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© 2012, Copyright the Authors Artificial Organs © 2012, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
Blood Trauma Testing of CentriMag and RotaFlow Centrifugal Flow Devices: A Pilot Study Michael A. Sobieski, Guruprasad A. Giridharan, Mickey Ising, Steven C. Koenig, and Mark S. Slaughter Departments of Bioengineering & Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA
Abstract: Mechanical circulatory assist devices that provide temporary support in heart failure patients are needed to enable recovery or provide a bridge to decision. Minimizing risk of blood damage (i.e., hemolysis) with these devices is critical, especially if the length of support needs to be extended. Hematologic responses of the RotaFlow (Maquet) and CentriMag (Thoratec) temporary support devices were characterized in an in vitro feasibility study. Paired static mock flow loops primed with fresh bovine blood (700 mL, hematocrit [Hct] = 25 ⫾ 3%, heparin titrated for activated clotting time >300 s) pooled from a single-source donor were used to test hematologic responses to RotaFlow (n = 2) and CentriMag (n = 2) simultaneously. Pump differential pressures, temperature, and flow were maintained at 250 ⫾ 10 mm Hg, 25 ⫾ 2°C, and 4.2 ⫾ 0.25 L/min, respectively. Blood samples (3 mL) were collected at 0, 60, 120, 180, 240, 300, and 360 min after starting pumps in accordance with recommended Food and Drug Administration and American Society for Testing and
Materials guidelines. The CentriMag operated at a higher average pump speed (3425 rpm) than the RotaFlow (3000 rpm) while maintaining similar constant flow rates (4.2 L/min). Hematologic indicators of blood trauma (hemoglobin, Hct, platelet count, plasma free hemoglobin, and white blood cell) for all measured time points as well as normalized and modified indices of hemolysis were similar (RotaFlow: normalized index of hemolysis [NIH] = 0.021 ⫾ 0.003 g/100 L, modified index of hemolysis [MIH] = 3.28 ⫾ 0.52 mg/mg compared to CentriMag: NIH = 0.041 ⫾ 0.010 g/100 L, MIH = 6.08 ⫾ 1.45 mg/mg). In this feasibility study, the blood trauma performance of the RotaFlow was similar or better than the CentriMag device under clinically equivalent, worst-case test conditions. The RotaFlow device may be a more cost-effective alternative to the CentriMag. Key Words: Hemolysis testing— Blood trauma—Mechanical circulatory support—Temporary support.
Temporary placement of continuous-flow, mechanical circulatory support devices (MCSDs) has become standard therapy for providing perioperative or postcardiotomy circulatory support in heart failure patients (1–3). Short-term support with rotary blood pumps may be extended by a few days to enable
clinicians time to evaluate the patients’ potential for recovery or as a bridge to decision (4).The CentriMag ventricular assist system is currently undergoing clinical trials in the USA for short-term support in patients with cardiac dysfunction who fail to wean from cardiopulmonary bypass. Concerns exist that the high operational speeds associated with these temporary rotary blood pumps may cause hemolysis due to blood trauma caused by turbulent flow, high shear stresses, and surface interactions (5,6). Subsequently, risk of hemolysis may increase if temporary MCSD duration is extended for a few days. Additionally, a variety of temporary blood pumps that have distinct design characteristics may also affect hematologic responses. Minimizing blood trauma is a fundamental requirement for all blood pumps. The Food and Drug
doi:10.1111/j.1525-1594.2012.01514.x Received February 2012; revised June 2012. Address correspondence and reprint requests to Prof. Mark S. Slaughter, Professor and Chief, Division of Thoracic and Cardiovascular Surgery, Cardiovascular Innovation Institute, Rm 411, 302 East Muhammad Ali Blvd, University of Louisville, Louisville, KY 40202, USA. E-mail:
[email protected] Presented in part at the 19th Congress of the International Society for Rotary Blood Pumps, held on September 8–10, 2011, in Louisville, KY, USA.
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Administration (FDA) has mandated in vitro testing to demonstrate hemocompatibility and safety. Furthermore, the FDA and American Society for Testing and Materials (ASTM) have published guidelines for hemolysis testing of MCSDs (7–10). In this study, the hematologic performance of two temporary, centrifugal MCSDs (RotaFlow, Maquet Cardiovascular, Wayne, NJ, USA and CentriMag, Thoratec Corp., Pleasanton, CA, USA) were characterized simultaneously in an in vitro static mock flow loop (11).These centrifugal pumps were chosen for comparison as they have been demonstrated to be superior to roller pumps or centrifugal pumps with solid drive axles (e.g., Biomedicus, Eden Praire, MN, USA) for hemolysis and may be best suited for extended support durations (12). The CentriMag and RotaFlow are magnetically levitated centrifugal-flow temporary MCSDs that can provide flows of up to 10 L/min. We hypothesized that the RotaFlow would produce similar hematologic responses to the CentriMag, as both devices are magnetically coupled centrifugal pumps.The RotaFlow may be a low-cost alternative to the current clinical standard CentriMag.
METHODS Mock circulation model Mock flow loops consisting of a 1-L reservoir, 75 cm of 3/8” diameter connective tygon tubing (Carmedia coated, Medtronic, Minneapolis, MN, USA) with a sampling port, resistor, and RotaFlow (n = 2) or CentriMag (n = 2) MCSD, were constructed for paired hematologic testing (Fig. 1). Each mock loop was instrumented with fluid-filled pressure sensors (BD DTXplus, BD, Franklin Lakes, NJ, USA) at the inlet and outlet of the MCSD to measure the differential pressure across the MCSD, and a high-fidelity flow probe (Transonics, Ithaca, NY, USA) across the outflow conduit to measure outlet flow. A total blood volume of 700 mL was used in each mock flow loop per ASTM F1841 standards (7). To minimize protein activation, each test was performed in a loop comprised of new sterile tubing and reservoir components. Each mock loop was placed in a temperaturecontrolled water bath to maintain the blood temperature at 25 ⫾ 2°C, per FDA recommendation. An inline filter was placed between the reservoir and the inlet conduit to the MCSD to prevent debris from entering the blood pump and adversely impacting hemolysis results. A C-clamp resistor was placed on the outflow conduit downstream of the MCSD to maintain the same pressure differential across both MCSDs. Artif Organs, Vol. 36, No. 8, 2012
A
B
FIG. 1. Schematic and picture of the hemolysis test loop. The hemolysis setup allows for control of temperature, flow rate, and MCSD pressure head. Four different mock loops were constructed for head-to-head, paired blood trauma testing of RotaFlow and CentriMag devices.
Blood for hemolysis testing Fresh, whole, bovine blood drawn within 24 h of initiating test procedures was used. The blood was acquired from a single donor animal, prefiltered to remove clots and debris through a standard 20-micron blood administration system (Baxter Y-type blood administration set, Deerfield, IL, USA). Individual units from the single donor source were mixed to create a homogeneous blood pool. The pooled blood was diluted using PlasmaLyte solution (Abbott Laboratories, Deerfield, IL, USA) to obtain a hematocrit (Hct) of 25 ⫾ 3%. Heparin was added to the blood pool to maintain an activated clotting time of greater than 300 s per FDA and ISO 7199 standards. The pooled blood was used for simultaneous paired testing of both devices. Device operation and specifications Sterilized and previously unused RotaFlow (n = 2) and CentriMag (n = 2) devices were used to minimize risk of protein activation. The MCSDs were operated at their typical clinical operational speed as prescribed by the Indications for Use provided to the FDA. The resistor was adjusted to maintain equivalent differential pressure (250 ⫾ 10 mm Hg) across both the devices. Pump flow rates were equivalent for both devices (4.2 ⫾ 0.3 L/min). Measurements and analyses Hematologic response was assessed by measuring plasma free hemoglobin (PfHb), Hct, red blood cell
BLOOD TRAUMA TESTING (RBC), white blood cell (WBC), and platelet (Plt) counts. Specifically, 3-mL samples were collected at the following time points: (1) pooled blood sample, (2) before device operation (baseline), and (3) 60-min (Q60 min) intervals during MCSD operation over a 6-h period (Q6 h). The serum for quantifying PfHb was obtained by centrifuging blood samples at 6000 rpm for 15 min. The PfHb was quantified using a Plasma Photometer (HemoCue, Mission Viejo, CA, USA) with paired sample results taken at each time point averaged (assuming paired samples within ⫾12% of each other). Plt count and Hct were measured using CDC Mascot (CDC Technologies, Oxford, CT, USA). Modified index of hemolysis (MIH) and normalized index of hemolysis (NIH) were calculated by ASTM standards using the following formulae (3):
NIH [g / 100L] = [(PfHb / t) × ((100 − Hct) / 100) × Vol. × 1000] / (Q × 1000), and MIH [mg / mg] = [(PfHb / t) × ((100 − Hct) / 100) × Vol × 106 ] / (Q × Hb), where PfHb/t (mg/dL min) = the slope of the plasma hemoglobin concentration (mg/dL) versus time (min) obtained from a linear best-fit of data; Hct (%) = average hematocrit of the blood circuit, Vol (L) = average blood volume of the circuit; Q (L/min) = blood flow rate during testing; and Hb (mg/ dL) = average total hemoglobin concentration in the circuit. All measured data were analyzed for significant differences between the predicate and test devices using paired t-tests. RESULTS The CentriMag operated at a higher average pump speed (CentriMag 3425 rpm vs. RotaFlow 3000 rpm) to maintain an equivalent flow rate as the RotaFlow pump (4.20 vs. 4.17 L/min). Blood trauma indicators (hemoglobin, Hct, Plt count, PfHb, normalized and modified indices of hemolysis, and WBC) at all time points were similar for both pumps in loop pair 1, but Plt reduction and PfHb were significantly higher for CentriMag in loop pair 2. The RotaFlow had a lower NIH (0.021 ⫾ 0.003 g/100 L) compared to the CentriMag (0.041 ⫾ 0.010 g/100 L) pump. The RotaFlow also had a lower MIH (3.28 ⫾ 0.52 mg/mg) compared to the CentriMag (6.08 ⫾ 1.45 mg/mg) (Fig. 2). However, paired t-tests showed no statistically discernible differences (P < 0.05) between the RotaFlow and CentriMag pumps for all measured parameters (PfHb, Hct, RBC, WBC, Plt, NIH, MIH) over the 6-h test period.
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The findings from this feasibility study suggest similar or better hematologic responses for RotaFlow compared to CentriMag MCSD. DISCUSSION Blood trauma, including hemolysis, poses a potentially significant problem with MCSDs (5). Specifically, MCSDs may cause blood trauma due to flow stasis, cavitation, surface interactions, turbulent stresses, and high shear forces leading to hemolysis and activation of Plts, leukocytes, and erythrocytes (13–16). Hemolysis is associated with many clinical complications including anemia, renal damage, hypercoagulation, thromboembolism, and bleeding (13–16). To ensure device safety and hemocompatibility, the FDA has mandated in vitro testing for all MCSDs. For FDA 510K approval, comparison to a previously approved device (predicate) is required, because it provides a well-controlled setting for direct comparison between the two devices (predicate and test). In this study, a previously approved FDA 510K protocol for hemolysis testing was used to compare the RotaFlow and CentriMag for temporary mechanical circulatory support (11). Many factors can influence blood trauma results, including but not limited to tubing (material, size, and length), priming blood volume, differential pressure, flow rate, and source/age of blood. Paired testing using identical mock flow loops and pooled blood were used to minimize these variables. Sterile and previously unused devices were used to minimize the influence of inflammatory blood components. Furthermore, both devices were operated at identical flow rates (4.2 ⫾ 0.3 L/min) and differential pressures (250 ⫾ 10 mm Hg) for a test period of 6 h. Importantly, the hemolysis test loop acts as an accelerated testing bench. The total blood volume in the hemolysis test loop was 700 mL, significantly less than the blood volume of 4–5 L in humans. Thus, for a given flow rate of 4.2 L/min, the blood in the hemolysis loop passes through the pump at a rate that is six times higher than it would in a patient. Thus, a 6-h hemolysis test simulates approximately 36 h of circulation time in a patient. The RotaFlow utilizes a magnetic suspension with a single, continually washed, sapphire monopivot bearing to reduce heat generation and hemolysis. The CentriMag is a magnetically levitated pump with no bearings or seals to minimize heat generation. It is reasonable to expect a reduced blood trauma profile from the CentriMag due to the bearingless design. However, the results of this pilot study indicate that the RotaFlow produced significantly less blood Artif Organs, Vol. 36, No. 8, 2012
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B. Pair 2
C
FIG. 2. Comparison of temporal changes in plasma free hemoglobin (PfHb), hematocrit (Hct), platelet (Plt), and white blood cell (WBC) count between RotaFlow and CentriMag temporary mechanical circulatory support devices for (A) pair 1, and (B) pair 2. (C) Normalized and modified indices of hemolysis (NIH, MIH) for the two paired tests. Blood trauma indicators (hemoglobin, Hct, Plt, PfHb, WBC, NIH, and MIH) at all time points were similar or better for the RotaFlow (RotaFlow: NIH = 0.021 ⫾ 0.003 g/100 L, MIH = 3.28 ⫾ 0.52 mg/mg vs. CentriMag: NIH = 0.041 ⫾ 0.010 g/100 L, MIH = 6.08 ⫾ 1.45 mg/mg) compared to CentriMag. The results of this pilot study demonstrated that the RotaFlow and CentriMag blood pumps could be operated under similar clinical conditions for short-term use.
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BLOOD TRAUMA TESTING trauma compared to CentriMag in both paired loops during the 6-h test period. The increased hemolysis associated with CentriMag is potentially due to the higher operational speeds (3450 rpm) compared to CentriMag (3000 rpm) necessary to achieve the same pressure head and flow. Previous comparative studies between the RotaFlow and CentriMag have demonstrated that the RotaFlow is more mechanically efficient than the CentriMag MCSD (17). However, this feasibility study was limited to two paired loops, which is an insufficient sample size for statistical analyses. A larger sample size (8–10 paired loops) is required to discern statistical differences for the hematologic parameters between the devices at a 95% confidence interval (P < 0.05).
681 CONCLUSIONS
This feasibility study demonstrated that the RotaFlow and CentriMag blood pumps may be operated under similar clinical conditions. Preliminary findings suggest that the RotaFlow disposable pump head has similar or better mechanical and blood trauma performance as the CentriMag during short-term support. A more comprehensive study with a larger sample size is required to discern statistical differences between each device. Acknowledgments: Funding for this project was provided by a generous gift from the Walter and Avis Jacobs Foundation. The authors also thank Maquet Cardiovascular for providing RotaFlow devices and controllers used in this study.
LIMITATIONS AND RECOMMENDATIONS
REFERENCES
The hemolysis testing previously described was conducted at temperature (25°C, hypothermia) and Hct levels (25%) recommended by the FDA. The justification was that the blood viscosity of the hypothermic, low Hct blood represented a worst-case clinical scenario compared to normal clinical hemodynamic parameters. However, several factors including shear rates, RBC wall rigidity, and the interaction of particulate matter in the blood are affected by the temperature and Hct concentration and may alter blood trauma results (5). Thus, we propose that future blood trauma testing should be conducted at normal levels of temperature (37 ⫾ 2°C) and Hct of end-stage congestive heart failure patients (35 ⫾ 3%). Importantly, the Hct of end-stage congestive heart failure patients is lower than normal Hct levels due to hemodilution or anemia (18). The pilot blood trauma test protocols did not incorporate measurements to quantify device-related Plt activation or the effect on coagulation pathways which have been shown to affect clinical outcomes (19–23). Hence, measurements to quantify Plt activation (P-selectin, CD 40) and changes in coagulation cascade pathway (multimers, von Willebrand) should also be incorporated in future blood trauma testing. Inclusion of these measurements will improve clinical relevance of these tests and may better predict the performance of these devices in the clinical setting. The Plt and WBC counts plotted in Fig. 2 are measured using calibrated counters.These CBC machines can potentially count small particles like destroyed erythrocytes leading to a small incorrect increase in measured WBC and Plt counts between two time points (24).
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