**3.2 Modification of PPPHD**

Repetitive ultrafiltration and backfiltration offers a simple and efficient HDF strategy. However, the pulsatile circulation of blood during extracorporeal renal replacement treatment appears to be potentially problematic. In particular, instant suction generated by a pulse pump through a narrow needle or catheter may cause blood damage, vessel narrowing, or vessel collapse. In addition, instantaneous negative pressures generated upstream of a pulsatile blood pump not only introduce the risk of circuit aeration, but also lead to a failure to maintain predetermined blood flow rates (Depner et al., 1990, Teruel et al., 2000).

Hence, we revised PPPHD and many aspects of the original PPPHD were retained in the revised version, including an alternating water flux across the membrane, but blood pulsation was excluded. This was achieved by employing dual pulsation in the dialysate stream, that is, pulsatile devices in the dialysate stream both upstream (a dialysate pump) and downstream (an effluent pump) of the dialyzer. Backfiltration occurs when the sum of the cross-membrane pressures is negative, but ultrafiltration when the sum is positive. The hydraulic pressures of blood and dialysate were both manipulated in the original PPPHD, but since blood pulsation was eliminated, the dialysate pressure is the only variable that regulates TMP in the revised unit. Therefore, an assumption was made; (1) dialysate compartment pressures must be far higher than blood-side pressures when pure dialysate is forced into the dialyzer (that is, when the dialysate sac is squeezed), but (2) dialysate pressures drop to lower than blood pressures during effluent pump expansion. For this purpose, the dialysate and effluent pumps are replaced with a dual pulse pump (K. Lee et al., 2008).

The dual pulse pump (DPP) is a pulsatile device that was developed to eliminate the oneway valves that are generally required for pulsatile devices to prevent retrograde flow; instead, time-delayed tube openings and closings constitutes a cycle of pulse generation (Fig. 6). In other words, two separate silicone tubes in the DPP are periodically opened or closed. Pulse generation with DPP can be described in terms of four phases as determined by cam rotation, which translates motor rotation to actuator linear displacement. As the cam rotates, the four actuators periodically push on the tubing segments at the positions shown in the Fig. 6. Actuator 1 pushes on the tubing segments at positions 1 and 6 (p1 and p6) simultaneously, and actuator 3 squeezes the tubing segments at positions 3 and 4. Actuators 2 and 4 squeeze tubing segments at p 2 and p5, respectively, and caused the dialysate in the tube to move in the required direction. The first phase was defined as a cam rotation angle (θ) between 0 and 90°. Likewise, the 2nd and 3rd phases were defined as cam rotation angles between 90°~180° and 180°~270°, respectively. For pulse generation by the dialysate pump, as the cam rotates from θ=0° to 90°, the p2 tubing segment opens and p1 closes, and these processes overlap such that pure dialysate fills p2 tubing. While p2 expands, p3 remains closed, acting as an upstream valve to prevent retrograde dialysate. These tube openings and closings are also depicted in the tube openness diagram in Fig. 7. Tube openness is defined as the ratio of compressed tube diameter to the original internal diameter, as described elsewhere (K. Lee et al., 2008). During the first phase, with p3 closed, p2 tube

Pulse push/pull HD is conceptually similar to push/pull HDF. Both modalities were devised to increase total filtration level by alternating forward and backward filtration. However, the underlying design of PPPHD differs from push/pull HDF, and thus, the supplementary component required to switch from ultrafiltration to backfiltration phases or vice versa used in push/pull HDF was eliminated for PPPHD and the entire system was remarkably simplified.

Repetitive ultrafiltration and backfiltration offers a simple and efficient HDF strategy. However, the pulsatile circulation of blood during extracorporeal renal replacement treatment appears to be potentially problematic. In particular, instant suction generated by a pulse pump through a narrow needle or catheter may cause blood damage, vessel narrowing, or vessel collapse. In addition, instantaneous negative pressures generated upstream of a pulsatile blood pump not only introduce the risk of circuit aeration, but also lead to a failure to maintain

Hence, we revised PPPHD and many aspects of the original PPPHD were retained in the revised version, including an alternating water flux across the membrane, but blood pulsation was excluded. This was achieved by employing dual pulsation in the dialysate stream, that is, pulsatile devices in the dialysate stream both upstream (a dialysate pump) and downstream (an effluent pump) of the dialyzer. Backfiltration occurs when the sum of the cross-membrane pressures is negative, but ultrafiltration when the sum is positive. The hydraulic pressures of blood and dialysate were both manipulated in the original PPPHD, but since blood pulsation was eliminated, the dialysate pressure is the only variable that regulates TMP in the revised unit. Therefore, an assumption was made; (1) dialysate compartment pressures must be far higher than blood-side pressures when pure dialysate is forced into the dialyzer (that is, when the dialysate sac is squeezed), but (2) dialysate pressures drop to lower than blood pressures during effluent pump expansion. For this purpose, the dialysate and effluent pumps are

The dual pulse pump (DPP) is a pulsatile device that was developed to eliminate the oneway valves that are generally required for pulsatile devices to prevent retrograde flow; instead, time-delayed tube openings and closings constitutes a cycle of pulse generation (Fig. 6). In other words, two separate silicone tubes in the DPP are periodically opened or closed. Pulse generation with DPP can be described in terms of four phases as determined by cam rotation, which translates motor rotation to actuator linear displacement. As the cam rotates, the four actuators periodically push on the tubing segments at the positions shown in the Fig. 6. Actuator 1 pushes on the tubing segments at positions 1 and 6 (p1 and p6) simultaneously, and actuator 3 squeezes the tubing segments at positions 3 and 4. Actuators 2 and 4 squeeze tubing segments at p 2 and p5, respectively, and caused the dialysate in the tube to move in the required direction. The first phase was defined as a cam rotation angle (θ) between 0 and 90°. Likewise, the 2nd and 3rd phases were defined as cam rotation angles between 90°~180° and 180°~270°, respectively. For pulse generation by the dialysate pump, as the cam rotates from θ=0° to 90°, the p2 tubing segment opens and p1 closes, and these processes overlap such that pure dialysate fills p2 tubing. While p2 expands, p3 remains closed, acting as an upstream valve to prevent retrograde dialysate. These tube openings and closings are also depicted in the tube openness diagram in Fig. 7. Tube openness is defined as the ratio of compressed tube diameter to the original internal diameter, as described elsewhere (K. Lee et al., 2008). During the first phase, with p3 closed, p2 tube

predetermined blood flow rates (Depner et al., 1990, Teruel et al., 2000).

replaced with a dual pulse pump (K. Lee et al., 2008).

**3.2 Modification of PPPHD** 

Fig. 6. Dual Pulse Pump (DPP). Its body is made of an aluminum alloy, and comprises a base plate, a unidirectional electric motor (not seen), a cam, and four actuators. It can also contain two separate silicone tubes. Pulsatile flow is generated by squeezing each dialysate and effluent tubing segments. (A1~A4, actuators 1 to 4; p1~p6, silicone tubing segments at positions 1 to 6, respectively)

Fig. 7. Tube Openness Diagram for Dialysate (upper) and Effluent Pump (below) of DPP.

openness increases whereas p1 tube openness decreases. During the 2nd phase (θ=90°~180°), with p1 closed, p2 begins to be squeezed and simultaneously p3 begins to open, and pure dialysate is driven into the hemodialyzer. Closure of p1 fulfills the same function as atrioventricular valve closure during left ventricular systole, which prevents retrograde flow. During the 3rd phase (θ=180°~270°), p3 is closed, while p1 and p2 remain

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 131

In addition, as stated before, the DPP is characterized by a lack of valves, which makes the pulsatile device simple and inexpensive, and thus, any medical-grade silicone tubes can be used as dialysate and effluent sacs. Furthermore, with the exception of small tubing sections at p1, p3, p4, and p5, most of the tubing is operated non-occlusively, which reduces the probabilities of tubing rupture and spallation (W. G. Kim & Yoon, 1998, Leong et al., 1982).

(h) PCV TP ALB Glu Ca2+ Na+ K+ BUN Crea 0 28.5±4.6 5.3±0.4 3.1±0.1 119±7 12.4±0.8 136±5.7 5.7±0.6 90.3±12.7 6.5±0.9 2 28.0±3.6 5.6±0.7 3.1±0.2 111±4 11.5±0.8 134±4.2 5.1±0.6 63.7±5.7 4.6±0.7 4 27.3±3.5 5.3±0.4 3.1±0.2 126±44 10.8±0.5 132±3.1 4.3±0.5 47±7.2 3.8±0.4 Table 2. Animal Experiment Results. PCV, packed cell volume (%); TP, total protein (g/dl); ALB, albumin (g/dl) ; Glu, glucose (mg/dl); BUN, blood urea nitrogen (mg/dl); Crea,

Recently, the dual pulsatile pump integrated into the dialysate stream has been remarkably ameliorated to achieve a substantial increase in the accuracy of volume control. Maintaining pre-determined flow rates and precise volume control are pre-requisites of extracorporeal renal replacement treatments for ESRD patients, particularly when using membranes with high-water permeability. Therefore, the dual pulsation system acting on the PPPHD dialysate compartment was replaced with a dual piston pump, as shown in Fig. 9. This modification allows pulse generation and push/pull to be achieved, not only by the novel design of the piston pump, but also by the unique control of piston movements offered (Fig. 10). As the dialysate piston compresses the cylinder, pure dialysate is forced into the dialyzer, but at this time, the effluent stream is functionally closed at the effluent piston pump, and thus, dialysate compartment pressures increase rapidly and backfiltration occurs (Phase 1).The effluent piston then begins to expand and dialysate moves into the effluent cylinder, while the dialysate supply line is still closed at the dialysate pump. Because of effluent suction, dialysate compartment pressures fall sharply and water flux from blood lumen to dialysate occurs (Phase 2). During the final step, pure dialysate fills the dialysate

In an *in vitro* test of PPPHD with the dual piston pump, in which bovine blood was circulated through the blood lumen of the hemodialyzer at 200 ml/min and isotonic saline solution was used as dialysate at the rate of 400 ml/min, the phenomena of push (backfiltration) and pull (ultrafiltration) were well sustained throughout sessions, and their levels perfectly matched those of stroke volumes of the dialysate and effluent pumps, respectively. In addition, as was expected, dialysate and effluent piston pumps served as a flow equalizer, and controlled isovolumetic dialysate flow rates upstream and downstream of the dialyzer. Hydrostatic dialysate pressures were maintained at 520~700 mmHg during the backfiltration phase (Phase

In addition, PPPHD is also versatile and can be easily converted to conventional high-flux HD. Time-controlled piston operations perform the push and pull operations, but when the two piston movements are synchronized alternately (that is, dialysate piston compression and effluent piston expansion or dialysate piston expansion and effluent piston compression

cylinder, and simultaneously used dialysate is drained (Phase 3).

1) and at -400~-540 mmHg during the ultrafiltration phase (Phase 2).

PPPHD

creatinine (mg/dl)

**3.3 Fluid management in PPPHD** 

closed and in the final phase (θ=270°~360°), p1 is open, and p2 and p3 remain closed in preparedness for the next filling phase. These time-delayed tube openings and closures constitute one cycle of pulse generation. In the same manner, effluent pulsations were also generated through the effluent tube, although in this case, the actions of actuators 1 and 3 were reversed, and the pulsatile flow pattern was 180O out of phase with that in the dialysate tube.

Theoretically, forward and backward filtration rates during one cycle of PPPHD are identical to effluent and dialysate flow rates, respectively. The moment when pure dialysate is driven to the dialyzer (i.e., during p2 squeezing), the effluent dialysate path is closed at p6. At the same time, p1 is also closed, and thus, the pure dialysate pushed into dialyzer should move into the blood stream (backfiltration), because the whole dialysate compartment is fixed and closed. Immediately after the backfiltration is completed, the effluent tubing (p5) begins to expand (i.e., p5 expansion), and since the dialysate and effluent pathways are still closed at p1 and p6, respectively, dialysate pressures in the hemodialyzer drop steeply and ultrafiltration takes place at a rate determined by effluent stroke volume.

During animal experiments using the PPPHD, in which we used an acute canine renal failure model (achieved by ligating renal arteries and veins), the animals remained stable without any procedurally related complications. Molecular removals were satisfactory, and total protein levels, albumin concentrations, and glucose levels were preserved uniformly throughout PPPHD sessions (Table 2). Furthermore, TMPs clearly cycled positive and negative due to huge fluctuations in hydraulic dialysate pressures (Fig. 8). In addition, despite the use of a peristaltic roller pump for blood, the blood pressures acquired during PPPHD showed an obvious fluctuation which was perfectly synchronized with dialysate pressure pulsation. Generally, peristaltic roller pumps create small fluctuations in flow and pressure, because of the way they squeeze tubing. However, the blood pressure fluctuations acquired during PPPHD were much larger than that observed for conventional HD, which provides evidence of dialysate flux to the blood stream or vice versa (Fig. 8).

Fig. 8. Pressure Profiles during PPPHD treatment (upper), and Changes in Blood Pressures for PPPHD and CHD (below). (MDP, mean dialysate pressure; MBP, mean blood pressure; CHD, conventional HD)

In addition, as stated before, the DPP is characterized by a lack of valves, which makes the pulsatile device simple and inexpensive, and thus, any medical-grade silicone tubes can be used as dialysate and effluent sacs. Furthermore, with the exception of small tubing sections at p1, p3, p4, and p5, most of the tubing is operated non-occlusively, which reduces the probabilities of tubing rupture and spallation (W. G. Kim & Yoon, 1998, Leong et al., 1982).


Table 2. Animal Experiment Results. PCV, packed cell volume (%); TP, total protein (g/dl); ALB, albumin (g/dl) ; Glu, glucose (mg/dl); BUN, blood urea nitrogen (mg/dl); Crea, creatinine (mg/dl)
