HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Leonard A. R. Golding Yoshio Ootaki Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doi, K. Articles by Fukamachi, K. Search for Related Content PubMed PubMed Citation Articles by Doi, K. Articles by Fukamachi, K. Related Collections Mechanical Circulatory Assistance

Ann Thorac Surg 2004;77:2103-2110
© 2004 The Society of Thoracic Surgeons

---

Original article: cardiovascular

Preclinical readiness testing of the arrow international CorAide left ventricular assist system

^a Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Accepted for publication July 8, 2003.

^* Address reprint requests to Dr Golding, Department of Biomedical Engineering, ND20, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH, USA 44195
e-mail: golding{at}bme.ri.ccf.org

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
BACKGROUND: Left ventricular assist system technologies are currently being developed as effective alternatives to cardiac transplantation. In this study, in vivo testing of the Arrow International CorAide left ventricular assist system was conducted to determine its preclinical readiness based on demonstrated system performance and biocompatibility.

METHODS: Arrow International CorAide blood pump assemblies were implanted in 7 calves for 1-month (n = 4) and 3-month (n = 3) durations without the use of chronic anticoagulation therapy. Hemodynamic performance, physiologic pump control, end-organ function, and device-related adverse events were evaluated during the studies and at autopsy.

RESULTS: Hemodynamics were stable in all cases with a mean pump flow of 4.1 ± 0.8 L/min and a mean arterial pressure of 101 ± 4 mm Hg. In all calves, renal and hepatic function remained normal with no incidence of hemolysis, infection, bleeding, or embolism. The CorAide physiologic control algorithm demonstrated appropriate pump speed and flow adjustments in response to physiologically induced inputs, and the system's external electronic components demonstrated no hardware or software malfunction. All 7 cases were sacrificed electively. Autopsy revealed no sign of end-organ disease on gross and histologic examinations, and no device failure, malfunction, or mechanical wear of the pump blood-bearing surfaces was found.

CONCLUSIONS: The Arrow CorAide left ventricular assist system demonstrated effective pump performance and good biocompatibility with no incidence of device-related adverse events. This system has completed its preclinical readiness testing and is approved for clinical trials in Europe in 2003.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Mechanical circulatory support by implantable left ventricular assist devices (LVADs) has successfully demonstrated its ability to treat the failing circulation and end-organ dysfunction of patients with end-stage heart failure and an increased survival rate to cardiac transplantation [1–6]. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial has reported superior benefit from LVAD support both for survival rate and for quality of life for the patients with end-stage heart failure who were ineligible for transplantation, when compared with medical management [7]. These successful results and the persistent deficit of donor organs have encouraged LVAD applications to be extended toward long-term use as a permanent implant (destination therapy), which is the ultimate goal of LVAD technology. However, there remain several critical problems associated with LVAD implantation, such as infection, bleeding, and thromboembolism, as well as the durability of the devices themselves [1, 2, 6–8]. To achieve the goal of long-term successful LVAD use, further improvement of the LVAD technology is needed so that device-related adverse events can be eliminated.

The Arrow International CorAide left ventricular assist system (LVAS: LVD-4000, Arrow International, Inc, Reading, PA) was originally designed and developed at the Cleveland Clinic Foundation [9, 10]. The system consists of an implantable blood pump and an external portable electronic controller. The CorAide pump is a third-generation, implantable, centrifugal pump in which the only moving component (the rotating assembly) is magnetically and hydrodynamically suspended without mechanical contact or wear, or blood stagnation within the pump. With this innovative bearing technology, the CorAide pump has the potential to be nonthrombogenic and durable for prolonged use. After freezing the blood pump design, the CorAide LVAS demonstrated effective pump performance and excellent biocompatibility in its initial 18 in vivo chronic studies [11–13]. These additional seven chronic in vivo studies were conducted with Arrow-fabricated systems for preclinical readiness testing of the Arrow CorAide LVAS. The results presented in this paper were submitted to European medical and regulatory bodies and gained approval to begin initial clinical trials.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Arrow CorAide system description
The CorAide pump is a centrifugal pump with a weight of 293 g and displacement volume of 84 mL. It consists of only three subassemblies: the rotating assembly, the stator assembly, and volute housing assembly. A detailed description was reported previously [9–13]. The most important innovative technology of this blood pump is the blood-lubricated fluid film bearing with ascending blood flow in the space between the completely suspended rotating and stationary stator assemblies. This feature results in no mechanical contact or wear and the prevention of any blood stagnation within the pump, contributing to the nonthrombogenicity and durability of the pump (Fig 1).

View larger version (26K): [in this window] [in a new window]   Fig 1. Schematic of blood-lubricated fluid film bearing of the CorAide pump. The secondary flow path washes the bearing surfaces and supports the rotating assembly, preventing mechanical contact or wear.

View larger version (24K): [in this window] [in a new window]   Fig 2. The Arrow CorAide left ventricular assist system implantable components.

View larger version (88K): [in this window] [in a new window]   Fig 3. The Arrow CorAide left ventricular assist system external components.

In vivo experiments
From April 2002 through January 2003, the Arrow CorAide pump was implanted in a total of 10 calves. There were 3 early deaths (within 72 hours) in this series, 1 from nitroprusside toxicity, 1 from postoperative pulmonary artery rupture of the cannulation site, and the third from inlet cannula obstruction. The remaining 7 animals (weight, 101 ± 7 kg) were evaluated for durations of either 1 month or 3 months for preclinical readiness testing and are the basis of this report. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals," prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996.

Surgical procedures
To simulate the clinical situation, the inlet cannula of the CorAide pump was inserted into the left ventricle (LV) with cardiopulmonary bypass support in all 7 cases in this report, although it was performed without cardiopulmonary bypass in the previous cases [11–13]. Animals were anesthetized with inhalational halothane or isoflurane, and ventilated through an endotracheal tube. Through a left thoracotomy, an outflow graft was anastomosed to the descending aorta in an end-to-side fashion. After systemic heparinization (300 U/kg), cardiopulmonary bypass was established by inserting cannulas into the left carotid artery and the right ventricle through the pulmonary artery, respectively. The outflow graft and inlet cannula were connected to the CorAide pump. With the beating heart emptied under the cardiopulmonary bypass support, a ventriculotomy for the inlet cannula was made at the LV apex with a core cutter. An apical cuff, which has a patented clamping system to secure the inlet cannula, was sutured to the ventriculotomy margins. The inlet cannula was inserted into the LV through the apical cuff and secured using the apical cuff clamp. After an ultrasonic perivascular flow probe (Transonic Systems, Inc, Ithaca, NY) was placed around the outflow graft to monitor the pump flow and the cardiopulmonary bypass discontinued, the CorAide LVAS was started. The inlet cannula position in the LV was evaluated with epicardial echocardiography, and the blood pump was positioned in the left chest so that the inlet cannula orifices were widely patent without obstruction by the ventricular septum. A pump motor cable, a flow probe cable, a venous infusion line, and an arterial pressure line were exteriorized, and the monitoring lines were maintained throughout the study duration in all cases.

Postoperative animal care and physiologic monitoring
After surgery, animals were transferred to a chronic care facility and maintained in cages with continuous physiologic monitoring. Antibiotics were given for the first postoperative 7 days. A continuous intravenous drip of heparin was administrated in 4 of 7 cases for only 1 to 3 postoperative days as an early postoperative anticoagulation therapy with activated clotting times maintained at 1.2 times baseline. In the other 3 cases, the pump was run without any anticoagulation therapy for study durations of 3 months (Table 1). Serial blood samples were collected to detect signs of infection, bleeding, coagulopathy, renal or hepatic dysfunction, or hemolysis during the study duration.

Autopsy
At the completion of each study, the animal was electively sacrificed after full heparinization (500 U/kg bolus injection), and a thorough autopsy was performed. The main focuses were device infection and thrombus formation, signs of systemic infection, bleeding, and thromboembolism to the major organs. Macroscopic examination included (1) opening all major branches of the arterial system to the common iliac artery, (2) gross examination followed by 1.5-cm sectioning of the lungs, kidneys, liver, spleen, adrenals, and pancreas, (3) gross examination of the digestive tract through its length for signs of hemorrhage or infarction, and (4) routine histologic evaluation of specimens from the kidney, liver, lungs, spleen, and tissue-contacting surfaces at the pump body, subcutaneous pump drive cable, and inlet and outlet cannulas. Any organ disease or device deposition noted was further investigated by histologic evaluation.

Data analysis
Data were expressed as mean ± standard deviation. A paired Student's t test was used for statistical analyses, and p less than 0.05 was considered to be statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Postoperative course and outcomes
All 7 animals recovered from the surgery uneventfully, were extubated on the day of the surgery with stable hemodynamics, and were terminated electively after their scheduled durations (Table 1).

Hemodynamics and CorAide pump performance
All calves remained alert, active, and hemodynamically stable after recovery from surgery with no incidence of pump performance malfunction or failure. CorAide pump support averaged 4.8 and 5.4 L/min in cases 3 and 6 and was lower (3.3 to 4.4 L/min) in the remaining cases (Table 1) because of partial obstruction of the inlet cannula main orifice by the ventricular septal wall as observed at autopsy. Inlet cannula contact with the septal wall was a result of our evaluation of the human pump cannula configuration in the normal healthy calf animal model with a thick LV wall and relatively narrow LV chamber. The pump flow was pulsatile and synchronized with the cardiac cycle with an average maximum and minimum flow during ventricular systole and diastole of 10.1 and –0.2 L/min, respectively, for all cases. Short periods (2 to 3 days) of bradycardia (heart rate 45 to 65 beats/min) were a consistent finding in all cases except case 5. The bradycardia appeared to be a physiologic adaptation to chronic LVAD support, developing gradually after the calves had recovered from surgery and reached a stable hemodynamic state. Although presenting no hemodynamic complications, the bradycardia was treated with atrial pacing at 90 to 100 beats/min.

The Arrow CorAide external electronic subsystems (portable electronic module, power supply, system interface, and battery packs) powered, controlled, and monitored pump function without failure in all cases. The system was typically powered by the CorAide power supply unit with a single CorAide battery pack as back-up. The system was also routinely (56% of total implant days) powered by two CorAide battery packs for 4-hour duration to simulate portable operation. The low CorAide motor power requirement (4.6 W) demonstrated in this study resulted in system run times of 7.5 and 6.5 hours on two fully charged CorAide batteries in cases 1 and 3, respectively.

In all cases the system was initially controlled in a fixed-speed operating mode until the calves achieved a stable postoperative hemodynamic state and was then switched to automatic operating mode by the end of the first postoperative week. Eighty-six percent of the total duration of these studies was conducted under CorAide physiologic algorithm control of pump speed and flow. The CorAide "sensorless" physiologic monitoring system does not require implanted flow, electrocardiogram, or pressure sensors. Pump flow and pump differential pressure are calculated from pump motor power and speed. From case 6, Figure 4 shows the relationship between measured pump flow and calculated pump flow, and Figure 5 shows pump speed adjustments (2,600 to 2,800 rpm) made by the CorAide physiologic control algorithm to achieve targeted pump flows ranging from 4.0 to 7.0 L/min. The range of targeted pump flows and the allowable range of pump speed adjustment in automatic mode were programed specific to the physiologic condition and pump performance seen in each of the 7 cases.

View larger version (20K): [in this window] [in a new window]   Fig 4. The relationship between measured pump flow versus calculated pump flow in case 6.

View larger version (20K): [in this window] [in a new window]   Fig 5. The relationship between pump speed adjustments by automatic control algorithm versus postoperative day in case 6.

View larger version (17K): [in this window] [in a new window]   Fig 6. Changes in hemoglobin and hematocrit of the 7 cases. *p < 0.05 versus Pre. (Pre = preoperative day.)

View larger version (18K): [in this window] [in a new window]   Fig 7. Changes in platelet count of the 7 cases. *p < 0.05 versus Pre. (APTT = activated partial thromboplastin time; Pre = preoperative day.)

View larger version (16K): [in this window] [in a new window]   Fig 8. Changes in liver function versus time of the 7 cases. *p < 0.05 versus Pre. (ALT = alanine aminotransferase; AST = aspartate aminotransferase; Pre = preoperative day; T-Bil = total bilirubin.)

View larger version (10K): [in this window] [in a new window]   Fig 9. Changes in serum free hemoglobin of the 7 cases. *p < 0.05 versus Pre. The normal range of serum free Hb is 0 to 5.0 mg/dL. (Hb = hemoglobin; Pre = preoperative day.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The Arrow CorAide pump demonstrated satisfactory pump performance with stable hemodynamics, no end-organ dysfunction, and no adverse events. The CorAide external electronic subsystems provided reliable and effective power, control, and monitoring of pump function. The CorAide pump's low power consumption and high CorAide battery capacity demonstrated in this study will provide reliable and extended portable operation of the CorAide LVAS. The low energy requirement is also advantageous to the future conversion of the CorAide LVAS to a totally implantable system with a transcutaneous energy transmission system.

Although the CorAide pump is a continuous flow device, pump flow becomes pulsatile, synchronizing with the changing pressure gradient between the LV inlet cannulation site and the arterial pressures at the outlet anastomosis [11]. In this study, the blood pump demonstrated significant synchronous pulsatile pump flow as a result of the use of healthy calves with normal LV contractility. In the clinical cases with end-stage heart failure, the pulsatility of the CorAide pump flow would be diminished or possibly disappear because of the poor LV contractility (small pressure gradient between the LV and arterial pressures) of the patients. The effect of the long-term nonpulsatile circulation is still controversial [14, 15]. Even the effectiveness of synchronous versus asynchronous pulsatile pump flow is still debated, especially for the myocardial perfusion that is important for the purpose of bridge-to-recovery LVAD use [16].

Drive line infection is a frequent and major complication for LVAD patients, and it has been reported that infection was the most frequent cause of death [3, 7, 8]. A small pump surface area and a single small-diameter (4 mm) percutaneous cable of the Arrow CorAide LVAS provide several advantages against infection. This small blood pump will minimize the surgical invasion and compression of the surrounding tissues such as the skin and gastrointestinal system, which results in a rapid recovery from the surgery and a risk reduction of pocket bleeding, wound infection, and malnutrition [7]. The continuous flow pump design without valves, compliance chamber, or external vent tube also offers advantages over pulsatile LVAD in reducing the risk of infection. The incorporation of a transcutaneous energy transmission system in future Arrow CorAide LVAS designs will eliminate the risk of drive line infection and resulting pocket infection.

The CorAide noncontacting, blood-lubricated pump bearing design eliminates blood stagnation, mechanical wear, and heat generation, thus removing the need for anticoagulation therapy and its resulting bleeding complications. Because patients with end-stage heart failure tend to suffer from cachexia, liver dysfunction, or coagulopathy, postoperative anticoagulation therapy increases the risk of bleeding complication. It is reported that within 6 months after LVAD implantation, the frequency of bleeding complication was 42% [7]. Its small size and the elimination of anticoagulation therapy are clear, beneficial advantages of the Arrow CorAide LVAS against bleeding complications.

No bleeding complication or hemolysis were found in any of the 7 cases despite reductions in hemoglobin, hematocrit, and platelet counts. In this series of the study, platelet functions such as aggregation, adhesion, and secretion were not evaluated. The increase in microaggregation resulting in platelet consumption and the decrease in platelet life span after LVAD implantation were reported in the previous literature [17]. Furthermore, potential activation of coagulation pathway was also reported [18]. Although platelet count, activated partial thromboplastin time, and hemoglobin level stabilized during the postoperative course, interaction between the blood and blood-contacting surface of the CorAide LVAS might affect their values. Further evaluations of platelet function and coagulation system are needed to evaluate the biocompatibility of the Arrow CorAide LVAS.

Manufacturing surface defects were noted in 2 cases in this study, leading to minute biologic pump deposition. These defects have been eliminated by improved manufacturing process development and inspection procedures. Most importantly, there were no system failures or any sign of mechanical wear in the CorAide fluid film bearing during these studies and in the last 18 in vivo studies conducted at the Cleveland Clinic Foundation [11–13]. The bearing mechanism, a magnetically levitated rotating assembly riding on a blood-lubricated fluid film, has no contacting parts, providing a significant advantage for device durability and reliability. The in vitro device reliability testing also provides referential information for device durability [19]. A total of eight Arrow CorAide LVASs are currently undergoing in vitro device reliability testing.

In conclusion, the Arrow CorAide LVAS demonstrated effective pump performance, good biocompatibility, and nonthrombogenicity with no device-related adverse events in 7 chronic in vivo preclinical studies without chronic anticoagulation therapy. These results were incorporated into comprehensive submissions to national and local ethics committees. The submissions were compiled in accordance with EN540, which included sections describing the Arrow CorAide system, the in vitro and in vivo preclinical test results, the essential requirements checklist, and the clinical investigational plan. On review of the submissions, Arrow International, Incorporated was granted approval to initiate the clinical investigation of the Arrow CorAide LVAS in 2003 at select investigational centers in Europe. We believe that the Arrow CorAide LVAS will demonstrate good system performance and biocompatibility with a lower rate of adverse events in this initial clinical experience in Europe, and ultimately be implanted for permanent LVAD use as an alternative to cardiac transplantation.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported in part by contract N01-HV-58155, issued by the National Heart, Lung, and Blood Institute, National Institutes of Health, and Arrow International, Inc. We gratefully thank David J. Horvath, MSME, Ji-Feng Chen, BS, Stephen Benefit, AA, and Alexander L. Medvedev, PhD, for their invaluable help in this study.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Stevenson L.W., Kormos R.L., Bourge R.C., et al. Mechanical cardiac support 2000: current applications and future trial design. J Am Coll Cardiol 2001;37:340-370.[Free Full Text]
2. McCarthy P.M., Smedira N.O., Vargo R.L., et al. One hundred patients with the HeartMate left ventricular assist device: evolving concepts and technology. J Thorac Cardiovasc Surg 1998;115:904-912.[Abstract/Free Full Text]
3. Frazier O.H., Rose E.A., Oz M.C., et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg 2001;122:1186-1195.[Abstract/Free Full Text]
4. Khot U.N., Mishra M., Yamani M.H., et al. Severe renal dysfunction complicating cardiogenic shock is not a contraindication to mechanical support as a bridge to cardiac transplantation. J Am Coll Cardiol 2003;41:381-385.[Abstract/Free Full Text]
5. Portner P.M., Jansen P.G.M., Oyer P.E., Wheeldon D.R., Ramasamy N. Improved outcomes with an implantable left ventricular assist system: a multicenter study. Ann Thorac Surg 2001;71:205-209.[Abstract/Free Full Text]
6. El-Banayosy A., Arusoglu L., Kizner L., et al. Novacor left ventricular assist system versus HeartMate vented electric left ventricular assist system as a long-term mechanical circulatory support device in bridging patients: a prospective study. J Thorac Cardiovasc Surg 2000;119:581-587.[Abstract/Free Full Text]
7. Rose E.A., Gelijns A.C., Moskowitz A.J., et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435-1443.[Abstract/Free Full Text]
8. Navia J.L., McCarthy P.M., Hoercher K.J., Smedira N.G., Banbury M.K., Blackstone E.H. Do left ventricular assist device (LVAD) bridge-to-transplantation outcomes predict the results of permanent LVAD implantation?. Ann Thorac Surg 2002;74:2051-2063.[Abstract/Free Full Text]
9. Golding L.A.R., Smith W.A. Cleveland Clinic rotodynamic pump. Ann Thorac Surg 1996;61:457-462.[Abstract/Free Full Text]
10. Horvath D.J., Golding L.A.R., Massiello A., et al. The CorAide blood pump. Ann Thorac Surg 2001;71(Suppl):S191.[Free Full Text]
11. Ochiai Y., Golding L.A.R., Massiello A.L., et al. In vivo hemodynamic performance of the Cleveland Clinic CorAide blood pump in calves. Ann Thorac Surg 2001;72:747-752.[Abstract/Free Full Text]
12. Ochiai Y., Golding L.A.R., Massiello A.L., et al. Cleveland Clinic CorAide blood pump circulatory support without anticoagulation. ASAIO J 2002;48:249-252.[Medline]
13. Fukamachi K., Ochiai Y., Doi K., et al. Chronic evaluation of the Cleveland Clinic CorAide left ventricular assist system in calves. Artif Organs 2002;26:529-533.[Medline]
14. Ündar A., Masai T., Frazier O.H., Fraser C.D., Jr Pulsatile and nonpulsatile flows can be quantified in terms of energy equivalent pressure during cardiopulmonary bypass for direct comparisons. ASAIO J 2002;48:449-452.[Medline]
15. Saito S., Westaby S., Piggot D., et al. End-organ function during chronic nonpulsatile circulation. Ann Thorac Surg 2002;74:1080-1085.[Abstract/Free Full Text]
16. Kanamori Y., Simono T., Tanaka K., Yada I., Kusagawa M. Effect of left heart assist device for the heart: a comparative study of asynchronous pulsatile, synchronous pulsatile, and nonpulsatile left heart bypass. Artif Organs 1991;14:92-96.
17. Snyder T.A., Watach M.J., Litwak K.N., Wagner W.R. Platelet activation, aggregation, and life span in calves implanted with axial flow ventricular assist devices. Ann Thorac Surg 2002;73:1933-1938.[Abstract/Free Full Text]
18. Spanier T., Oz M., Levin H., et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112:1090-1097.[Abstract/Free Full Text]
19. Pasque M.K., Rogers J.G. Adverse events in the use of HeartMate vented electric and Novacor left ventricular assist devices: comparing apples and oranges [Editorial]. J Thorac Cardiovasc Surg 2002;124:1063-1067.[Free Full Text]

This article has been cited by other articles:

				F. Gazzoli, A. Alloni, F. Pagani, C. Pellegrini, A. Longobardi, D. Ricci, M. Rinaldi, and M. Vigano Arrow CorAide Left Ventricular Assist System: Initial Experience of the Cardio-Thoracic Surgery Center in Pavia Ann. Thorac. Surg., January 1, 2007; 83(1): 279 - 282. [Abstract] [Full Text] [PDF]

				S. Large Invited commentary Ann. Thorac. Surg., January 1, 2007; 83(1): 282 - 282. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Leonard A. R. Golding Yoshio Ootaki Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doi, K. Articles by Fukamachi, K. Search for Related Content PubMed PubMed Citation Articles by Doi, K. Articles by Fukamachi, K. Related Collections Mechanical Circulatory Assistance