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Ann Thorac Surg 2006;81:S2367-S2372
© 2006 The Society of Thoracic Surgeons

Supplement

Effects of Circuit Miniaturization in Reducing Inflammatory Response to Infant Cardiopulmonary Bypass by Elimination of Allogeneic Blood Products

Edward Hickey, MRCS a , Tara Karamlou, MD a , b , Jamie You, CCP a , Ross M. Ungerleider, MD a , *

a Division of Pediatric Cardiac Surgery, Oregon Health Sciences University, Portland Oregon
b Division of Cardiovascular Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada

* Address correspondence to Dr Ungerleider, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Mail Code L3, Portland, OR, 97201-3098 (Email: ungerlei{at}ohsu.edu).

Presented at the Symposium on Harnessing the Effects of Neonatal Cardiopulmonary Bypass at the Fourth World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, Sept 21, 2005.


   Abstract
Top
 Abstract
Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
 References
 
Conventional neonatal cardiopulmonary bypass requires the use of large volumes of allogeneic blood to prevent unacceptable hemodilution. Evidence is accumulating to suggest that the use of blood products during cardiopulmonary bypass has a negative effect on clinical recovery through inflammatory side effects. This would suggest an advantage for eliminating blood use in infant cardiopulmonary bypass through circuit miniaturization. In this article, we review the data supporting this rationale and provide the results from studies in our laboratory that emphasize the benefits of circuit miniaturization.


   Introduction
Top
 Abstract
 Introduction
Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
 References
 
The onset of cardiopulmonary bypass (CPB) is associated with generalized activation of the innate immune system [1], and this phenomenon is exaggerated at the extremes of age [2]. No facet of the inflammatory response is spared: neutrophils become primed, complement and kallikrein–kinin systems are activated, inflammatory (and antiinflammatory) cytokines are generated, and activated platelets litter the surface of the extracorporeal circuit resulting in coagulation disturbances and thrombocytopenia [1, 3–5]. These processes have a direct role in commonly encountered postoperative complications including capillary leak syndrome, acute lung injury, systemic inflammatory response syndrome, coagulopathies, and multiorgan failure [1, 6]. In addition, evidence is accumulating to suggest that inflammation directly exacerbates the progression of injury after prolonged periods of cerebral ischemia. In particular, the apical cytokines (tumor necrosis factor {alpha} [TNF-{alpha}], interleukin 1ß [IL-1ß]) and products of neutrophil degranulation (activated oxygen species) are recognized to be central to the progression of neuronal loss after periods of cerebral ischemia in virtually every model studied [7–9]. Techniques for harnessing the CPB inflammatory response are therefore of considerable interest. One potential target unique to the neonate is the enormously disproportionate extracorporeal volume with respect to patient size. Attempts to bring this ratio more in line with that of older children and adults (through circuit miniaturization) are fraught with technical and practical difficulty, but early experimental models suggest that these efforts will improve patient recovery. Although the benefits of miniaturization may, at least in part, be related to the smaller circuit surface area, recent investigations from our laboratory suggest that avoiding the use of allogeneic blood in the pump prime (which can be achieved if circuit size is adequately restricted) may significantly reduce CPB-induced inflammation.


   Allogeneic Blood Exacerbates the Cardiopulmonary Bypass Inflammatory Response
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
 References
 
Conventional neonatal CPB necessitates the use of allogeneic blood in the circuit prime to prevent unacceptable hemodilution. Since its first use in the mid-17th century [10], transfusion has been used liberally with a seemingly risk-free attitude until only recently. Aside from the potential for transmissible infection, blood is also a trigger for altered immunologic function [11]. Among the described immunomodulatory consequences are decreased CD4+ and IL-2R+ helper T cells, increased CD8+ suppressor T cells, increased circulating B cells, decreased IL-2 production, and elevated complement, eicosanoids, and inflammatory cytokines [12, 13]. Central to the drive behind miniaturization is the assumption that blood transfusion exaggerates the overall harmful effects of CPB.

In the late 1990s, suggestions that (fresh) whole blood contributed to improved hemostasis led to its widespread introduction for neonatal CPB [14–16]. Several series have, in fact, failed to demonstrate a benefit in terms of bleeding or postoperative blood requirement, but of greater concern was a report detailing worse recovery from intensive care after its use. Mou and colleagues [17], in a well-conducted double-blind randomized study of 200 patients, demonstrated that fresh whole blood resulted in longer intensive care unit stay and increased fluid retention (capillary leak), with no hemostatic advantage. This came as a surprise as many believed that reconstituted blood (packed red blood cells [RBCs] and fresh-frozen plasma) would be more inflammatory [14]. The notion that non-RBC constituents of transfused blood are major instigators of the inflammatory response is supported by the benefits seen through leukocyte depletion of transfused blood [18] and hemofiltration of either whole blood prime before bypass [19] or the perfusate during deep hypothermic circulatory arrest (DHCA) [20]. The advantages of leukocyte filtration during CPB have clearly been established [21, 22], and it is likely that these are attributable in part to removal of allogeneic leukocytes.

Acquisition of fresh blood has practical and cost implications, and whole blood has usually therefore been stored, which also adversely affects its quality. Not only does potassium increase in parallel with free hemoglobin from erythrocyte lysis [23] but activated complement fragments and inflammatory cytokine levels (IL-8 and TNF-{alpha}) also increase with duration of storage [24, 25]. The significance of lactate in stored blood is unclear. Although a causal relationship between outcome and the increased lactate concentrations during CPB using stored blood [26] has not been established, lactate levels per se during CPB are associated with increased morbidity and mortality [27]. However, others have instead reported that the lactate concentration of stored blood has little bearing on the overall composition of the final prime solution [28].

All of these findings would justify a strategy for neonatal CPB that can obviate the need to add blood to the pump prime.


   Development of Miniaturized Circuits
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
 References
 
Accumulating evidence surrounding the deleterious effects of blood use prompted the investigation of circuit miniaturization for infant CPB. A small feasibility study by Lau and associates [29] in neonatal piglets showed that a low-volume, asanguinous prime can be achieved safely, and that total blood requirements were significantly reduced from 314 ± 32 mL with use of a conventional neonatal circuit to 47 ± 6 mL with use of the miniaturized circuit. Previously, Wabeke and coworkers [30] had demonstrated that a smaller prime (90 versus 330 mL) and the use of vacuum-assisted venous drainage in a rabbit model normalized resistance in the peripheral microcirculation. In our laboratory, we have used a neonatal piglet model of CPB to pursue an asanguinous prime. Using equipment currently in clinical use, a total prime volume of 109 mL [31], and with further modification 60 mL [32], permits completion of a deep hypothermic CPB strategy using a modified crystalloid prime while maintaining a minimum hematocrit greater than 18%. Although this model lacks ancillary equipment such as filters and cardioplegia, it has allowed the investigation of the potential benefits conferred by asanguinous prime in the closest animal model of human neonatal CPB. Despite not representing an infant model, You and colleagues [33] have recently described a miniature circuit in a rat model that employed a crystalloid prime volume of only 9.5 mL using a custom-made oxygenator. Above all, these achievements indicate that technical challenges of creating and managing smaller circuits can be overcome.

The first consequence of eliminating blood use in these experimental circuits is hemodilution. Major hemodilution during CPB is not only a problem for RBC-dependent gas transport, but also for platelet and humoral factor–dependent coagulation and protein-dependent intravascular oncotic pressure [34, 35]. Although higher hematocrits are becoming preferred [36–38], the threshold for "unacceptable" hematocrit is a matter of controversy, although most clinical studies implicate a value of between 17% and 20% [39, 40]. Experiments in our laboratory are conducted on piglets as small as 2 kg, and a minimum hematocrit of 18% is consistently achievable [31, 32], despite the typically lower normal baseline hematocrit in newborn swine (approximately 30%). An early study by Jonas and associates [38] suggesting hematocrits of 30% to be better than hematocrits of 20% is frequently cited as a deterrent to significant hemodilution. However, it is critical to understand that this study examined a model that used a prolonged period of uninterrupted DHCA. Use of prolonged uninterrupted DHCA is becoming less common in light of the recent trends toward either continuous hypothermic CPB or intermittent perfusion during limited exposures to circulatory arrest [41]. Unless a prolonged exposure to DHCA is planned, hemodilution to hematocrits of 20% in conjunction with avoiding a blood prime may have more advantage than using a blood prime, with its attendant impact on inflammation, to achieve a higher hematocrit. Similarly, although clinical investigations by the same group [42] confirmed superior neurologic outcome in children after exposure to higher hematocrits during CPB, both experimental groups received allogeneic blood and it is not known what outcome might have been achieved in a group of patients in which no blood prime was used.


   Antiinflammatory Effects of Circuit Miniaturization
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
Technical Aspects of Circuit...
 Conclusion
 References
 
To elucidate whether there were beneficial effects of circuit miniaturization, we investigated whether the inflammatory response generated by conventional CPB using whole blood could be ameliorated by using a miniaturized circuit and an asanguinous prime using our neonatal piglet model [31]. Following a strategy of deep hypothermic CPB, this circuit was associated with a reduction in TNF-{alpha} and neutrophil priming capacity, decreased fluid sequestration, and an improvement in both right ventricular function and pulmonary compliance. Furthermore, we showed, in agreement with previous work by Silliman and colleagues [43] and others [44], that the deleterious effect of whole blood in the prime was further exacerbated by "storage" and that older blood created an even more exaggerated inflammatory response.

Of particular interest is the role of inflammation in the pathophysiologic response to ischemia during CPB. One particular consequence is cerebral no-reflow, a reperfusion anomaly consistently observed after periods of experimental and clinical DHCA that is believed to correlate with functional recovery. No-reflow is a phenomenon that is believed to have both a physiologic component (imbalanced activity of vasoconstrictors including endothelin, nitric oxide, and eicosanoids) and a mechanical component (sequestration of neutrophils, platelets, endothelial casts, and noncellular inflammatory debris) [21, 45–50]. We therefore used our model to test the hypothesis that the reduced inflammatory response observed in our asanguinous miniaturized circuit might confer advantages in terms of recovery from cerebral no-reflow. Interestingly, in contrast to cerebral no-reflow of approximately 40% after DHCA with a whole-blood prime, our asanguinous miniaturized circuit yielded a mild reactive hyperemia despite only small drops in hematocrit [32]. This is the first time that an increase in cerebral blood flow has ever been described after extended exposure to DHCA and implies that the use of an asanguinous prime may dramatically alter the brain response and potential for injury related to circulatory arrest (Table 1). Although only a snapshot of the physiologic recovery after DHCA, this observation suggests that a bloodless prime can alter the inflammatory profile during CPB with potentially beneficial downstream consequences. This study again confirmed a reduction in serum TNF-{alpha} using an asanguinous prime [32]. Furthermore, the analysis of intracerebral production of TNF-{alpha} mRNA revealed significantly higher levels after deep hypothermic CPB using a conventional blood prime [32]. Our interest in TNF-{alpha} is related to its increasing implication in the postischemic progression of brain injury [51, 52]. In fact, in other non-CPB models of perinatal brain injury TNF-{alpha} (and IL-1ß) can even initiate brain injury in the absence of ischemia [53, 54]. After experimental cerebral ischemia, exogenous TNF-{alpha} exacerbates the extent of neuronal apoptosis [9]. Tumor necrosis factor {alpha} is liberated as a direct consequence of cerebral ischemia [55], and methods that ameliorate this—including neutralizing antibodies [56] or delayed preconditioning [57]—are considered neuroprotective. Considerable energy is being spent trying to harness this local inflammatory response after brain injury, which is known to worsen outcome after stroke [58], trauma [59], or perinatal brain injury [60]. Efforts to limit the inflammatory load during CPB are likely to be reflected in similar benefits after either intentional (DHCA) or unintentional intraoperative cerebral ischemia.


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  		Table 1. Cerebral Benefits Conferred by Asanguinous Prime and Miniaturized Circuitry a
 
One important drawback with established animal models is that experimental CPB typically involves the use of "whole" donor blood: although in theory allogeneic blood could be leukocyte-depleted, concentrated, or even cross-matched, these techniques would be exorbitantly costly or challenging, and have not been attempted in swine or other animal CPB models. Therefore, although our studies support the clinical observations that whole fresh blood during CPB is detrimental, the experimental comparison between completely asanguinous CPB and the use of leukocyte-depleted packed RBCs (as is used in the clinical setting) has not yet been made. In adult perfusion (a correlate using asanguinous prime), a prospective study of 114 patients demonstrated significantly elevated levels of IL-6 in the initial 24 hours after the use of packed RBCs during CPB [61]. No IL-6 was detectable in the packed RBC supernatant before transfusion, and no differences could be identified in the patient profiles either preoperatively or by careful regression analysis, to otherwise explain elevated IL-6 levels. Moreover, in addition to elevated IL-6, patients receiving packed RBCs during CPB had significantly longer intubation, intensive care unit stay, and hospitalization, and almost double the incidence of surgical wound infections [61]. This is particularly interesting because of the absence (in contrast to whole blood) of any obvious inflammatory mediator other than erythrocytes. Other studies of inflammatory mediators within the supernatant of packed RBCs have failed to identify raised levels of cytokines (IL-1ß, IL-6, IL-8, or transforming growth factor ß1) or eicosanoids (thromboxane B2, prostaglandin E2) [24, 62], supporting the suggestion that these are instead removed by leukocyte and plasma depletion [63]. Similarly, although endogenous neutrophils can be primed by the supernatant from whole blood, some groups have reported this not to be the case for packed RBCs [44]. However, others have instead refuted this [64] and in addition demonstrated that lipids and plasma from stored packed RBCs can contribute to lung injury in animal models [43]. Packed RBC administration to trauma patients is also associated with elevated cytokine levels [13]. Overall, although no direct comparison has yet been made between an asanguinous and packed RBC prime in infant CPB, considerable circumstantial evidence exists to suggest benefits in avoiding even packed RBCs.

Several groups have therefore engaged in important efforts to reduce circuit size and priming volumes for neonatal CPB in the clinical arena. Jansen and coworkers [65] found that colloid osmotic pressure was maintained in infants primed with a low-volume circuit (245 mL) compared with infants receiving a higher volume prime (364 mL). This translated into improved postoperative fluid balance and superior cardiopulmonary function in these infants postoperatively. Fukumura and colleagues [66] used a low-volume prime in conjunction with dilutional ultrafiltration in 19 neonates with transposition of the great arteries undergoing arterial switch operation. The miniaturized circuit improved systolic blood pressure and reduced both postoperative water gain and duration of ventilatory support. Reduction in inflammatory mediators was similarly shown by Fromes and associates [67] who incorporated biocompatible components into a minimal extracorporeal circuit in adult patients. Recently, the ultimate achievement of successful CPB in a series of human infants between 3.4 and 6.0 kg using asanguinous prime with a volume as low as 190 mL has been reported [68]. The mean hematocrit on CPB was 23% (range, 17% to 29%), and all 9 patients recovered uneventfully. Although inflammatory end points were not examined in this series, this report indicates that more routine application of these novel techniques is possible, and will permit the investigation of the clinical benefits in the near future.


   Technical Aspects of Circuit Miniaturization
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
Conclusion
 References
 
The concept of miniaturization is not new, and the technique has been attempted as far back as 1972 [69]. A systematic approach needs to be adopted to target all CPB components, including tubing, pumps, oxygenator and heat exchanger structures, cardiotomy suction, and filters.

Tubing length and diameter are two important factors when trying to minimize circuit priming volume. Downsizing from 1/4-inch to 3/16-inch tubing almost halves the volume to 1.73 mL per 10-cm length. Some centers apparently even use 1/8-inch tubing for arterial lines in very small neonates with a volume of 0.75 mL per 10 cm [68]. Tubing length can be significantly reduced by repositioning the venous reservoir and arterial roller pump console closer to the patient, as in our model. Alternatively, a conventional console with a mast-mounted arterial roller pump has resulted in a 29% reduction of priming volume [70]. Suction and venting lines can hold a substantial volume, which can impact on the dynamic priming of the extracorporeal circuit as it needs to be replaced during CPB. Poiseuille's law states that flow is proportional to the fourth power of the radius, and therefore small decreases in diameter can drastically reduce flow. Drainage may therefore need to be encouraged through the use of kinetic-assisted venous return or vacuum-assisted venous drainage. These techniques introduce potential risks of air aspiration should venous return become momentarily insufficient. However, with the use of automated reservoir sensor levels, this risk should be minimized. We have routinely used vacuum-assisted venous drainage both clinically and in our experimental model at –20 mm Hg without untoward effects.

The arterial pump in our experimental circuit was a COBE roller pump with 3/8-inch tubing and 40-cm boot length, yielding a tubing prime of 6 mL. Theoretically a shorter raceway would allow for further reductions in tubing length, but the higher revolutions per minute would make hand-cranking more difficult in the event of power failure. Although centrifugal pumps are used in pediatric patients, none are available with 1/4-inch or 3/16-inch connectors, precluding their use in miniaturized circuits.

The priming volume of oxygenators has been tremendously reduced since the screen-type oxygenator was used for the first successful open heart surgery in 1953. Current oxygenators for neonatal perfusion have static priming volumes of 43 mL (Capiox RX 05, Terumo, Japan), 52 mL (Safe Micro, Polystan, Denmark), and 60 mL (Lilliput I, Dideco, Italy). The Capiox RX 05 is currently under evaluation [71, 72], and is the oxygenator we currently use in our experimental circuit. Recently, Fuji Systems successfully developed a thin silicone rubber hollow-fiber oxygenator with no plasma leakage, better blood compatibility, low blood prime, and low flow resistance in the ex vivo studies [73, 74]. Silicone is generally perceived to be more biocompatible than polyethylene or plastic.

An arterial line filter is a safety device used in a high percentage of pediatric patients [75]. Some departments, however, have eliminated arterial line filters because they have priming volumes comparable to oxygenator modules [68] (Dideco D 736 Newborn 40 mL, and Terumo Capiox AF02 40 mL). However, removal of the arterial filter would increase the chances of microemboli and sacrifice the bubble purge line, which is usually connected from the filter to the reservoir, necessitating an additional bubble sensor filter. Potential volume reductions may also be possible for other integral parts of neonatal circuits, including hemofilters and cardioplegia systems, and need to be targeted by the biomedical corporations.

Finally, substantial reduction in prime volume can be achieved by eliminating the cardioplegia circuit and the hemoconcentrator used for modified ultrafiltration. Cardioplegia would need to be given directly by the surgeon (handheld) and we do not believe that would significantly impair neonatal myocardial protection. Likewise, the significant reduction in inflammation found from an asanguinous prime would help us feel comfortable "trading" away the ability to perform modified ultrafiltration at the completion of the procedure.


   Conclusion
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
References
 
Infant CPB has advanced hugely since its introduction in the middle of the last century. Among the technical leaps that have occurred are the replacement of large membrane oxygenators with bubble and then smaller hollow-fiber units, the development of cardioplegia, and the introduction of novel strategies to reduce or even eliminate cerebral ischemia. Considerable energy has been spent delineating optimal CPB conditions, including the management of arterial pH, temperature, hematocrit, and ultrafiltration, through the use of animal models. The importance of systemic inflammation is now beginning to be appreciated, in particular its impact on postischemic reperfusion and the progression of ischemic injury. Several strategies for attenuating the inflammatory processes triggered by CPB have proven beneficial and have entered the clinical arena, including leukocyte filters, steroid administration, and circuit coating. Evidence is mounting to implicate allogeneic blood—both whole and leukocyte-depleted—as a significant instigator of systemic inflammation. Our experimental models examining the impact of asanguinous primes in neonatal CPB have supported this concept. Postoperative advantages have been demonstrated in right ventricular function, pulmonary compliance, alveolar gas exchange, recovery of cerebral perfusion, and the inflammatory cytokine load. Clinical attempts to reduce priming volume with conventional equipment have also been encouraging. Continued miniaturization, especially of the ancillary equipment, may render asanguinous neonatal CPB a more routine possibility in the future.


   References
Top
 Abstract
 Introduction
 Allogeneic Blood Exacerbates the...
 Development of Miniaturized...
 Antiinflammatory Effects of...
 Technical Aspects of Circuit...
 Conclusion
 References
 

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