Congenital Heart Surgery World Journal for Pediatric

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Pediatric Cardiopulmonary Bypass : Does Perfusion Mode Matter? Jonathan J. Talor and Akif Ündar World Journal for Pediatric and Congenital Heart Surgery 2011 2: 296 DOI: 10.1177/2150135110394218 The online version of this article can be found at: http://pch.sagepub.com/content/2/2/296

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Review Article

Pediatric Cardiopulmonary Bypass: Does Perfusion Mode Matter?

World Journal for Pediatric and Congenital Heart Surgery 2(2) 296-300 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2150135110394218 http://pch.sagepub.com

¨ ndar, PhD1 Jonathan J. Talor, BSE1 and Akif U

Abstract This current review describes how components of the cardiopulmonary bypass (CPB) circuit are selected and examines the benefits of pulsatile perfusion for use during CPB. Pulsatile flow generates significantly greater surplus hemodynamic energy (SHE) than nonpulsatile flow; higher SHE values have been associated with better microcirculation perfusion, lower rates of systemic inflammatory response, and better vital organ protection. Pulsatile perfusion may have a positive effect on clinical outcomes, play a role in preserving homeostasis, and help to decrease morbidity associated with CPB. Keywords cardiopulmonary bypass (CPB), neonate, pediatric, perfusion Submitted October 15, 2010; Accepted November 22, 2010. Presented at the 2010 Regional Meeting of the World Society for Pediatric and Congenital Heart Surgery, Shanghai, China, October 20-23, 2010.

Congenital heart disease is estimated to occur in as many as 19/1000 live births and carries lifelong potential complications.1 Despite advances in surgical techniques, significant morbidity is still associated with cardiopulmonary bypass (CPB).2,3 In an effort to mitigate the morbidity associated with these procedures, many facets of the CPB circuit and procedures have been investigated for improvement. One such parameter is the inclusion of pulsatile flow as the perfusion manifold, which mimics more physiological flow, versus conventional nonpulsatile flow. Despite increasing evidence for the possible benefits of pulsatile flow, more than 85% of institutions still use nonpulsatile flow.4-7 There are two main reasons that pulsatile flow has not been routinely adopted in the pediatric populations. The first reason is choice of extracorporeal circuit components. Pulsatile pumps, membrane oxygenators, and aortic cannulas are equally important for generating adequate pulsatility. Roller pumps cannot produce physiologic pulsatile flow; they generate only diminished pulsatility. The extra energy generated by pulsatile flow is transmitted in all directions, including the components of the bypass circuit. Therefore, investigators must carefully select the proper membrane oxygenator, which has a significant impact on the quality of pulsatility. We have clearly shown that hollow-fiber membrane oxygenators dampen pulsatility significantly less than do flat-sheet membrane oxygenators. However, the different hollow-fiber structures significantly affect the pulsatile pressure-flow waveforms. In addition, the geometry of the aortic cannula has an extremely important influence on pulsatile flow.8-13 The second major reason for the controversy over the benefits of pulsatile perfusion is a lack of precise quantification of arterial pressure and pump-flow waveforms.8 Without a

universal definition and quantification of pulsatility, it is impossible to make direct, meaningful comparisons between different perfusion modes. In more than 95% of all published reports concerning this topic to date, the pulse pressure has been used for direct comparison. Flow that produces a pulse pressure of greater than 15 to 20 mm Hg is considered pulsatile, whereas flow that produces a pulse pressure of less than 15 mm Hg is considered nonpulsatile. We have repeatedly objected to the use of pulse pressure to define or quantify pulsatility because generation of pulsatile flow depends on the energy gradient, not the pressure gradient. For direct, complete comparison, both the arterial pressure and the pump flow rate must be included. We have clearly documented that pulsatile pumps (hydraulically driven physiologic pulsatile and roller pumps) generate significantly higher hemodynamic energy than do conventional nonpulsatile pumps.10 The extra energy generated by pulsatile pumps is used to enhance myocardial, renal, and cerebral blood flow after 60 minutes of deep hypothermic cardiac arrest.6,14 However, some pulsatile roller pumps do not generate any more hemodynamic energy than do conventional nonpulsatile pumps. In fact, inadequate pulsatile flow pumps cannot possibly have any benefits compared with nonpulsatile

1 Penn State Hershey Pediatric Cardiovascular Research Center and Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Penn State Children’s Hospital, Hershey, PA, USA

Corresponding Author: ¨ ndar, PhD, Department of Pediatrics—H085, Penn State College of Akif U Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033–0850 Email: [email protected]


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Abbreviations and Acronyms CPB EEP FDA FT3 FT4 ICU MP PI SHE SIRS TCD TSH

cardiopulmonary bypass energy equivalent pressure US Food and Drug Administration free T3 free T4 intensive care unit mean pressure pulsatility index surplus hemodynamic energy systemic inflammatory response transcranial Doppler thyroid-stimulating hormone

pumps.10 In the 1980s and 1990s, with older versions of pulsatile pumps and flat sheet membrane oxygenators, pulsatile flow produced more circuit pressure and hemolysis compared with the nonpulsatile perfusion. However, the latest perfusion pumps do not increase the risk for hemolysis.14 The best pediatric hollow-fiber membrane oxygenators currently used were designed with minimal pressure decreases and higher microemboli-capturing capabilities.9,15

Selection of Circuit Components Generation of Pulsatile Flow The components of the CPB circuit (Figure 1) play a large role in determining the quality of perfusion delivered to the patient. In this section, we review the results of pulsatile versus nonpulsatile flow for various circuit components in a pediatric CPB model. Most pumps approved by the US Food and Drug Administration (FDA) are capable of producing pulsatile flow, which itself can be characterized in several ways.10 Commonly, the settings of the pump are referred to when discussing the generation of pulsatile flow; the flow is split into 2 portions: a base flow (nonpulsatile portion) and a pulsatile portion.11 Under these settings, a flow with 0% base flow can be described as being completely pulsatile—blood flow stops between each pulse. With an increasing amount of base flow, blood continues to flow during times of nonpeak flow until completely nonpulsatile flow occurs. The number of pulses per minute can be varied to further approximate the patient’s natural heart rhythm during aortic cross-clamping.11 It is also possible to quantify pulsatile blood flow using an energy balance. This is because blood flow is generated by an energy gradient rather than a pressure gradient. Shepard et al16 introduced the idea of energy equivalent pressure (EEP) to quantify pulsatile flow: R2 fpdt EEP ¼ R1 2 1 fdt where f is the pump flow rate, p is the arterial pressure (mm Hg), and dt is the change in time at the end of flow and pressure cycles.16

In pulsatile flow, both flow and pressure vary and are dependent on time. In this way, it is possible to see the extra energy generated from pulsatile flow, called surplus hemodynamic energy (SHE): SHE ¼ 1332ðEEP MPÞ where 1332 converts from mm Hg to dyne/cm2 and MP is the mean pressure. During pulsatile flow, EEP is always greater than MP. However, in nonpulsatile flow, both flow and pressure are constant and so the equation for EEP reduces to pressure alone, EEP ¼ MP, so no additional energy is generated, theoretically. In practice, roller pumps, which move blood via occlusion, do generate some pulsatility even in nonpulsatile mode and have positive SHE values associated with nonpulsatile flow. An increase in SHE value has been associated with better microcirculation perfusion as well as lower rates of systemic inflammatory response and better vital organ protection.4-7

Pump In our Pediatric Cardiovascular Research Center, we9 tested 2 pumps: a Jostra HL 20 (Jostra USA, Austin, TX) roller pump and a MEDOS Deltastream DP1 (MEDOS Medizintechnik, Stolberg, Germany) rotary pump. We tested 2 oxygenators as well: a MEDOS Hilite 800LT (MEDOS Medizintechnik) and a Capiox Baby RX05 (Terumo Corporation, Tokyo, Japan) in a CPB circuit model using an identical 10F cannula (Terumo Corporation) to determine the effects that pumps and oxygenators had on pulsatility and SHE. We determined that the Jostra pump had higher SHE values than the MEDOS pump in nonpulsatile mode—this due to the occluding nature of the roller pump compared with the rotary pump. Additionally, the Jostra pump had significantly higher SHE values at 2500 rpm. However, the MEDOS pump had significantly higher SHE values at 3500 and 4500 rpm, indicating that at higher rpm, the rotary pump delivers better pulsatility. Under all conditions, the SHE values generated in pulsatile flow mode were significantly higher than those in nonpulsatile mode.9 We10 also investigated 6 different roller or hydraulic pumps: a hydraulically driven physiologic pulsatile pump, a Jostra HL 20 pulsatile roller pump, a Sto¨ckert SIII pulsatile roller pump (Sto¨ckert, Munich, Germany), a Sto¨ckert SIII mast-mounted pulsatile roller pump with a miniature roller head, a Sto¨ckert SIII mast-mounted nonpulsatile roller pump with a miniature roller head, and a Sto¨ckert CAPS nonpulsatile roller pump. We found that the nonpulsatile pump produced no extra hemodynamic energy, whereas the physiologic pump produced the greatest amount of extra hemodynamic energy. For the roller pumps, the Jostra HL 20 and the Sto¨ckert SIII had significantly higher increases in hemodynamic energy during pulsatile flow mode than the other pumps.10 Based on the research above, we selected the Jostra HL-20 for use in our experiments and clinical use. However, pump settings contribute greatly to the generation and quality of pulsatile flow. We11 determined that SHE increases as base flow decreases, that


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Figure 1. Components of the CPB circuit.

is, as the flow tends toward complete pulsatility. The time between pulses is important; the start time refers to when a pulse begins and the stop time to when the pulse stops and base flow returns. These are expressed as a fraction of the R-R interval and must differ by at least 20%. We found that 20% start and 80% stop generate high-quality pulsatile flow—these settings have since been used in many of our experiments.11

Oxygenator All components that come after the pump dampen the pulsatility of the blood flow; the oxygenator is no exception. When comparing oxygenators in the CPB circuit, we9 found that in all cases, the pressure decrease through the Capiox oxygenator was

higher than that through the MEDOS one. From this we can conclude that the MEDOS Hilite 800 LT preserved pulsatility better than the Capiox Baby RX05; however, the maximum flow rate for the MEDOS oxygenator is only 800 mL/min, whereas the Capiox oxygenator can go up to 1500 mL/min. We12 investigated the pressure decreases and SHE generated during pulsatile and nonpulsatile flow for 2 hollow-fiber membrane oxygenators in a simulated neonatal CPB circuit: Capiox Baby RX and Lilliput 1-D901 (Dideco, SpA, Mirandola, Italy) in a CPB cycle of normothermia ! hypothermia (25 C) ! rewarming. We found that the Capiox Baby RX had a significantly lower pressure decrease through the oxygenator than the Lilliput 1-D901 at all points in the CPB cycle for both pulsatile and nonpulsatile flow. At all points in the CPB


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cycle and at all sites (preoxygenator, postoxygenator, precannula), SHE for both oxygenators was significantly increased during pulsatile flow. During normothermic CPB and after rewarming, the SHE values for the Capiox Baby RX were significantly higher than those for the Lilliput 1-D901 at the postoxygenator site only. However, during the hypothermic phase, SHE for the Capiox Baby RX was significantly higher at the postoxygenator site as well as the precannula site.12

Arterial Cannula The arterial cannula usually represents the largest pressure decrease for any circuit component, and therefore it is vital to design the cannula so as much energy as possible is preserved across it. We13 investigated 8 geometrically different 10F cannulas in a simulated CPB circuit under both nonpulsatile and pulsatile flow. We found that regardless of geometry or construction, SHE values increased 6- to 9-fold in pulsatile flow compared with nonpulsatile flow. However, we noted that despite all the cannulas being marked as 10F, the cannulas varied in inside diameter (from 2.08 to 2.69 mm). This variation in cannula wall thickness, in addition to cannula length, is a likely cause of differing pressure decreases and SHE levels, leading to a spectrum of cannula performance, as increased pressure decrease correlated with decreased internal diameter.13

Arterial Filter The arterial filter, which traps both gaseous and thrombotic emboli in order to prevent them from being delivered to the patient, is located between the oxygenator and the arterial cannula. ‘‘In a CPB circuit, the blood from the purge line of the arterial filter passes directly to the venous side of the circuit, bypassing the patient completely.’’17 However, because blood flow is now being split physically, the flow delivered to the patient may be less than expected.17 This ‘‘stolen’’ flow can be a significant portion of the total blood flow and needs to be taken into account for adequate patient perfusion in a setting where the purge line is open, in particular for neonatal patients. To overcome this, we place a flow probe after the arterial filter and match the flow going to the arterial cannula (and therefore to the patient) with the pump flow rate. However, the arterial filter does not affect the quality of the pulsatility in the flow.

Clinical Outcomes In addition to simulated CPB circuits and their components, the impact of flow profile on pediatric cardiac patients has been examined. We18 used pulsatility index (PI) as a measure of cerebral blood flow in the right middle cerebral artery in pediatric patients undergoing CPB. The PI was measured using transcranial Doppler (TCD). Although the patient groups receiving pulsatile and nonpulsatile flow had a similar PI before incision, the pulsatile group had significantly smaller decreases in PI at all time points between 5 and

60 minutes post cross-clamp. In a neonatal piglet model of CPB, we6 found that pulsatile flow does not cause cerebral oxygen deficiency as seen in nonpulsatile flow, cerebral blood flow is significantly increased compared with nonpulsatile flow, and cerebral vascular resistance is significantly lower during pulsatile perfusion during and after normothermic CPB. From these studies, it can be concluded that pulsatile flow preserves cerebral blood flow significantly closer to baseline and may help reduce neurologic morbidity traditionally associated with CPB. Akçevin et al5 investigated the effect of pulsatile flow during CPB on vital organ recovery and thyroid hormone homeostasis in 289 pediatric CPB cases (pulsatile, n ¼ 208; nonpulsatile, n ¼ 81). The patients in the pulsatile group required significantly less inotropic support and lower intubation period and had shorter duration of intensive care unit (ICU) and hospital stay. The pulsatile group also had a higher urine output in the ICU. CPB surgery had a major impact on thyroid hormone levels5: in both the pulsatile and nonpulsatile groups, thyroid-stimulating hormone (TSH), total T3, total T4, free T3 (FT3), and free T4 (FT4) were all greatly reduced at 72 hours post surgery compared with their baseline values before surgery. However, in the nonpulsatile group, FT3 and FT4 levels were reduced significantly further than in the pulsatile group. Akçevin et al5 also found that the pulsatile group had significantly improved plasma biomarkers compared with the nonpulsatile group at 4 days post surgery. Plasma lactate levels were significantly lower and albumin levels significantly higher in the pulsatile group. Lowered albumin levels are associated with a shift toward higher inflammatory protein production; therefore, it could be suggested that pulsatile flow mitigates inflammation. Systemic inflammatory response (SIRS) is a complex postoperative complication that can lead to vital organ dysfunction and failure.19 We20,21 investigated the change in plasma biomarkers in pediatric patients who underwent CPB. After surgery, 36 proteins were found to be consistently and significantly changed by the CPB procedure after application of the Bonferroni correction (a method used to address the problem of multiple comparisons). In addition to reduced levels of proteins such as TSH, increased expression of inflammatory proteins was found. The 2 proteins that exhibited the highest percentage change as a result of CPB were calcitonin and C-reactive protein. Further investigation is required to determine whether pulsatile flow has a significant effect on preserving protein levels closer to baseline after a pediatric CPB procedure.

Conclusions ‘‘Pulsatile flow has a significantly positive effect on the quality of hemodynamic energy delivered to pediatric CPB patients and this effect can be seen in every CPB circuit component that modifies flow profiles. The better preservation of homeostasis in pulsatile flow as compared with


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nonpulsatile flow has been partly demonstrated, but further investigation into the mitigation of SIRS is necessary. However, pulsatile perfusion only minimizes the morbidity, it does not eliminate the adverse effects of CPB procedures in pediatric cardiac patients.’’4-6,14,18 Acknowledgements We acknowledge Feng Qiu, MD, for his contribution to the figure.

Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding The author(s) received no financial support for the research and/or authorship of this article.

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¨ ndar A. Comparison 9. Haines N, Wang S, Kunselman A, Myers J, U of pumps and oxygenators with pulsatile and nonpulsatile modes in an infant cardiopulmonary bypass model. Artif Organs. 2009;33:993-1001. ¨ ndar A, Eichstaedt H, Masai T, et al. Comparison of six pediatric 10. U cardiopulmonary bypass pumps during pulsatile and non-pulsatile perfusion. J Thorac Cardiovasc Surg. 2001;122:827-829. 11. Rider A, Ressler N, Karkhanis T, Kunselman A, Wang S, ¨ ndar A. The impact of pump settings on the quality of pulsatiU lity. ASAIO J. 2009;55:100-105. ¨ ndar A, Ji B, Lukic B, et al. Comparison of hollow-fiber mem12. U brane oxygenators with different perfusion modes during normothermic and hypothermic CPB in a simulated neonatal model. Perfusion. 2006;21:381-390. ¨ ndar A. A per13. Rider A, Ji B, Kunselman A, Weiss W, Myers J, U formance evaluation of eight geometrically different 10 Fr pediatric arterial cannulae under pulsatile and nonpulsatile perfusion in an infant cardiopulmonary bypass model. ASAIO J. 2008;54:306-315. ¨ ndar A. Myths and truths of pulsatile and non-pulsatile perfu14. U sion during acute and chronic cardiac support [editorial]. Artif Organs. 2004;28:439-443. ¨ ndar A. Evaluation of the 15. Salavitabar A, Qiu F, Kunselman A, U Quadrox-I neonatal oxygenator with an integrated arterial filter. Perfusion. In press; doi:10.1177/0267659110380773. 16. Shepard R, Simpson D, Sharp J. Energy equivalent pressure. Arch Surg. 1966;93:730-740. ¨ ndar A. ‘‘Stolen’’ blood flow: effect 17. Wang S, Miller A, Myers J, U of an open arterial filter purge line in a simulated neonatal CPB model. ASAIO J. 2008;54:432-435. 18. Rogerson A, Guan Y, Kimatian S, et al. Transcranial Doppler ultrasonography: a reliable method for monitoring pulsatile flow during cardiopulmonary bypass in infants and young children. J Thorac Cardiovasc Surg. 2010;139:e80-e82. 19. Day JR, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Int J Surg. 2005;3:129-140. 20. Umstead T, Lu CK, Freeman W, et al. Dual-platform proteomics study of plasma biomarkers in pediatric patients undergoing cardiopulmonary bypass. Pediatr Res. 2010;67:641-649. 21. Agirbasli M, Nguyen M, Win K, et al. Inflammatory and hemostatic response to cardiopulmonary bypass in pediatric population: feasibility of seriological testing of multiple biomarkers. Artif Organs. 2010; 34:987-995.
