Hemofiltration as an Adjunct to for Total Oxygenator Volume Control

David W. Holt, Gregory H. Landis, David A. Dumond, Scott B. Hardin, Jerry Bartosik, Max Miller

Abstract, ______indications as in fluid overload from chronic renal failure. Oxygenator volume can be controlled with A comprehensive literature review of hemofiltration HFT especially in conditions of excessive hemodilution. (HFT) and subsequent application to cardiopulmonary Large amounts of , high circulating blood bypass is discussed. Any existing hypervolemic situa­ volumes, pre or peri-pump oliguria or anuria, or inad­ tion is an indication for H FT. No contraindications for vertent acquisition of disposable fluids all lead to ex­ HFT are known when used in conjunction with bypass. cessive oxygenator levels which may be easily removed A detailed methodology as well as practical guidelines with HFT. are presented. Specific details associated with HFT Post-bypass hemoconcentration of red cells and have been addressed including choice of diafilter, ul­ clotting factors by the recirculation of the remaining trafiltrate composition, hemoconcentration, hemolysis oxygenator blood through a diafilter is possible. The and other blood damage, acid-base effects, final product of this concentration process may be more clearance, loss of proteins and amino acids, acidemia, physiological than that offered by centrifugal blood and rebound hyperkalemia. processing devices.

Introduction[ ______Materials and Methods, ______It is the intent of this publication to introduce the concept of hemofiltration (HFT) to cardiopulmonary Hemofiltration during CPB is a simple process if the bypass (CPB) by literature review. The theory behind proper preparations are made in advance. An option and clinical application of HFT during bypass as well is presented here where one can either pump the H FT as specific indications and contraindications and blood or not. In either case, the perfusionist should be guidelines for use will be discussed. familiar with the hemofilter. The Cordis units are Hemofiltration was clinically introduced as an ad­ packed in a glycerin compound to maintain fiber junct to for severe fluid overload.I.2 Cir­ moisture during storage. This glycerin must be rinsed culation of blood through a diafilter (a modified dia­ and discarded with at least 500 cc of normal saline prior lyzer) with vacuum applied to the dialysate side to to use. Failure to do so may result in severe hemolysis create a high transmembrane pressure (TMP) was with secondary acute renal failure. 4 found to remove remarkable amounts of fluid.3 How­ If the perfusionist elects to pump the HFT blood, the ever, during this process of fluid removal, solutes small HFT subcircuit must then be pre-measured, assembled, enough to pass through the membrane pores are also and sterilized. During the set-up of the CPB circuit, a 1 removed, the driving force being the pressure gradient sterile capped six-inch piece of /4" 1.0. PVC tubing rather than a concentration gradient. This technique should be attached to the coronary perfusion port of the allows control in removal of both low molecular weight oxygenator allowing easy access for the HFT subcir­ plasma solutes as well as fluid. cuit. When priming the CPB circuit, this six-inch line The application of HFT to CPB has much the same should be carefully de-bubbled and clamped with a screw clamp. Using a tubing clamp should be avoided as it can be accidentally dislodged resulting in a rapid Address correspondence to: David W. Holt, C.C.T. Circulation draining of the blood volume in the arterial reservoir. Technology, Riverside Methodist Hospital, 3535 Olentangy River Road, Once the decision has been made to use HFT, the Columbus, OH 43214 614/261-5304 Submitted 2/3/82 pre-assembled circuit is easily connected to the CPB Accepted 3/31/82 circuit. (Figure 1).

Volume 14, Number 3, 1982 The Journal of Extra-Corporeal Technology 373 to oxy·;enatur

art if JCJ8l •tJne

, r FIGURE 1. This is a block diagram of a circuit used to pump blood for hemofiltration during cardiopulmonary bypass. Blood is pumped from the coronary outlet (A) of the oxygenator via the arter!81 pump hend to the artificial kidney. The upper dialysate port is f1lter 1 sealed with a piece of clamped /2'' tubing (B) and the lower di­ FIGURE 2. This is a block diagram of a circuit used to retrieve alysate port is connected to a vacuum cannister where the ul­ blood from the arterial filter for hemofiltration during cardio­ trafiltrate is measured. The hemoconcentrated blood leaves the pulmonary bypass. A large bore monitering line is con­ diafilter and then is either emptied into a cardiotomy reservoir nected to a stopcock (A) directly on the arterial filter. The or directly into the oxygenator. stopcock is turned to allow blood to flow from the filter to the artificial kidney. The upper dialysate port is sealed with a piece Blood is pumped from the coronary port via a roller of clamped 1/z" tubing (B) and the lower dialysate port is con­ head to the diafiltera and emptied into the cardiotomy nected to a vacuum cannister where the ultrafiltrate is measured. The hemoconcentrated blood leaves the diafilter and then is ei­ reservoir. The upper dialysate port is sealed and the ther returned to a cardiotomy reservoir or directly into the oxy­ lower dialysate port is connected to vacuum. genator. The H FT circuit requires no special priming tech­ cardiotomy reservoir. Blood flow through the diafilter niques. Care should be taken to ensure that the direc­ is then a function of the arterial line pressure. Vacuum tion of blood flow is away from the oxygenator, should be connected to one of the dialysate ports and avoiding accidental air embolism to the patient. The the other port sealed off. blood flow rate should be kept constant at about 200 ccjmin and the TMP maintained at about 500 mmHg. Ultrafiltrate is then measured in the vacuum can­ Discussiont ______nister. The glomerulus of the natural kidney is a hemofilter The alternative to pumping the HFT blood is not and all metabolites which traverse it and which are not pumping it, which leads to a somewhat simpler circuit reabsorbed or secreted by the tubules are cleared from design (Figure 2). In this case, the diafilter is connected the bloodstream at the same rate.5 While the idea of to the CPB circuit by the use of large bore monitoring artificial hemofiltration was first discussed in 1928,6•7 lines (for example Cobe Laboratories Catalog Number the application of this technique for the replacement 26-750-000).b These particular lines have a male leur of renal function has awaited the availability of syn­ 3 lock connection on one end and open /16" tubing on the thetic membranes with appropriate hydraulic perme­ other. The leur lock end should be connected to a ability and solute retention properties.5 In 1947, AI wall stopcock where the arterial filter bleed line is also fed. described the first artificial kidney in which the prin­ The open end should then be connected to the diafilter ciples of H FT were applied for removal of water and and the outflow of the diafilter connected the same way sodium from over-hydrated patients.8 The use of H FT with the remaining leur either into the oxygenator or as it is known today for the treatment of fluid overload and blood toxemia in end-stage renal failure was pio­ neered by Henderson eta! in 1967.9•10 The use of HFT • Cordis Dow C-Dak 3500, Cordis-Dow Corp., Concord, CA 94520 with CPB is a topic yet to be firmly established. b Cobe Laboratories, Lakewood, Colorado, 80215 Hemofiltration is known by several names in the

374 The Journal of Extra-Corporeal Technology Volume 14, Number 3, 1982 literature. Ultrafiltration, hemo-ultrafiltration, di­ ther a normal or abnormal hematocrit. Removal of afiltration, or hemodiafiltration are all terms meaning cardioplegia volumes or simple hemoconcentration the same thing. Hemofiltration is the name preferred prior to the termination of bypass are other reasons to due to its establishment in scientific literature and is use H FT. A post-bypass indication is the hemocon­ therefore the term we will use. 11 centration of the remaining pump circuit blood. There Hemofiltration is fundamentally different from are no absolute contra-indications for use of HFT conventional dialysis. Dialysis is a diffusive process during bypass. where smaller molecules diffuse more rapidly than As an example of post-bypass hemoconcentration, larger molecules. H FT is a convective process where if the termination hematocrit is 20% with I 000 cc of all the solutes transfer at the same rate. The driving blood remaining in the circuit, then simple proportions force for H FT is the transmembrane pressure differ­ can be used to make calculations. The red cell volume ential across the membrane. The value of TMP is de­ can be determined as twenty percent of I 000 cc, termined from the sum of the positive pressure applied yielding 200 cc of RBC's. If the desired hematocrit is to the blood path and the absolute value of the applied 60% with the 200 cc of RBC's, then the final blood vacuum. The limiting factor for solute removal in HFT volume would be 200 cc divided by 60% or 333 cc of is the membrane pore size. Large proteins and albumin blood. Thus 667 cc of effluent needs to be removed will be retained on the blood side of the diafilter. from the original I 000 cc. If the diafilter used has a flux The ultrafiltration rate (UFR) is the rate at which rate of 50 ccj min, then the removal of 667 cc will take effluent is removed from the blood in the diafilter. UFR about thirteen and a half minutes of recirculation. is dependent upon TMP and the surface area of the The effluent removed from the blood, referred to as diafilter. There is a linear increase in UFR with in­ either the filtrate, ultrafiltrate, or hemofiltrate, has creasing TMP to a point. This point is where the UFR been the subject of much investigation. This filtrate levels off as a function of the surface area of the par­ contains molecules with a molecular dimension below ticular diafilter. All toxins and solutes smaller than the the membrane pore size. The concentration of the cut-off of the membrane pore size are passed and those molecules is the same in both the filtrate and the plas­ larger are retained.12 ma because this is a convective mass transport mech­ The choice of hemofiltration unit is usually made anism.5·13·14 The composition of this ultrafiltrate is from parallel plate or hollow fiber diafilters.2 Hollow entirely analogous to glomerular filtrate. 1 Leakage of fiber diafilters are the membrane of choice for HFT some small proteins across the membrane has been because of their intrinsically high ratio of surface area documented. 1·8·13 to volume, relatively low end-to-end pressure drop, and Many advantages of H FT with respect to its appli­ because they provide a simple and convenient method cation in renal failure have been docu­ of obtaining thin channels required to minimize con­ mented.2·3·15·16·17·18·19 Of these, most can be inferred centration polarization and thereby obtain high flux. 12 to be advantageous for use during CPB, although the Plate or hollow fiber dialyzers can produce a medium theory and clinical application of HFT to CPB is not HFT flux rate of about 25 to 35 ccjmin with a TMP to be found in the literature. of about 500 mmHg.c.d.e High flux rates of 50 to 75 The most obvious advantage of HFT is hemocon­ ccjmin are also available_f,g centration. With hemodilution included among modern The application of H FT to CPB can be divided into bypass techniques, diafiltration provides a simple pre, during, and post-bypass indications. Pre-bypass method of reversal, when indicated. The removal of indications include oliguria or anuria and acute/ plasma water results in increased hematocrit, plasma chronic renal failure with resultant over-hydration albumin concentrations and plasma colloidal osmotic and/or blood toxemia. During bypass, HFT is indicated pressures. 15·16·17 ·18 Plasma and extracellular volumes with excessive oxygenator volume associated with ei- can be reduced. 19·20 Third spacing, which is physiologically similar to

c Cordis Dow C-Dak 2.5 or 3500, Cordis-Dow Corp., Concord, CA overhydration subsequent to renal failure is common 94520 to CPB. Ing et al. have proposed that the increased d CF1500, Travenol Laboratories, Inc., Deerfield. Ill., 92705 plasma oncotic pressure secondary to the increased • PPD I. 6m 2 Co be Laboratories, Lakewood, Colo., 80215 f Gambro Ultradiffuser, Gambro, Inc., Barrington, Ill., 60010 concentration of plasma proteins promotes the ab­ 2 g Amicon Diafilter 66, Amicon Corp., Lexington, MA, 02173 sorption of edematous fluids.

Volume 14, Number 3, 1982 The Journal of Extra-Corporeal Technology 375 Another complication associated with hemodilution molecule ( 16,000 mw) is cleared at the U FR.I2,I8 during bypass is the ultimate dilution of the circulating Therefore, if H FT via a true diafilter is used during clotting factors. Hemoconcentration of these factors CPB, especially during the rewarming phase of the may lead to a decrease in peri-, and post-operative procedure, the perfusionist should be even more acutely blood losses and thus a decrease in the use of bank a ware of the anticoagulation status of the patient. Some blood. Aside from removing the risks to the patient allowance for this heparin clearance should be made associated with blood administration, a tremendous at that time and also during post-bypass hemocon­ cost advantage could develop. centration. In addition to the hemoconcentration virtue of HFT The loss of amino-acids and proteins by H FT has is the subsequent removal of small and middle molec­ received much attention. The protein loss problem ular weight uremic toxins.3 In the instance of acute raises many questions about the loss of intermediate renal failure (ARF) on CPB, control of these toxins molecular weight solutes normally retrieved by the may alleviate further ARF and other toxic systemic kidney as well as their importance to metabo­ complications. lism.14·25·26·27 This protein loss is really only significant Blood damage has been a point of concern when if they are irreplaceable. Dog and goat studies per­ using H FT due to high TMP and high shear rates. formed in attempt to correlate any depletion syndromes However, in studies performed from conventional he­ to the protein loss have yielded no clinical signifi­ mofiltration for renal failure the fact that plasma free cance28·29 even after six months of maintenance H FT. 30 hemoglobin has not been detected in significant The total protein loss during forty-five minutes of HFT amounts in either the effluent or the plasma would al­ on bypass does not even approach that of six months of leviate the concern.21 Silverstein has stated that the maintenance HFT. Quellhorst has found the amino­ hemolysis encountered during HFT is in fact less than acid loss to be dependent only on plasma levels, as ex­ that encountered when using occlusive pumps currently pected, amounting to a loss smaller than by peritoneal in wide clinical use in hemodialysis.' dialysis and insignificantly higher than hemodialysis. 24 There have been no reported changes in patient's Friedman has found the loss to be clinically "toler­ blood gas/acid base status as a result of HFT2,22 able."'' However, our results demonstrate a vacuum-induced The phenomenon of rebound hyperkalemia has also respiratory alkalemia when the residual CPB circuit been found to occur when HFT exceeds a total volume blood is repeatedly recirculated post-bypass for the of three to five liters. 31 The reason for such an effect is purpose of hemoconcentration. We have observed no obscure. It is conceivable that such a hyperkalemia may clinical effects on patient's acid-base status when the be caused by excessive hemolysis,2 acute stimulation concentrated blood is returned. This is a point that may of alpha adrenergic receptors, 32 or the exit of potassium warrant further investigation. from the intracellular compartment as a result of ex­ Keshaviah et a! have reported the use of H FT for tracellular dehydration. Regardless of cause, serial more than one to two hours may result in a mild met­ potassium levels should be closely monitored, especially abolic acidemia.23 The pathophysiology of this aci­ in conjunction with the use of a hyperkalemic cardio­ demia has been suggested to be a depletion of plasma plegia during bypass. bicarbonate due to preferential movement of the anion The use of H FT has certain advantages over external into the ultrafiltrate. This movement is thought to be cell centrifugation/processing devices. First, from a related to the Gibbs-Donnan phenomenon as a result cost point of view, HFT requires only the dialyzer, of an HFT induced increase in plasma protein con­ vacuum cannister, tubing and connectors amounting centration. Lactic acidosis due to excessive H FT cannot to less than thirty-five dollars per case. No capital ex­ be excluded.2 Routine blood gas monitoring during pense is required. This is about ten dollars less per bypass provides a constant monitoring of any possible procedure than for the Haemonetics Cell Saverh dis­ acidemia. posables alone. Both HFT and centrifugation require Another point to be made is that concerning heparin. about the same set-up time. The true distinction lies in When using a conventional hemodialyzer modified for the final product. H FT yields a product of re-concen- H FT, the membrane pore size is less than the size of the heparin molecule. However, if using a true diafilter

(membrane pore size 40,000-45,000 mw) the heparin h Haemonetics Corporation, Braintree, MA, 02184

376 The Journal of Extra-Corporeal Technology Volume 14, Number 3, 1982 trated whole blood with formed elements. Centrifu­ (ed): Strategy in Renal Failure, New York, J. Wiley & Sons, 1978. gation for bypass volume reduction yields only packed 12. What is Diafiltration') Publication Number 1425, Amicon Corpo­ red cells. Both procedures help to eliminate plasma ration, Lexington, Mass, p. 1-9. toxin build-ups. 13. Schneider, H; Streicher, E.: Technical Aspects of Hemofiltration, Dial. Transplant. 8(4):371-374, 1979. In addition to the points made in the Methods and 14. Henderson, L. W.; Colton, C. K.; Ford, C. A.: Kinetics of Hemodi­ Materials section; the authors have compiled some afiltration II; Clinical Characterization of a New Blood Cleansing Modality,}. Lab. Clin. Med. 85(3):372-391, 1975. practical guidelines for use. First, the transmembrane 15. Asaba, H.; Bergstrom, J .; Furst, P.: Sequential Ultrafiltration and pressure should be limited to a maximum of 700 mmHg Diffusion as an Alternative to Conventional Hemodi!aysis, Proc. Clin. Dial. Transp. Forum 6:129-135, 1976. to minimize hemolysis with resultant hyperkalemia.2•33 16. Bosch, J. P.; Kirpalani, A. L.; von Albertini, B.: Ultrafiltration lng has suggest that this TMP not exceed 500 mmHg without Hemodialysis, Abstrcts of 23rd Annual Meeting of Amer­ and that this be achieved by maximizing the vacuum ican Society for Artificial Internal Organs, p. 8, 1977. 17. Bower, J. D.; Hellems, E. W.; Jones, Q.: Mechanism of Fluid Re­ of Zhe negative pressure side of the diafilter, as opposed moval with Ultrafiltration; Abstracts of 23rd Annual Meeting of to increasing the positive pressure with a screw clamp American Society for Artificial Internal Organs, p. 9, 1977. on the outflow side. Blood will not be excessively 18. Shaldon, S.; Asaba, H.; Lindh, K.: The Technique and Application of Ultradiffusion. Technical Aspects of Renal Dialysis, Frost, T. H. squeezed through constricted channels and, therefore, (Ed.), New York: Pitman Medical Publishing Co., 1977. less trauma to the red cells will result.2 Increasing the 19. Pogglitsch, V. H.; Waller, J.; Giebauf, W.: Die Hamofiltration zur Behandlung Generalisierter Odeme, Acta Med. Austriaca. 3:73- positive pressure increases the shear force, which is 77;1976. more hemolytic. 20. Chen, W. T.; Chaignon, M.; Tarazi, R. C.: Hemodynamic Studies in Chronic Hemodialysis Patients with Hemofiltration, Abstracts Finally, the blood flow rate should be limited to of 24th Annual Meeting of the American Society for Artificial In­ about 200 cc/min. Blood flow rate influences the UFR ternal Organs, p. I 0, 1978. by both altering the shear force at the luminal mem­ 21. lvanovich, P.; Huang, C.; Stefanovic, N .: Hemofiltration: A Useful Adjunct to Dialysis, Proc. Eur. Dial. Transplant Assoc. 14:605-606, brane surface and by varying the rate of plasma water 1977. delivery to the membrane. 1 The shear force is propor­ 22. von Albertini, B; Kirpalani, A. L.; Goldstein, M. H.: Partial Arterial Oxygen Pressure and Acid-Base Measurements during Separated tional to the flow rate and should be held at this optimal Ultrafiltration, Abstracts of 8th Annual Meeting of the Western level giving maximal results with minimal trauma. Dialysis and Transplant Society and the Kidney Foundation of Southern California, p. 14, 1977. 23. Keshaviah, P.; Cadwell, K.; Wathen, R.: Acid-Base Changes in Se­ References. ______quential Therapy, Abstracts of 7th Annual Meeting of the Clinical Dialysis and Transplant Forum of the National Kidney Foundation, I. Silverstein, M. E.; Ford, C. A.; Lysaght, M. J.; Henderson, L. W.: p. 12, 1977. Treatment of Severe Fluid Overload by Ultrafiltration; New England 24. Quellhorst, E.; Schvenemann, B.: Metabolic and Hemodynamic J.ofMed. 291(15):747-751, 1974. Aspects of Hemofiltration, Dial. Transplant. 7(4):369-372, 2. lng, T. S.; Vi! bar, R. M.;Shin, K. D.; Viol, G. W.; Bansal, V. K.;Geis, 1978. W. P.; Hano, J. E.: Predialytic Isolated Ultrafiltration, Dial. 25. Christopher, T. G.; Cambi, V.; Harker, L.A.: A Study of Hemodi­ Transplant. 7(6):557-559, 1978. laysis with Lowered Dialysate Flow Rate, Trans. Am. Soc. Artif 3. Henderson, L. W.; Livoti, L. G.; Ford, C. A.; Kelly, A. B.; Lysaght, Org. 17:92-95, 1971. M. J.: Clinical Experience with Intermittent Hemodiafiltration, 26. Quadracci, L. J.; Cambi, V.; Christopher, T. G.: Assay of Serum Trans. Am. Soc. Art. Int. Org. 19:119-123, 1973. Abnormalities in Uremic and Dialysis Patients; Evidence for De­ 4. Hagnevik, K.; Gordon, E.; Lins, L.; Wilhelmsson, S.; Forster, D.: pletion of Vital Substances in Hemodialysis, Trans. Am. Soc. Art if Glycerol-Induced Haemolysis with Haemoglobinuria and Acute Int. Org. 17:96-101, 1971. Renal Failure, Lancet. January 19:75-77, 1974. 27. Cambi, V.; Quadracci, L. J.; Betteti, C.: Further Studies on "De­ 5. Colton, C. K.; Henderson, L. W.; Ford, C. A.; Lysaght, M. J.: Ki­ peltion" in Dialyzed Patients, Fifth International Congress of Ne­ netics of Hemodiafiltration I; In Vitro Transport Characteristics of phrology Abstract No. 86, p. 25, 1972. a Hollow-Fiber Blood Ultrafilter, J. Lab. Clin. Med. 85:355-371, 28. Henderson, L. W.; Ford, C. A.; Colton, C. K.: Uremic Blood 1975. Cleansing by Diafiltration Using a Hollow-Fiber Ultrafilter, Trans. 6. Brull, L.: Realization de !'ultrafiltration in cico, Compt. Rend. Soc. Am. Soc. Art if Int. Org. 16: I 07-112, 1970. Bioi. 99:1605-1607, 1928. 29. Hamilton, R.; Ford, C.; Colton, C.: Blood Cleansing by Diafiltration 7. Brull, L.: L'ultrafiltration in cico, Compt. Rend. Soc. Bioi. 99: in Uremic Dog and Man, Trans. Am. Soc. Arllf Int. Org. 17: 1607-1608, 1928. 259-265, 1971. 8. Bergstrom, J.; Changes in Blood Pressure and Hemodynamics 30. Silverstein, M .; Ford, C. A.; Lysaght, M. J .: Response to Rapid During Ultrafiltration and Dialysis, Dial. Transplant. 7( II): Removal of Intermediate Molecular Weight Solutes in Uremic Man, 1087-1092, 1978. Trans Am. Soc. Artif Int. Org. 20:168-175, 1974. 9. Henderson, L. W.; Besarab, A.M.; Michaels, A.; Blucmle, L. W.: 31. Kopp, K. F.: Hemofiltration, Nephron. 20:65-74, 19n. Blood Purification by Ultrafiltration and Fluid Replacement, Trans. 32. Kuschel, J. P.: Role of Glucoregulatory Hormones in Potassium Am. Soc. Art. Int. Org. 13:216-222, 1967. Hemostasis, Kidney Int. II :443-452, 1977. 10. Henderson, L. W., Lilley, J. J.; Ford, C. A.: Hemodiafiltration, J. 33. Reigner, J.; Qucllhorst, E.; Lowitz, H. D.: Ultrafiltration for Middle Dial. I :211-238, 1977. Molecules in Uraemia, Proc. Eur. Dial. Transplant Assoc. II: II. Friedman, E. A.: Future Treatment of Renal Failure, In Friedman 158-164, 1974.

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