Recently, the surgical outcomes of pediatric open-heart surgeries have improved partially because of improved cardiopulmonary support technologies during and after open-heart surgeries.1,2 Pediatric cardiopulmonary bypass systems have improved in efficiency and safety; whereas, the extracorporeal priming volume and the blood-contacting surface areas with foreign materials have decreased.3 There have been many efforts to increase the perfusion flows (ml·kg–1·min–1) for pediatric patients4 because higher perfusion flows are required per kilogram of body weight in pediatric patients. It was generally believed that at least two to three times more blood flow (ml·kg–1·min–1) was required in pediatric patients than in adult patients.5
In the past, several manufacturers around the world developed pediatric pulsatile blood pumps primarily to support circulation for up to 2 weeks.6,7 Unfortunately, a pediatric nonpulsatile blood pump applicable beyond 1 month was not available until recently. The DeBakey-Noon axial flow blood pump is a small nonpulsatile blood pump applicable for pediatric patients for longer than 1 year.6
In this article, the need for a pediatric biventricular bypass device will be discussed. To improve cardiopulmonary bypass procedures, it is stressed that a biventricular bypass procedure would eliminate the need for an oxygenator and would greatly benefit a selected pediatric patient population for open-heart surgery. To adopt the biventricular bypass procedure during heart surgery, a patient’s natural lung would be used. Thus, this procedure is termed self-lung cardiac bypass (SELCAB) instead of cardiopulmonary bypass (CPB). A patient’s right and left hearts are bypassed, yet the patient’s own lungs remain in the circulation process. The complicated and voluminous CPB extracorporeal circulation is simplified, and two small heart-bypass circuits are used. Better outcomes of pediatric open-heart surgeries are expected from SELCABs in a selected pediatric patient population.
Figure 1 illustrates the differences between CPB and SELCAB procedures. As indicated in the figure, the SELCAB arrangement is analogous to a BVAD (biventricular assist device). We are not advocating that all biventricular assist devices (BVADs) be called SELCABs. To avoid confusion, these procedures are distinguished as follows. The SELCAB pump is implanted for up to 2 weeks, whereas the BVAD pump is implanted for longer than 2 weeks. The inflow cannula of the SELCAB system will be implanted in atrial or venous systems, whereas the BVAD cannulae will be implanted in the ventricles. The SELCAB pumps are primarily nonpulsatile blood pumps, whereas the BVAD pumps are either pulsatile or nonpulsatile. In addition, it is preferable that the SELCAB system is a tabletop or wearable system, whereas the BVAD system is wearable or implantable. After surgery, postcardiotomy cardiac failure develops in approximately 1–2% of patients.7 The SELCAB system could remain in place until myocardial recovery so that postoperative circulatory support may be extended without any change in the SELCAB system during surgery. Thus, the SELCAB system should be applicable for up to 20 weeks, not for 2days as with a typical CPB pump. In addition, the SELCAB system should be a wearable pump system to cope with postoperative use. It is also preferable that it be a small pump-actuator package that is easily operated by the surgeon on the operating table. Positioning this pump in the cranial position of the operating field at the shoulder area of the patient would allow an anesthesiologist to have better control of the left and right pump. One of the most important features of the SELCAB system is the ability to position these two pumps outside of the surgical field but as close as possible to reduce, as much as possible, the priming volume of the SELCAB system.
Typically, nonpulsatile blood pumps should be used because they are smaller than pulsatile blood pumps. Typically, a blood pump with a priming volume of less than 10 ml is preferred, yet its pump output should be more than 5 l/min. BVADs with pulsatile blood pumps have been clinically used, particularly in patients with biventricular failure.8,9 After a left ventricular assist device (LVAD) implantation, multiorgan failure develops in approximately 30% of patients.8 In this group of patients, an extremely high level of serum bilirubin manifests, indicating hypertension and congestion of splanchnic organs.9 However, pulsatile blood pumps are generally too large to implant two of them, and the priming volumes are dictated by the maximum pulse rate of less than 150 bpm. Contrary to nonpulsatile blood pumps, there is no limit in impeller speed, and miniaturization of the pump does not prohibit an increase in revolutions per minute.
Advantages of SELCAB over CPB
The SELCAB procedure is associated with a reduction of priming volume in extracorporeal circulation.
There are two major problems associated with the pediatric CPB procedures. For pediatric patients, the priming volume and blood foreign body contact surface area of the currently available oxygenator system are relatively too large (Figure 2, upper panel). One is hemodilution, which requires a comparatively large priming volume in the oxygenator system. For a pediatric patient, the approximately 1 l (400–1,200 ml) of priming volume required in the oxygenator system is too much. This hemodilution situation is a serious problem for the pediatric patient. If excessive hemodilution is imposed, then in addition to a decrease in hematocrit, the clotting factors and plasma proteins become significantly diluted, resulting in dilutional coagulopathy for pediatric CPB. If the priming volume of the system is reduced to around 200 ml, then hemodilution and a required blood transfusion would be manageable for pediatric patients. Thus, the SELCAB system would be beneficial to the pediatric patient (Figure 2, lower panel).
The SELCAB procedure is beneficial for hypothermia.
The metabolic demands of neonates and infants require much higher flows per body surface area. Neonates are often perfused at flow rates up to 200 ml·kg–1·min–1 (Table 1). As body temperature is reduced, flow rates can be reduced because the need for oxygen to the tissues is reduced (Table 2). Small children also have impaired thermoregulation that requires significant attention to temperature monitoring. In some instances, patients are cooled to profound hypothermic temperatures below 15°C (Table 3). Afterwards, the pump may be turned off and the cannulae removed for proper anatomical repair of the heart. Infants tolerate longer periods of deep hypothermic circulating arrest than older children or adults. This is why deep hypothermia is very often used for the repair of congenital anomaly of the heart. To produce hypothermia, an oxygenator is not required. A SELCAB will produce deep hypothermia without any excessive hemodilution or a complicated extracorporeal circulatory system. Furthermore, during the cooling and rewarming stages, the natural lung is participating in the oxygenation process of the blood. More physiologically acceptable gas exchanges during different temperatures can be provided with the SELCAB procedure. Naturally, low SELCAB blood flow rates are required during hypothermia.
The SELCAB procedure maintains physiologic function of the lung.
During CPB, the patient lung functions are assumed by the oxygenator, and oxygen supply to the airways ceases and alveolar function is not maintained. During this period, lung collapse after a thoracotomy easily occurs. The nutritional blood supply to the lungs is maintained by the bronchial artery. SELCAB procedures allow normal lung function in pediatric patients. Lungs do not fully develop until an individual is 8 years old,10 and at birth the number of alveoli present is approximately one tenth of what it is in the adult. The lungs of the neonate are quite fragile and have a great potential for pulmonary edema and hypertension.11 That is why it is extremely important to maintain physiologically established lung function during heart surgeries. To put an immature lung under unphysiologic conditions is not desirable. The right heart bypass in congenital heart surgery with autologous lung as oxygenator was reported by an Indian group with successful results.12
The SELCAB procedure reduces foreign surface exposure to blood.
Even though polypropylene microporous membranes and other gas-permeable membranes used in the oxygenator have been proven to be clinically acceptable in adult patients, various effects of CPB systems in pediatric patients should not be overlooked. Compared with adult CPB patients, there is a substantially higher surface area per cubic centimeter of the pediatric patient’s blood exposure to foreign surface, which augments complement activation,13 coagulation system activation,14 platelet activation,15 and other humoral16 and cellular changes17 occurring in adult patients. These humorally and cellularly induced reactions to CPB are particularly serious to the immaturely developed organs and tissues of pediatric patients.
It is well known that CPB induces a massive amount of microembolic products,18 including aggregated cells, polymerized fibrin, oxygenator-induced microbubbles, and microdebris. The pediatric circulatory system and microcirculation poorly tolerate microembolic phenomena.19 Elimination of these microembolic products generated by CPB would be beneficial for SELCAB procedures.
The SELCAB procedure is beneficial for postsurgical circulatory support.
It is well recognized that postcardiotomy cardiac failure develops in approximately 1–2% of open-heart surgery patients. Even though they may not have severe heart failure condition, there are many patients who would benefit from having postoperative circulatory support. Because a SELCAB procedure is analogous to a BVAD, postoperative circulatory assistance can be easily provided without any additional procedures. Thus, the SELCAB concept is included in up to 2 weeks during and after cardiac surgery.
The SELCAB procedure reduces nonphysiologic consequences of CPB.
It is well known that during and after CPB procedures, various types of physiologic abnormalities are revealed.20 They include accumulation of fluid in the interstitial space (edema), reduction of lymph flow, sludging and stasis of red blood cells, and the opening of the A-V shunt. These physiologic abnormalities are caused by 1) nonpulsatile perfusion, 2) low perfusion flow, 3) the retention of nonfunctioning lung, 4) excessive hemodilution, and 5) oxygenator-induced problems. However, if we eliminate the oxygenator and switch from CPB to SELCAB, the only possible causes of physiologic abnormalities would be reduced to 1) nonpulsatile perfusion and its physiologic acceptance, and 2) proper blood flows required for the right and left heart circulation.
Disadvantages of SELCAB Compared with CPB and Studies Required for Acceptance of SELCAB
In the previous section, the advantages of SELCAB over CPB were discussed. However, SELCAB has several disadvantages over CPB. To establish biventricular bypass, four cannulations are required, compared with the two required for CPB (right atrium and aorta). The four cannulations are the right atrium and the pulmonary artery for the right bypass pump and the left atrium and the aorta for the left bypass pump. Four cannulae could be in the operating field. However, if both bypass pumps are in a cranial position from the operating field, interference of the cannulae in the operating field would be minimal. A second important issue is the need to balance the right and left bypass flows. It should be demonstrated whether such balanced flow control for the SELCAB would be difficult. Also, if the higher blood flows required in pediatric biventricular bypass are acceptable for underdeveloped pediatric lung tissues, then no development of pulmonary hypertension should be demonstrated. Certainly, the most important issue to be studied is whether nonpulsatile biventricular bypass flows not only for systemic circulation but also pulmonary circulation are physiologically acceptable in pediatric subjects.
Adaptation Hypothesis for Recipient of Cardiac Prosthesis
Since 1964, one of the authors (YN) has implanted many different types of total artificial hearts after the removal of natural ventricles and implanted biventricular bypass pumps with nonfunctioning ventricles in pediatric experimental animals, namely, calves (Half-Dexter female, 5–7 months old, 60–80 kg). Regardless of the type of prosthesis implanted, all the recipients responded in a similar adaptation fashion.21 In the initial 2 days after implantation, proper flow and balancing the right and left blood flows are difficult. During this period, red thrombosis forms inside any improperly designed blood pump. After these initial 2 days, suddenly the blood pumps can be easily controlled and high blood flow is easily obtained. Unfortunately, within a 2-week period, higher venous pressures (left atrium and right atrium), higher arterial pressures (pulmonary artery and aorta), and higher circulating blood volume are exhibited. Yet, rarely is red thrombosis seen, which would have formed by the stimulation of coagulation cascades. Instead of red thrombosis, platelet-derived white thrombosis will form if the blood pump used was improperly designed. Upon the recipient’s survival of 2 weeks, all the circulating parameters will suddenly become near-normal. During the initial 6 weeks, interfacial tissue hyperplasia (pannus formation) takes place if the tissue–device interface is not properly constructed (Table 4). In 1998, one of us proposed the physiologic adaptation hypothesis for cardiac prostheses.22 In this hypothesis, the initial 2 days is the hematologic adaptation period and is termed the “confusion stage.” The initial 2 weeks is the physiologic adaptation period and is termed the “fighting stage.” The initial 6 weeks after implantation of the cardiac prosthesis is the interfacial (tissue and prosthesis) adaptation period, and is termed the “live together stage” (Table 5). After implantation of a biventricular bypass nonpulsatile blood pump and induction of ventricular fibrillation, the recipient will experience these three stages. One important finding associated with using a nonpulsatile blood pump is that it is essential to maintain approximately 20% higher blood flows over and above the pulsatile biventricular bypass flows for the right and left pumps (Figure 3). It is well known that approximately 20% less flow than physiologically maintained pulsatile blood flows is used for CPB.4 To date, five experimental animals subjected to 34–99-day nonpulsatile biventricular bypass implantation with ventricular fibrillation have been studied.23 As indicated in Figure 3, when 20% more flow than a pulsatile total artificial heart is used, no physiologic abnormalities occurred with BVAD implantations with fibrillating ventricles.24 The flow balance between the right and left pump was easily achieved by maintaining both atrial pressures below 15 mm Hg. Approximately 10% more blood flow is required for the left pump than the right pump. So far, there have been no findings of pulmonary hypertension during the physiologic adaptation period (2 weeks) or after. Encouraged by the above-mentioned results, the SELCAB pump (2 weeks) and BVAD pump (2 weeks to 5 years) development program was initiated approximately 15 years ago.12,25
Development of SELCAB and BVAD Blood Pumps
A cardiopulmonary bypass (2 days) pump was developed with Nikkiso Co., Ltd. (Tokyo, Japan).25 Currently, approximately 25% of open-heart surgeries in Japan use the Nikkiso pump (Figure 4). Also, with the Kyocera Corporation (new division, Japan Medical Materials Corporation, Kyoto, Japan), a 2-week blood pump was developed26 (Figure 5). Both of these pumps are activated by a console-type actuator-controller. To convert these pumps to SELCAB pumps, a smaller actuator was developed for each blood pump. Later, a ubiquitous multipurpose actuator adaptable for both blood pumps was developed (Figure 6). To utilize the pediatric SELCAB, the KP Pump was also developed27 (Figure 7). Its size is substantially reduced, and its priming volume is approximately 70% of that for the Kyocera pump (35 ml vs. 25 ml), including inlet and outlet connectors. Its maximum pump output against 100 mm Hg afterload was maintained at 5 l/min. The Kyocera 2-week pump and the pediatric KP pump were also converted to titanium long-term BVAD pumps (Figure 8).28 The only difference between the SELCAB 2-week pump and the long-term titanium BVAD pump was the clearance between the male and female bearings of the impeller. The SELCAB’s pump clearance is maintained between 80–400 μm, whereas the long-term BVAD pump’s clearance is maintained at 400–600 μm. The metallic NEDO BVAD pump’s impeller is shown in Figure 9. The metallic NEDO BVAD adult pump and its actuator are shown in Figure 10. Two of these pumps can be implanted in either the wearable fashion or implantable fashion (Figure 11). Pump output is up to 8 l/min for the metallic NEDO adult pump (Figure 12) and up to 5 l/min for the KP pump. The hemolysis rates of all these pumps were measured using the ASTM test method.29,30 The hemolysis rates measured between 0.0007 and 0.005 g/100 l of Normalized Index of Hemolysis (NIH), and they were well below the clinically acceptable level, NIH 0.02 g/100 l.
Chronic Nonpulsatile BVAD with Fibrillating Ventricles.
As described in “Adaptation Hypothesis for Recipient of Cardiac Prosthesis,” the experiments conducted by the first author’s group during 1967 and 1983 revealed that chronic BVAD with fibrillating ventricles did not produce any physiologic abnormalities, not only during the physiologic adaptation period of 2 weeks, but also for up to 99 days (Table 6).27
SELCAB Pump Implantation (3.5 days with fibrillating ventricles)
With the newly developed SELCAB pump, a BVAD implantation with ventricular fibrillation was performed in a 61-kg calf. An approximately 3.5-day experiment was performed to determine whether there was any difference between the experiments performed more than 20 years ago with an old-fashioned centrifugal blood pump and the modern SELCAB pump. For the SELCAB pump, specific consideration was given to Frank-Starling autoregulatory flow control (Figure 13). With the SELCAB, when the impeller’s speed was at 2,000 rpm, the pump outflows increased from below 4 l/min to over 6 l/min when venous pressure changed from near 0 mm Hg to 15 mm Hg. Figure 14 shows that after 66 hours of ventricular fibrillation imposed on this experimental animal, both pumps demonstrated delivery of nonpulsatile flows for pulmonary and systemic circulation. With manual control of right and left atrial pressures below 15 mm Hg, the pulmonary artery pressures remained below 30 mm Hg during the entire study period (Figure 15). There were increased changes in blood flows in both circulatory systems after ventricular fibrillation, approximately 20% (left, 18%; right, 19%). As proven before, approximately 10% more flow for the left heart than the right heart was necessary (Table 7).
Chronic Nonpulsatile BVAD Implantation with Beating Heart
Fourteen experiments were performed with BVAD implantations and beating ventricles ranging from 30 to 90 days (Table 8). Three experiments were terminated after 90 days, as determined by experimental protocol. Other experiments were terminated for various reasons, but there was no single experiment terminated due to physiologic abnormality, including pulmonary hypertension or respiratory failure. Manual control of the right and left pump flows were practically unnecessary after the initial 2 days of blood pump implantation. Even though there is a tendency for pulmonary hypertension during the initial 2 weeks of implantation, any physiologic competition between the normal healthy heart and the implantable pump seems to diminish by reducing the left blood pump flow by approximately 20% during the initial 2 weeks after BVAD pump implantation. Upon completing Phase II, the fighting stage, the recipient of the implanted device (experimental calf) accepted BVAD pumps without any difficulties.
Advantages or Disadvantages of Retaining Ventricle in Nonpulsatile BVAD Studies
We strongly recommend that when implanting a BVAD in diseased heart subjects, it is advantageous not to remove the diseased ventricle based upon the following.
Possible ventricular functional recovery.
As described by Frazier, et al., left ventricular unloading may promote ventricular recovery in poorly functioning ventricles.29 Only 13% of the patients seemed to experience this recovery after LVAD implantation.30 It is expected that implanting a right ventricular assist device in addition to a left ventricular assist device further increases the rate of recovery. In addition to these implantations, the removal of pathological macro-mini molecules causing heart diseases by apheresis procedures should further enhance recovery.31 Certainly stem cell injection into such diseased hearts should provide additional myocardial recovery.32 Thus, using a BVAD as bridge to recovery in combination with various therapies should provide future therapy for end-stage heart failure patients.
Easier control of right and left pump: ventricles as venous reservoirs.
If ventricles are retained, they will function as large volume inflow reservoirs. Thus, flow control for the right and left pumps is easier. After the removal of the natural ventricles, a small inflow reservoir should cause an easier collapse of the inflow by the suction which is imposed by a rotary blood pump. Easier control and operation of implantable pumps are expected with functioning or nonfunctioning ventricles as demonstrated in “Results.”
Clinically, most patients who require BVADs have beating ventricles.
As described in the section “Chronic Nonpulsatile BVAD Implantation with Beating Heart,” the implantation of a BVAD in beating ventricles demonstrates the easier control of the right and left blood pump. Because the patient who requires a BVAD has a weak heart that does not compete with an implanted blood pump (no physiologic fighting stage), as indicated above, practically no additional control for pump flows in either pump is necessary. If the ventricles are removed, feedback control by monitoring venous pressures would be necessary. In most rotary blood pumps, the Frank-Starling automatic flow control will not be sufficient if the ventricles are removed.
Less surgery is involved in the removal of ventricles.
To implant a BVAD, the implantations of four cannulae are required, namely, right atrium, pulmonary artery, left atrium and aorta. However, these procedures involve the simple insertion of cannulae, and it is unnecessary to even use CPB. However, if both ventricles are removed, CPB is essential. Additional surgical procedures or blood transfusion are not favorable for the patients.
Harmless existence of nonbeating ventricles with BVAD system.
As demonstrated in the previous section, the existence of nonbeating ventricles in patients for a long period of up to 99 days did not reveal any negative impacts on the nonbeating heart or the rest of the organs. On this basis, we suggest that it is more beneficial to patients that their nonfunctioning natural heart not be removed when a BVAD implantation is indicated.
The implantation of a SELCAB and BVAD pumps with a beating or nonbeating natural heart demonstrated safe and effective circulatory assistance for an extended period.
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