre Set was used. This device is alocked circuit, including a 0.9 m 2  AN69 filter previously connected with lines for blood, dialysate, predilutional in-fusion, effluent and anticoagulant. The circuit is not equipped with a bubble chamber; the upper part of the fil-ter works as an air-trapping system. Fluids  Five-liter bags of sterile electrolyte solution were used as ac-etate-free dialysate, the basic composition was Na 139mEq/L, K 2 mEq/L, Ca 3.0 mEq/L, Mg 2 mEq/L, Cl 146mEq/L and glucose 5.5 mmol/L. Sterile solutions of concentrated NaCl, KCl and CaCl 2  were used to modulate the basic dialysate composition ac-cording to the physician’s prescriptions.Pre-dilution infusion was performed with bicarbonate-con-taining bags currently used for standard intermittent AFB,ie Hospal Biosol ® (NaHCO 3 concentration 167 mmol/L). Anticoagulation was performed with unfractionated he-parin. Biochemistries  During CVVAFB, plasma urea and creatinine (Cr) were de-termined at the start and every 24 hr; electrolytes, bloodpH and HCO 3  were determined at the start and every 6 hr. In plasma, urea and Cr were assayed by routine methods;Na was assayed by potentiometry and, after the suitablecorrection for coefficients and protein activity, reported astotal plasma Na (NaP, equivalent to photometry assay); pHand ionized Ca, by ion-selective electrode. In whole blood,HCO 3  was calculated from CO 2 tension. Statistical analysis  Data are expressed as mean ±standard deviation (SD). Asfar as the relationships between predicted and observed values of plasma Na and HCO 3 at equilibrium were con-cerned, two regression models were performed: predictedNa = b 0 + b 1* observed Na (equation 1); predicted HCO 3 = b 0 + b 1* observed HCO 3 (equation 2). Correlations between estimated and measured plasma Naand HCO 3 levels were performed with Pearson’s correla-tion coefficients (r). P<0.05 was considered statistically significant. With equations 1 and 2, the Passing and Bablok linear re-gression procedure (method conversion) (10) was used tocalculate the slope b 1 and the intercept b 0  with their 95%confidence interval to test that b 0 is no different from 0and b 1 is no different from 1. R  ESULTS Table II details the equations used by our computer pro-gram to calculate plasma of Na and HCO 3 levels at equi-librium. Table I reports the worksheet used for CVVAFBprescription (running on MSExcel ® ). Table III reportsthe main features of CVVAFB sessions (average duration51 ±5 hr).The average actual  flow rates were lower than the corre-sponding  prescribed  flow rates: 1560 ±37 vs. 1636 ±42ml/min for dialysate (p<0.01), 617 ±63 vs. 639 ±74ml/min for infusate (p<0.01), and 141 ±4.0 vs. 150ml/min for blood ( in vitro  assay, p<0.01). On average, theprescribed flow rates tended to overestimate the actualflow rates by about 5%. For each CVVAFB session, dialysate composition was tai-lored to patient requirements by adding concentrated Na-Cl, KCl and CaCl 2 to the basic formula. Conversely, thesame infusate solution, i.e. hypertonic NaHCO 3 (167mEq/L), was used for all patients. Intravenous therapies were taken into account in calculating Na and fluid bal-ances. On average 49 ±15 ml/min of fluids (saline or glu-cose-containing solutions) were infused over CVVAFB ses-sions, and 96 ±37 mEq/24 hr of Na as well. Table IVreports plasma profiles of urea, Cr, pH and elec-trolytes during CVVAFB. As expected, with an adminis-tered urea clearance of about 38 ml/min, plasma urea andCr levels decreased progressively during CVVAFB. Na, pHand HCO 3 reached a plateau within 24 hr; thereafter, they leveled off until the 48th hr (p=ns). As concerns the plas-ma K and ionized Ca levels, wider fluctuations than Na andHCO 3 levels were observed, possibly due to the interfer-ence of several factors, including K content of transfusedblood and plasma, transcellular shift of K, and alteredbone turnover.In Table V the mean  predicted  and observed  plasma levels of Na and HCO 3 at equilibrium are compared. The averagesof the values at 24-48 hr of CVVAFB were taken as the ob- served values  . The correlation between predicted (140.2 ±1.8 mEq/L)and observed (141.3 ±1.7 mEq/L) plasma Na levels wassignificant (y = x - 0.55; r=0.61, p=0.021). From the analy-sis of their confidence intervals, it emerged that the in-tercept of the correlation (b 0 ) was not significantly dif-ferent from 0 (which suggests that no systematic  over- orunder-estimation of predicted Na occurred) and theslope (b 1 ) was not significantly different from 1 (whichmeans that there was not a  percent  over- or under-estima-
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