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© 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation
Use of a Novel Diagonal Pump in an In Vitro Neonatal Pulsatile Extracorporeal Life Support Circuit *Alissa Evenson, *Shigang Wang, †Allen R. Kunselman, and *‡§Akif Ündar *Pediatric Cardiovascular Research Center, Penn State Hershey Children’s Hospital, Penn State Milton S. Hershey Medical Center, Department of Pediatrics, Penn State Hershey College of Medicine; †Department of Public Health Sciences, Penn State Hershey College of Medicine; ‡Department of Surgery, Penn State Milton S. Hershey Medical Center, Penn State Hershey College of Medicine, Hershey, PA; and §Department of Bioengineering, College of Engineering, Pennsylvania State University, University Park, PA, USA
Abstract: One approach with the potential to improve morbidity and mortality rates following extracorporeal life support (ECLS) is the use of pulsatile perfusion. Currently, no ECLS pumps used in the United States can produce pulsatile flow. The objective of this experiment is to evaluate a novel diagonal pump used in Europe to determine whether it provides physiological pulsatility in a neonatal model. The ECLS circuit consisted of a Medos Deltastream DP3 diagonal pump, a Hilite 800LT polymethylpentene diffusion membrane oxygenator, and arterial/venous tubing. A 300-mL pseudopatient was connected to the circuit using an 8Fr arterial cannula and a 10Fr venous cannula. A clamp maintained constant pressure entering the pseudopatient. Trials (64 total) were conducted in nonpulsatile and pulsatile modes at flow rates of 200 mL/ min to 800 mL/min. Flow and pressure data were collected using a custom-based data acquisition system. The
Deltastream DP3 pump was capable of producing an adequate quality of pulsatility. Pulsatile flow produced increased mean arterial pressure, energy equivalent pressure (EEP), and surplus hemodynamic energy (SHE) at all flow rates compared to nonpulsatile flow. Pressure drop across the cannula accounted for the majority of pressure loss in the circuit. The greatest loss of SHE and total hemodynamic energy occurred across the arterial cannula due to its small diameter. The Deltastream DP3 pump produced physiological pulsatile flow without backflow while providing EEP and SHE to our neonatal pseudopatient. Further experiments are necessary to determine the impact of this pulsatile pump in an in vivo model prior to clinical use. Key Words: Extracorporeal life support— Diagonal pump—Pediatrics—Pulsatile—Surplus hemodynamic energy.
Extracorporeal life support (ECLS) is a life-saving technique that is used to provide support for patients with cardiac or respiratory disease. Over the past decade, there have been multiple technological advances in the components used during ECLS. Improvements have been made in the material used for the oxygenator, advancing from silicone membranes to microporous hollow-fiber membranes to the diffusion membranes that are the gold standard of oxygenators today. Additional improvements have been made to increase the efficiency of gas transfer across the membrane. Advances in the pumps used in
the ECLS circuit have resulted in lower priming volumes and higher outputs for neonatal, pediatric, and adult patients. There have also been advances in the coating technique used in all circuit components to improve biocompatibility during long-term ECLS. These and other technological advances have resulted in improved survival rates in patients undergoing ECLS. However, morbidity and mortality rates following ECLS remain unacceptably high, particularly in neonatal patients undergoing ECLS due to cardiac failure. According to the January 2013 Registry Report of the Extracorporeal Life Support Organization, 4987 neonatal patients (0–30 days old) were placed on ECLS from 1986 to 2012 due to cardiac failure at the 200 centers that submitted data for this report (1). Among this particular subset of patients, there was a staggering 60% mortality rate. Over the same period
doi:10.1111/aor.12240 Received August 2013; revised September 2013. Address correspondence and reprint requests to Dr. Akif Ündar, Penn State Hershey College of Medicine, Department of Pediatrics—H085, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850, USA. E-mail: [email protected]
Artificial Organs 2014, 38(1):E1–E9
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of time, 26 205 neonatal patients were placed on ECLS due to respiratory failure, with a mortality rate of 25%. Additionally, patients undergoing ECLS remain at risk for a variety of morbidities, including hemorrhage; injury to vital organs, such as the heart, brain, and kidneys; and mechanical complications in the ECLS circuit components. The high mortality rates due to ECLS in neonatal patients in addition to the risk of various morbidities are evidence that further research is necessary to identify novel approaches and devices to improve patient outcomes and limit the loss of life following a procedure that is being performed more frequently. An alternative approach that has the potential to improve patient outcomes is the utilization of pumps that are capable of producing pulsatile flow. Multiple studies in patients undergoing cardiopulmonary bypass (CPB) procedures or receiving support from ventricular assist devices using pulsatile flow have demonstrated increased blood flow and oxygenation to the brain (2–4), increased urine output (4,5), decreased cardiac inotropic support (5), less gastrointestinal bleeding (6), and better vital organ perfusion (6–9), all of which indicate the decreased potential for the types of complications that are most commonly reported in neonatal patients (1). Despite this evidence demonstrating better patient outcomes when pulsatile flow is used, none of the pumps currently used for ECLS in the United States are capable of producing pulsatile flow without backflow. The Medos Deltastream DP3 diagonal pump, which is used for ECLS procedures in Europe (10) but is not yet approved for use in the United States, has been shown to produce an adequate quality of pulsatility in a pediatric ECLS model in previous research conducted in our laboratory (11). The aim of our current experiment was to evaluate this novel diagonal pump in nonpulsatile and pulsatile mode to determine the effect of pulsatility on flow, pressure, and hemodynamic energy in a neonatal circuit.
capacity soft bag was connected as a pseudopatient to the ECLS circuit using an 8Fr Bio-Medicus pediatric arterial cannula and a 10Fr Bio-Medicus pediatric venous cannula (Medtronic, Minneapolis, MN, USA). A Hoffman clamp was positioned at the post-arterial cannula site to maintain a constant pressure entering the pseudopatient. An adjustable-height open-air bag served as the venous reservoir. The circuit was primed using lactated Ringer’s solution for deairing followed by heparinized packed human red blood cells. The hematocrit of the priming solution was 35%. The total priming volume of the circuit was approximately 440 mL.
MATERIALS AND METHODS
Data acquisition The flow probe outputs and pressure transducers were connected to a signal conditioning unit (SC2345, National Instruments, Austin, TX, USA) and a data acquisition device (NI USB-6521, National Instruments). Using a universal serial bus port connection, the digital signals from the data acquisition device were transferred to a computer equipped with a customized user interface based on Labview 7.1 software for Windows (National Instruments). Realtime data were recorded at 1000 samples per second. A 20-s segment of pressure and flow data was recorded at all sites and converted into hemodynamic
Experimental setup The neonatal ECLS circuit used for this experiment consisted of a Medos Deltastream DP3 diagonal pump (Medos Medizintechnik AG, Stolberg, Germany), a Medos Hilite 800LT polymethylpentene diffusion membrane oxygenator, 3 ft of tubing (1/4 in. inner diameter [ID] × 1/16-in. wall) for both arterial and venous lines, 20 cm of tubing (1/4 in. ID) connecting the pump to the oxygenator, and a Maquet HCU-30 heater–cooler unit (Maquet Cardiopulmonary AG, Hirrlingen, Germany; Fig. 1). A 300-mLArtif Organs, Vol. 38, No. 1, 2014
Pulsatile mode settings The pump driver was connected to the Medos Deltastream MDC console, which was used to control pulsatility settings. The Deltastream DP3 was used in pulsatile mode with a frequency of 90 bpm, systolic/diastolic ratio of 50%, and rotational speed differential of 1500 rpm. Previous research conducted in this laboratory has indicated these settings are capable of producing a physiological quality of pulsatility (11,12). Experimental design The experiments were conducted at flow rates of 200 mL/min to 800 mL/min, in increments of 200 mL/ min. Trials were conducted in both nonpulsatile and pulsatile modes at each flow rate. The mean arterial pressure (MAP) entering the pseudopatient was maintained at 50 mm Hg during all trials, and blood temperature was maintained at 36°C. Venous pressure was kept at 5 mm Hg. Two ultrasound flow probes (Transonic Systems, Ithaca, NY, USA) were placed at the preoxygenator and pre-arterial cannula sites. Five disposable pressure transducers (Maxxim Medical, Ithaca, NY, USA) were placed at the preoxygenator, postoxygenator, pre-arterial cannula, post-arterial cannula, and pre-venous cannula sites.
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FIG. 1. The experimental ECLS circuit is shown.
energy using the equations below. Data were obtained eight times for each unique combination of flow rate and pulsatility mode, yielding a total of 64 trials.
SHE ( ergs cm 3 ) = 1332 × ( EEP — MAP ) THE is equivalent to EEP and is calculated using the following equation:
THE ( ergs cm 3 ) = 1332 × EEP Calculating hemodynamic energy The hemodynamic energy generated during each trial was quantified using related mathematical formulas. Energy equivalent pressure (EEP) was calculated using Shepard’s formula (13), which uses flow (f) and pressure (p) data collected via the Labview 7.1 software over a time interval (t1 to t2) to quantify the amount of energy produced during each trial, measured in mm Hg. The equation for EEP is as follows: t2
EEP ( mm Hg ) = ∫ fpΔt t1
Surplus hemodynamic energy (SHE) and total hemodynamic energy (THE) were also calculated. SHE is the difference between EEP and MAP, found using the equation below:
The units for SHE and THE are ergs/cm3. The constant 1332 converts pressure from units of mm Hg to dynes/cm2 (1 mm Hg = 1332 dynes/cm2; 1 dyne/cm2 = 1 erg/cm3). Calculating pressure drops The pressure drops across the oxygenator, cannula, and total circuit were calculated using the following equations, where p is the pressure at the location denoted by the subscript description:
Oxygenator pressure drop (mm Hg ) = ppreoxygenator − ppostoxygenator Arterial cannula pressure drop ( mm Hg ) = ppre-arterial cannula − ppost-arterial cannula Artif Organs, Vol. 38, No. 1, 2014
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Circuit pressure drop ( mm Hg ) = ppreoxygenator − ppost-arterial cannula Statistical analysis Analysis of variance (ANOVA) models were fit to the continuous outcomes (e.g., pressure drops and percentage energy losses) to compare flow rate (200, 400, 600, 800 mL/min) and mode (nonpulsatile and pulsatile). A linear mixed-effects model was fit to the continuous outcomes (e.g., MAP, EEP, SHE, and THE) to compare the flow rate, mode, and location (e.g., preoxygenator, precannula, and postcannula) (14). The linear mixed-effects model is an extension of linear regression that accounts for the withinsubject variability inherent in repeated-measures designs. In this study, the repeated factor is the location. For each outcome, P values were adjusted for multiple comparisons testing using the Tukey– Kramer procedure. All hypothesis tests were twosided, and all analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, NC, USA). RESULTS Flow rate During this experiment, the observed rotational speed of the Deltastream DP3 pump was recorded in nonpulsatile mode at each flow rate. When the pump was switched to pulsatile mode, the rotational speed increased from the nonpulsatile mode observation, even though no other adjustments were made to the pump or circuit. In order to ensure consistency of data measurements, the rotational speed in pulsatile mode was adjusted to match the rotational speed in nonpulsatile mode. This resulted in average observed flow rates that varied by less than 1% across all trials (Table 1). Pulsatile mode produced higher observed
TABLE 1. Real flow rates and rotational speeds (rpm) in nonpulsatile (NP) and pulsatile (P) modes Group
Mode
200 mL/min
NP P NP P NP P NP P
400 mL/min 600 mL/min 800 mL/min
Rotational speed (rpm)*
Flow rate (mL/min)
3700 3700 4750 4750 5850 5850 7000 7000
214.3 ± 0.7 213.7 ± 2.2 413.3 ± 0.5 413.5 ± 1.2 606.1 ± 0.6 610.5 ± 1.4 804.4 ± 0.2 800.4 ± 1.4
*Pulsatile rotational speed was adjusted to match the observed nonpulsatile rotational speed.
flow rates at the same rotational speed differential in all groups except the 800 mL/min group. Additionally, there was no backflow noted in pulsatile mode at any of the flow rates. Figure 2 presents flow waveforms at 400 mL/min and 800 mL/min in both pulsatile and nonpulsatile modes. Pressure In both nonpulsatile and pulsatile modes, MAP increased as the flow rate increased. Additionally, MAP in pulsatile mode was significantly higher than in nonpulsatile mode (P < 0.001). Figure 2 presents pressure waveforms at 400 mL/min and 800 mL/min in both pulsatile and nonpulsatile modes. Nonpulsatile mode did not produce any EEP at any of the flow rates. EEP was produced at all flow rates in pulsatile mode. The greatest percentage increase of EEP in excess of MAP occurred at 200 mL/min flow rate at the preoxygenator site (24.0%). The percentage of EEP produced decreased as flow rate increased from 200 mL/min to 800 mL/ min. Table 2 contains a summary of MAP and EEP results.
TABLE 2. MAP and EEP (mm Hg) with percent increase at preoxygenator, pre-arterial cannula, and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) modes Preoxygenator Group
Mode
200 mL/min
NP P NP P NP P NP P
400 mL/min 600 mL/min 800 mL/min
Pre-arterial cannula
Post-arterial cannula
MAP
EEP (% increase)
MAP
EEP (% increase)
MAP
EEP (% increase)
85.4 ± 0.0 89.3 ± 1.3* 127.1 ± 0.2 134.0 ± 1.0* 184.0 ± 0.3 194.7 ± 0.7* 255.6 ± 0.2 266.1 ± 0.6*
85.4 ± 0.0 (0.0) 110.7 ± 1.7 (24.0)* 127.1 ± 0.2 (0.0) 158.2 ± 1.6 (18.0)* 184.0 ± 0.3 (0.0) 224.4 ± 0.7 (15.2)* 255.6 ± 0.2 (0.0) 297.5 ± 0.5 (11.8)*
78.9 ± 0.1 82.9 ± 1.1* 111.9 ± 0.2 118.6 ± 1.0* 159.9 ± 0.3 170.1 ± 0.6* 220.7 ± 0.2 231.2 ± 0.5*
78.9 ± 0.1 (0.0) 95.8 ± 1.4 (15.5)* 111.9 ± 0.2 (0.0) 134.1 ± 1.3 (13.1)* 159.9 ± 0.3 (0.0) 189.0 ± 0.6 (11.1)* 220.7 ± 0.2 (0.0) 250.9 ± 0.5 (8.5)*
50.6 ± 0.1 53.3 ± 0.8* 50.0 ± 0.1 53.1 ± 0.6* 50.5 ± 0.2 53.9 ± 0.2* 50.1 ± 0.1 51.7 ± 0.2*
50.6 ± 0.1 (0.0) 62.6 ± 1.0 (17.4)* 50.0 ± 0.1 (0.0) 60.6 ± 0.8 (14.1)* 50.5 ± 0.2 (0.0) 60.3 ± 0.2 (11.7)* 50.1 ± 0.1 (0.0) 56.0 ± 0.1 (8.4)*
Values in parentheses are EEP percentage increase compared to MAP, calculated using the following equation: [(EEP − MAP)/ MAP] × 100. *P < 0.001 versus NP. Artif Organs, Vol. 38, No. 1, 2014
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FIG. 2. Flow and pressure waveforms at 400 mL/min and 800 mL/min in pulsatile (P) and nonpulsatile (NP) mode.
Pressure drop Pressure drop across the oxygenator, cannula, and circuit increased steadily as flow rate increased from 200 mL/min to 800 mL/min (Table 3). The cannula pressure drop accounted for more than 80% of the total pressure drop in the circuit at all flow rates. Pressure drop across the cannula was significantly higher in pulsatile mode than nonpulsatile mode by an average of 5.4% (P < 0.001). Hemodynamic energy Negligible amounts of SHE (80% of the pressure loss in the circuit due to the small size of the cannula, with negligible pressure loss due to the tubing. Additionally, a lower percentage of SHE was delivered to the patient at higher flow rates because of the increased pressure drop across the arterial cannula. The small diameter of the arterial cannula also resulted in increased loss of SHE across the cannula at higher flow rates. The amount of THE delivered to the patient remained relatively consistent because the postcannula pres-
sure was maintained at 50 mm Hg across all trials. However, the percentage of THE lost in the circuit increased as flow rate increased to 800 mL/min, with the majority of THE loss occurring across the arterial cannula. If central cannulation continues from CPB, a larger size arterial cannula (10Fr instead of 8Fr) allows more hemodynamic energy to be delivered to the patient with a significantly improved quality of pulsatility. In addition to the ability to produce an adequate quality of pulsatility and hemodynamic energy in our neonatal model, the Deltastream DP3 pump features a low priming volume (16 mL) and a wide range of flow rates (0–8 L/min), while the Deltastream MDC console includes valuable safety mechanisms, such as a flow sensor with an integrated bubble detector, backflow detection, and temperature sensors. The
FIG. 3. Surplus hemodynamic energy at the preoxygenator and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) mode at varying flow rates.
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FIG. 4. Total hemodynamic energy at the preoxygenator and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) mode at varying flow rates.
Deltastream DP3 pump also has the ability to function in zero flow mode, which allows blood flow from the pump to be interrupted without risking unintentional backflow. Using the zero flow function, medical professionals can evaluate the patient’s native heart function by echocardiogram without having to crossclamp the circuit. Additionally, there are pressure sensors that can detect positive pressure in the circuit as well as negative pressure at the prepump site. When excessive negative pressure is detected at the prepump location, the Deltastream MDC console automatically decreases the rotational speed of the pump to offset the excessive negative pressure and sets off an alarm to alert the medical staff monitoring the circuit.All of these features make the Deltastream DP3 an appealing and viable option for use in ECLS circuits for a wide range of patients. LIMITATIONS The limitations of our current experiment include not comparing the Deltastream DP3 pump with other nonpulsatile ECLS pumps using the same cannula sizes and tubing length. We also did not vary the length or diameter of the tubing used for this experiment, which could impact the circuit performance in terms of hemodynamic energy, flow, and pressure. Additionally, the observation that no backflow was produced is limited by our inability to reproduce arterial compliance in the pseudopatient. CONCLUSIONS In the neonatal model used for this experiment, the Deltastream DP3 pump demonstrated optimal flow and pressure waveforms while producing a physiologiArtif Organs, Vol. 38, No. 1, 2014
cal quality of pulsatile flow and hemodynamic energy with no evidence of backflow. Further studies should be conducted to determine whether the pulsatile flow produced by this pump can improve patient outcomes. Acknowledgments: Special thanks go to Dr. Jürgen O. Böhm and Andreas Spilker from Medos Medizintechnik AG, Stolberg, Germany, and Ivo Simundic and Dr. Georg Matheis from Novalung GmbH, Heilbronn, Germany, for lending the DP3 pump console and sending disposables for this study. REFERENCES 1. Extracorporeal Life Support Organization. Extracorporeal Life Support Registry Report International Summary. Ann Arbor, MI: ELSO, 2013. 2. Su XW, Guan Y, Barnes M, Clark JB, Myers JL, Ündar A. Improved cerebral oxygen saturation and blood flow pulsatility with pulsatile perfusion during pediatric cardiopulmonary bypass. Pediatr Res 2011;70:181–5. 3. Zhao J, Yang J, Liu J, et al. Effects of pulsatile and nonpulsatile perfusion on cerebral regional oxygen saturation and endothelin-1 in tetralogy of Fallot infants. Artif Organs 2011;35:E54–8. 4. Rogerson A, Guan Y, Kimatian SJ, et al. Transcranial Doppler ultrasonography: a reliable method of monitoring pulsatile flow during cardiopulmonary bypass in infants and young children. J Thorac Cardiovasc Surg 2010;139:e80–2. 5. Akçevin A, Alkan-Bozkaya T, Qiu F, Ündar A. Evaluation of perfusion modes on vital organ recovery and thyroid hormone homeostasis in pediatric patients undergoing cardiopulmonary bypass. Artif Organs 2010;34:879–84. 6. Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009;137:208–15. 7. Travis AR, Giridharan GA, Pantalos GM, et al. Vascular pulsatility in patients with a pulsatile or continuous flow ventricular assist device. J Thorac Cardiovasc Surg 2007;133:517– 24. 8. Ündar A. Myths and truths of pulsatile and non-pulsatile perfusion during acute and chronic cardiac support [Invited editorial]. Artif Organs 2004;28:439–43.
NOVEL DIAGONAL PUMP FOR NEONATAL ECLS 9. Baba A, Dobsak P, Saito I, et al. Microcirculation of the bulbar conjunctiva in the goat implanted with a total artificial heart: effects of pulsatile and nonpulsatile flow. ASAIO J 2004;50: 321–7. 10. Tiedge S, Optenhöfel J. First uses of a new diagonal pump in extracorporeal support systems for children and infants. Kardiotechnik 2011;20:72–6. In German. 11. Wang S, Kunselman AR, Ündar A. Novel pulsatile diagonal pump for pediatric extracorporeal life support system. Artif Organs 2013;37:37–47.
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12. Krawiec C, Wang S, Kunselman AR, Ündar A. Impact of pulsatile flow on hemodynamic energy in a Medos Deltastream DP3 pediatric extracorporeal life support system. Artif Organs 2014;38:19–27. 13. Shepard RB, Simpson DC, Sharp JF. Energy equivalent pressure. Arch Surg 1966;93:730–40. 14. Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. Hoboken, NJ: John Wiley & Sons, 2004.
Artif Organs, Vol. 38, No. 1, 2014
© 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation
Use of a Novel Diagonal Pump in an In Vitro Neonatal Pulsatile Extracorporeal Life Support Circuit *Alissa Evenson, *Shigang Wang, †Allen R. Kunselman, and *‡§Akif Ündar *Pediatric Cardiovascular Research Center, Penn State Hershey Children’s Hospital, Penn State Milton S. Hershey Medical Center, Department of Pediatrics, Penn State Hershey College of Medicine; †Department of Public Health Sciences, Penn State Hershey College of Medicine; ‡Department of Surgery, Penn State Milton S. Hershey Medical Center, Penn State Hershey College of Medicine, Hershey, PA; and §Department of Bioengineering, College of Engineering, Pennsylvania State University, University Park, PA, USA
Abstract: One approach with the potential to improve morbidity and mortality rates following extracorporeal life support (ECLS) is the use of pulsatile perfusion. Currently, no ECLS pumps used in the United States can produce pulsatile flow. The objective of this experiment is to evaluate a novel diagonal pump used in Europe to determine whether it provides physiological pulsatility in a neonatal model. The ECLS circuit consisted of a Medos Deltastream DP3 diagonal pump, a Hilite 800LT polymethylpentene diffusion membrane oxygenator, and arterial/venous tubing. A 300-mL pseudopatient was connected to the circuit using an 8Fr arterial cannula and a 10Fr venous cannula. A clamp maintained constant pressure entering the pseudopatient. Trials (64 total) were conducted in nonpulsatile and pulsatile modes at flow rates of 200 mL/ min to 800 mL/min. Flow and pressure data were collected using a custom-based data acquisition system. The
Deltastream DP3 pump was capable of producing an adequate quality of pulsatility. Pulsatile flow produced increased mean arterial pressure, energy equivalent pressure (EEP), and surplus hemodynamic energy (SHE) at all flow rates compared to nonpulsatile flow. Pressure drop across the cannula accounted for the majority of pressure loss in the circuit. The greatest loss of SHE and total hemodynamic energy occurred across the arterial cannula due to its small diameter. The Deltastream DP3 pump produced physiological pulsatile flow without backflow while providing EEP and SHE to our neonatal pseudopatient. Further experiments are necessary to determine the impact of this pulsatile pump in an in vivo model prior to clinical use. Key Words: Extracorporeal life support— Diagonal pump—Pediatrics—Pulsatile—Surplus hemodynamic energy.
Extracorporeal life support (ECLS) is a life-saving technique that is used to provide support for patients with cardiac or respiratory disease. Over the past decade, there have been multiple technological advances in the components used during ECLS. Improvements have been made in the material used for the oxygenator, advancing from silicone membranes to microporous hollow-fiber membranes to the diffusion membranes that are the gold standard of oxygenators today. Additional improvements have been made to increase the efficiency of gas transfer across the membrane. Advances in the pumps used in
the ECLS circuit have resulted in lower priming volumes and higher outputs for neonatal, pediatric, and adult patients. There have also been advances in the coating technique used in all circuit components to improve biocompatibility during long-term ECLS. These and other technological advances have resulted in improved survival rates in patients undergoing ECLS. However, morbidity and mortality rates following ECLS remain unacceptably high, particularly in neonatal patients undergoing ECLS due to cardiac failure. According to the January 2013 Registry Report of the Extracorporeal Life Support Organization, 4987 neonatal patients (0–30 days old) were placed on ECLS from 1986 to 2012 due to cardiac failure at the 200 centers that submitted data for this report (1). Among this particular subset of patients, there was a staggering 60% mortality rate. Over the same period
doi:10.1111/aor.12240 Received August 2013; revised September 2013. Address correspondence and reprint requests to Dr. Akif Ündar, Penn State Hershey College of Medicine, Department of Pediatrics—H085, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850, USA. E-mail: [email protected]
Artificial Organs 2014, 38(1):E1–E9
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of time, 26 205 neonatal patients were placed on ECLS due to respiratory failure, with a mortality rate of 25%. Additionally, patients undergoing ECLS remain at risk for a variety of morbidities, including hemorrhage; injury to vital organs, such as the heart, brain, and kidneys; and mechanical complications in the ECLS circuit components. The high mortality rates due to ECLS in neonatal patients in addition to the risk of various morbidities are evidence that further research is necessary to identify novel approaches and devices to improve patient outcomes and limit the loss of life following a procedure that is being performed more frequently. An alternative approach that has the potential to improve patient outcomes is the utilization of pumps that are capable of producing pulsatile flow. Multiple studies in patients undergoing cardiopulmonary bypass (CPB) procedures or receiving support from ventricular assist devices using pulsatile flow have demonstrated increased blood flow and oxygenation to the brain (2–4), increased urine output (4,5), decreased cardiac inotropic support (5), less gastrointestinal bleeding (6), and better vital organ perfusion (6–9), all of which indicate the decreased potential for the types of complications that are most commonly reported in neonatal patients (1). Despite this evidence demonstrating better patient outcomes when pulsatile flow is used, none of the pumps currently used for ECLS in the United States are capable of producing pulsatile flow without backflow. The Medos Deltastream DP3 diagonal pump, which is used for ECLS procedures in Europe (10) but is not yet approved for use in the United States, has been shown to produce an adequate quality of pulsatility in a pediatric ECLS model in previous research conducted in our laboratory (11). The aim of our current experiment was to evaluate this novel diagonal pump in nonpulsatile and pulsatile mode to determine the effect of pulsatility on flow, pressure, and hemodynamic energy in a neonatal circuit.
capacity soft bag was connected as a pseudopatient to the ECLS circuit using an 8Fr Bio-Medicus pediatric arterial cannula and a 10Fr Bio-Medicus pediatric venous cannula (Medtronic, Minneapolis, MN, USA). A Hoffman clamp was positioned at the post-arterial cannula site to maintain a constant pressure entering the pseudopatient. An adjustable-height open-air bag served as the venous reservoir. The circuit was primed using lactated Ringer’s solution for deairing followed by heparinized packed human red blood cells. The hematocrit of the priming solution was 35%. The total priming volume of the circuit was approximately 440 mL.
MATERIALS AND METHODS
Data acquisition The flow probe outputs and pressure transducers were connected to a signal conditioning unit (SC2345, National Instruments, Austin, TX, USA) and a data acquisition device (NI USB-6521, National Instruments). Using a universal serial bus port connection, the digital signals from the data acquisition device were transferred to a computer equipped with a customized user interface based on Labview 7.1 software for Windows (National Instruments). Realtime data were recorded at 1000 samples per second. A 20-s segment of pressure and flow data was recorded at all sites and converted into hemodynamic
Experimental setup The neonatal ECLS circuit used for this experiment consisted of a Medos Deltastream DP3 diagonal pump (Medos Medizintechnik AG, Stolberg, Germany), a Medos Hilite 800LT polymethylpentene diffusion membrane oxygenator, 3 ft of tubing (1/4 in. inner diameter [ID] × 1/16-in. wall) for both arterial and venous lines, 20 cm of tubing (1/4 in. ID) connecting the pump to the oxygenator, and a Maquet HCU-30 heater–cooler unit (Maquet Cardiopulmonary AG, Hirrlingen, Germany; Fig. 1). A 300-mLArtif Organs, Vol. 38, No. 1, 2014
Pulsatile mode settings The pump driver was connected to the Medos Deltastream MDC console, which was used to control pulsatility settings. The Deltastream DP3 was used in pulsatile mode with a frequency of 90 bpm, systolic/diastolic ratio of 50%, and rotational speed differential of 1500 rpm. Previous research conducted in this laboratory has indicated these settings are capable of producing a physiological quality of pulsatility (11,12). Experimental design The experiments were conducted at flow rates of 200 mL/min to 800 mL/min, in increments of 200 mL/ min. Trials were conducted in both nonpulsatile and pulsatile modes at each flow rate. The mean arterial pressure (MAP) entering the pseudopatient was maintained at 50 mm Hg during all trials, and blood temperature was maintained at 36°C. Venous pressure was kept at 5 mm Hg. Two ultrasound flow probes (Transonic Systems, Ithaca, NY, USA) were placed at the preoxygenator and pre-arterial cannula sites. Five disposable pressure transducers (Maxxim Medical, Ithaca, NY, USA) were placed at the preoxygenator, postoxygenator, pre-arterial cannula, post-arterial cannula, and pre-venous cannula sites.
NOVEL DIAGONAL PUMP FOR NEONATAL ECLS
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FIG. 1. The experimental ECLS circuit is shown.
energy using the equations below. Data were obtained eight times for each unique combination of flow rate and pulsatility mode, yielding a total of 64 trials.
SHE ( ergs cm 3 ) = 1332 × ( EEP — MAP ) THE is equivalent to EEP and is calculated using the following equation:
THE ( ergs cm 3 ) = 1332 × EEP Calculating hemodynamic energy The hemodynamic energy generated during each trial was quantified using related mathematical formulas. Energy equivalent pressure (EEP) was calculated using Shepard’s formula (13), which uses flow (f) and pressure (p) data collected via the Labview 7.1 software over a time interval (t1 to t2) to quantify the amount of energy produced during each trial, measured in mm Hg. The equation for EEP is as follows: t2
EEP ( mm Hg ) = ∫ fpΔt t1
Surplus hemodynamic energy (SHE) and total hemodynamic energy (THE) were also calculated. SHE is the difference between EEP and MAP, found using the equation below:
The units for SHE and THE are ergs/cm3. The constant 1332 converts pressure from units of mm Hg to dynes/cm2 (1 mm Hg = 1332 dynes/cm2; 1 dyne/cm2 = 1 erg/cm3). Calculating pressure drops The pressure drops across the oxygenator, cannula, and total circuit were calculated using the following equations, where p is the pressure at the location denoted by the subscript description:
Oxygenator pressure drop (mm Hg ) = ppreoxygenator − ppostoxygenator Arterial cannula pressure drop ( mm Hg ) = ppre-arterial cannula − ppost-arterial cannula Artif Organs, Vol. 38, No. 1, 2014
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Circuit pressure drop ( mm Hg ) = ppreoxygenator − ppost-arterial cannula Statistical analysis Analysis of variance (ANOVA) models were fit to the continuous outcomes (e.g., pressure drops and percentage energy losses) to compare flow rate (200, 400, 600, 800 mL/min) and mode (nonpulsatile and pulsatile). A linear mixed-effects model was fit to the continuous outcomes (e.g., MAP, EEP, SHE, and THE) to compare the flow rate, mode, and location (e.g., preoxygenator, precannula, and postcannula) (14). The linear mixed-effects model is an extension of linear regression that accounts for the withinsubject variability inherent in repeated-measures designs. In this study, the repeated factor is the location. For each outcome, P values were adjusted for multiple comparisons testing using the Tukey– Kramer procedure. All hypothesis tests were twosided, and all analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, NC, USA). RESULTS Flow rate During this experiment, the observed rotational speed of the Deltastream DP3 pump was recorded in nonpulsatile mode at each flow rate. When the pump was switched to pulsatile mode, the rotational speed increased from the nonpulsatile mode observation, even though no other adjustments were made to the pump or circuit. In order to ensure consistency of data measurements, the rotational speed in pulsatile mode was adjusted to match the rotational speed in nonpulsatile mode. This resulted in average observed flow rates that varied by less than 1% across all trials (Table 1). Pulsatile mode produced higher observed
TABLE 1. Real flow rates and rotational speeds (rpm) in nonpulsatile (NP) and pulsatile (P) modes Group
Mode
200 mL/min
NP P NP P NP P NP P
400 mL/min 600 mL/min 800 mL/min
Rotational speed (rpm)*
Flow rate (mL/min)
3700 3700 4750 4750 5850 5850 7000 7000
214.3 ± 0.7 213.7 ± 2.2 413.3 ± 0.5 413.5 ± 1.2 606.1 ± 0.6 610.5 ± 1.4 804.4 ± 0.2 800.4 ± 1.4
*Pulsatile rotational speed was adjusted to match the observed nonpulsatile rotational speed.
flow rates at the same rotational speed differential in all groups except the 800 mL/min group. Additionally, there was no backflow noted in pulsatile mode at any of the flow rates. Figure 2 presents flow waveforms at 400 mL/min and 800 mL/min in both pulsatile and nonpulsatile modes. Pressure In both nonpulsatile and pulsatile modes, MAP increased as the flow rate increased. Additionally, MAP in pulsatile mode was significantly higher than in nonpulsatile mode (P < 0.001). Figure 2 presents pressure waveforms at 400 mL/min and 800 mL/min in both pulsatile and nonpulsatile modes. Nonpulsatile mode did not produce any EEP at any of the flow rates. EEP was produced at all flow rates in pulsatile mode. The greatest percentage increase of EEP in excess of MAP occurred at 200 mL/min flow rate at the preoxygenator site (24.0%). The percentage of EEP produced decreased as flow rate increased from 200 mL/min to 800 mL/ min. Table 2 contains a summary of MAP and EEP results.
TABLE 2. MAP and EEP (mm Hg) with percent increase at preoxygenator, pre-arterial cannula, and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) modes Preoxygenator Group
Mode
200 mL/min
NP P NP P NP P NP P
400 mL/min 600 mL/min 800 mL/min
Pre-arterial cannula
Post-arterial cannula
MAP
EEP (% increase)
MAP
EEP (% increase)
MAP
EEP (% increase)
85.4 ± 0.0 89.3 ± 1.3* 127.1 ± 0.2 134.0 ± 1.0* 184.0 ± 0.3 194.7 ± 0.7* 255.6 ± 0.2 266.1 ± 0.6*
85.4 ± 0.0 (0.0) 110.7 ± 1.7 (24.0)* 127.1 ± 0.2 (0.0) 158.2 ± 1.6 (18.0)* 184.0 ± 0.3 (0.0) 224.4 ± 0.7 (15.2)* 255.6 ± 0.2 (0.0) 297.5 ± 0.5 (11.8)*
78.9 ± 0.1 82.9 ± 1.1* 111.9 ± 0.2 118.6 ± 1.0* 159.9 ± 0.3 170.1 ± 0.6* 220.7 ± 0.2 231.2 ± 0.5*
78.9 ± 0.1 (0.0) 95.8 ± 1.4 (15.5)* 111.9 ± 0.2 (0.0) 134.1 ± 1.3 (13.1)* 159.9 ± 0.3 (0.0) 189.0 ± 0.6 (11.1)* 220.7 ± 0.2 (0.0) 250.9 ± 0.5 (8.5)*
50.6 ± 0.1 53.3 ± 0.8* 50.0 ± 0.1 53.1 ± 0.6* 50.5 ± 0.2 53.9 ± 0.2* 50.1 ± 0.1 51.7 ± 0.2*
50.6 ± 0.1 (0.0) 62.6 ± 1.0 (17.4)* 50.0 ± 0.1 (0.0) 60.6 ± 0.8 (14.1)* 50.5 ± 0.2 (0.0) 60.3 ± 0.2 (11.7)* 50.1 ± 0.1 (0.0) 56.0 ± 0.1 (8.4)*
Values in parentheses are EEP percentage increase compared to MAP, calculated using the following equation: [(EEP − MAP)/ MAP] × 100. *P < 0.001 versus NP. Artif Organs, Vol. 38, No. 1, 2014
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FIG. 2. Flow and pressure waveforms at 400 mL/min and 800 mL/min in pulsatile (P) and nonpulsatile (NP) mode.
Pressure drop Pressure drop across the oxygenator, cannula, and circuit increased steadily as flow rate increased from 200 mL/min to 800 mL/min (Table 3). The cannula pressure drop accounted for more than 80% of the total pressure drop in the circuit at all flow rates. Pressure drop across the cannula was significantly higher in pulsatile mode than nonpulsatile mode by an average of 5.4% (P < 0.001). Hemodynamic energy Negligible amounts of SHE (80% of the pressure loss in the circuit due to the small size of the cannula, with negligible pressure loss due to the tubing. Additionally, a lower percentage of SHE was delivered to the patient at higher flow rates because of the increased pressure drop across the arterial cannula. The small diameter of the arterial cannula also resulted in increased loss of SHE across the cannula at higher flow rates. The amount of THE delivered to the patient remained relatively consistent because the postcannula pres-
sure was maintained at 50 mm Hg across all trials. However, the percentage of THE lost in the circuit increased as flow rate increased to 800 mL/min, with the majority of THE loss occurring across the arterial cannula. If central cannulation continues from CPB, a larger size arterial cannula (10Fr instead of 8Fr) allows more hemodynamic energy to be delivered to the patient with a significantly improved quality of pulsatility. In addition to the ability to produce an adequate quality of pulsatility and hemodynamic energy in our neonatal model, the Deltastream DP3 pump features a low priming volume (16 mL) and a wide range of flow rates (0–8 L/min), while the Deltastream MDC console includes valuable safety mechanisms, such as a flow sensor with an integrated bubble detector, backflow detection, and temperature sensors. The
FIG. 3. Surplus hemodynamic energy at the preoxygenator and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) mode at varying flow rates.
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FIG. 4. Total hemodynamic energy at the preoxygenator and post-arterial cannula sites in nonpulsatile (NP) and pulsatile (P) mode at varying flow rates.
Deltastream DP3 pump also has the ability to function in zero flow mode, which allows blood flow from the pump to be interrupted without risking unintentional backflow. Using the zero flow function, medical professionals can evaluate the patient’s native heart function by echocardiogram without having to crossclamp the circuit. Additionally, there are pressure sensors that can detect positive pressure in the circuit as well as negative pressure at the prepump site. When excessive negative pressure is detected at the prepump location, the Deltastream MDC console automatically decreases the rotational speed of the pump to offset the excessive negative pressure and sets off an alarm to alert the medical staff monitoring the circuit.All of these features make the Deltastream DP3 an appealing and viable option for use in ECLS circuits for a wide range of patients. LIMITATIONS The limitations of our current experiment include not comparing the Deltastream DP3 pump with other nonpulsatile ECLS pumps using the same cannula sizes and tubing length. We also did not vary the length or diameter of the tubing used for this experiment, which could impact the circuit performance in terms of hemodynamic energy, flow, and pressure. Additionally, the observation that no backflow was produced is limited by our inability to reproduce arterial compliance in the pseudopatient. CONCLUSIONS In the neonatal model used for this experiment, the Deltastream DP3 pump demonstrated optimal flow and pressure waveforms while producing a physiologiArtif Organs, Vol. 38, No. 1, 2014
cal quality of pulsatile flow and hemodynamic energy with no evidence of backflow. Further studies should be conducted to determine whether the pulsatile flow produced by this pump can improve patient outcomes. Acknowledgments: Special thanks go to Dr. Jürgen O. Böhm and Andreas Spilker from Medos Medizintechnik AG, Stolberg, Germany, and Ivo Simundic and Dr. Georg Matheis from Novalung GmbH, Heilbronn, Germany, for lending the DP3 pump console and sending disposables for this study. REFERENCES 1. Extracorporeal Life Support Organization. Extracorporeal Life Support Registry Report International Summary. Ann Arbor, MI: ELSO, 2013. 2. Su XW, Guan Y, Barnes M, Clark JB, Myers JL, Ündar A. Improved cerebral oxygen saturation and blood flow pulsatility with pulsatile perfusion during pediatric cardiopulmonary bypass. Pediatr Res 2011;70:181–5. 3. Zhao J, Yang J, Liu J, et al. Effects of pulsatile and nonpulsatile perfusion on cerebral regional oxygen saturation and endothelin-1 in tetralogy of Fallot infants. Artif Organs 2011;35:E54–8. 4. Rogerson A, Guan Y, Kimatian SJ, et al. Transcranial Doppler ultrasonography: a reliable method of monitoring pulsatile flow during cardiopulmonary bypass in infants and young children. J Thorac Cardiovasc Surg 2010;139:e80–2. 5. Akçevin A, Alkan-Bozkaya T, Qiu F, Ündar A. Evaluation of perfusion modes on vital organ recovery and thyroid hormone homeostasis in pediatric patients undergoing cardiopulmonary bypass. Artif Organs 2010;34:879–84. 6. Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009;137:208–15. 7. Travis AR, Giridharan GA, Pantalos GM, et al. Vascular pulsatility in patients with a pulsatile or continuous flow ventricular assist device. J Thorac Cardiovasc Surg 2007;133:517– 24. 8. Ündar A. Myths and truths of pulsatile and non-pulsatile perfusion during acute and chronic cardiac support [Invited editorial]. Artif Organs 2004;28:439–43.
NOVEL DIAGONAL PUMP FOR NEONATAL ECLS 9. Baba A, Dobsak P, Saito I, et al. Microcirculation of the bulbar conjunctiva in the goat implanted with a total artificial heart: effects of pulsatile and nonpulsatile flow. ASAIO J 2004;50: 321–7. 10. Tiedge S, Optenhöfel J. First uses of a new diagonal pump in extracorporeal support systems for children and infants. Kardiotechnik 2011;20:72–6. In German. 11. Wang S, Kunselman AR, Ündar A. Novel pulsatile diagonal pump for pediatric extracorporeal life support system. Artif Organs 2013;37:37–47.
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12. Krawiec C, Wang S, Kunselman AR, Ündar A. Impact of pulsatile flow on hemodynamic energy in a Medos Deltastream DP3 pediatric extracorporeal life support system. Artif Organs 2014;38:19–27. 13. Shepard RB, Simpson DC, Sharp JF. Energy equivalent pressure. Arch Surg 1966;93:730–40. 14. Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. Hoboken, NJ: John Wiley & Sons, 2004.
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