臺灣博碩士論文加值系統

摘要
對末期心肌衰竭病患，當藥物仍無法維持其基本的血液循環時，或無法使用傳統的外科手術矯正時，只有等待心臟移植。然而，等待心臟移植前，如果再次發生急性心衰竭時，那就需要機械性輔助器系統。例如：主動脈氣球幫浦、心室輔助器、全人工心臟以及心肺體外循環系統─葉克膜體外維生系統等輔助方式，來拯救病患渡過難關到心臟移植。
目前的心室輔助器主要有隔膜型和旋轉型幫浦。隔膜式的心室輔助器體積龐大，控制系統與驅動系統的重量也對病人的行動造成很大不便；電子式離心型心室輔助器則具備了體積小、重量輕、攜帶方便、手術方式容易等優點，適合體型較纖細的東方人使用。
心室輔助器的流量控制，則可分為脈波輸出和連續輸出兩種；其中，隔膜型幫浦皆為脈波式流量控制，旋轉型幫浦則兼有之。根據現存文獻，採脈波式控制的旋轉型幫浦工作效能及目標物存活率普遍較差，因此在一般臨床應用上，仍以連續流量控制的旋轉型幫浦為主。然而在一般生物體內，血液皆經由心室以脈波的形式輸出，並透過循環系統提供維持生命所需的物質。因此，我們認為應存在一特殊的控制機制，可有效地提升脈波式心室輔助器的效能，並使實驗體之生理狀態達到最佳。
在本研究中，我們設計一可植入式葉輪離心型心室輔助器，並實際進行了動物實驗。在32頭小公牛長期存活實驗中，平均存活16.2±26.1天，其中超過30天的小公牛共有八頭，其存活時間從33天到148天。而實驗終止原因，百分之三十八為感染、多重器官衰竭最多；其次，百分之二十八為出血性休克，與手術以及術後照顧有關；第三，百分之十九為血栓形成機械故障。統計這八頭小公牛前二十天的每天血液之生化數據，其自由血色素維持在4.8±1.6 mg/dl左右，代表紅血球被破壞後釋放出自由血色素濃度不高，而其血色素維持8.4±1.6 mg/dl，血小板維持在4.50±0.84×105 /ul，紅血球數目在6.36±1.01×106 /ul的範圍內，代表此心室輔助器對血球的破壞不大，而且腎功能與肝功能都維持在正常範圍內。
由於離心型心室輔助器在轉速過低時會造成回流(backflow)，而轉速過高時則會有過度抽吸(suction)的現象。因此幫浦在實際應用中的血液動力參數，例如心電圖、血壓、血流量、幫浦電流和轉速之間的相關性研究就顯得相當重要；必須充分了解在心臟週期中幫浦的血液動力特性，才能發展出適當而有效率的控制方法。在動物實驗中，我們觀察到對應不同轉速時，心室輔助器的流量變化及與心電圖的時序關係，並定義出最適當的控制方式，希望進而改善實驗體存活情形。
本論文對於離心型左心室輔助器的設計與研製提供暫時的心臟輸血系統的功能，進行臨床性的動物實驗，生化物質與存活率的探討。特別是心臟週期性的心電圖與血流、血壓波形相關性的生理信號分析，對於心室輔助器的人體應用及控制模式，提供頗具意義的研究成果。

Abstract
Mechanical circulation support should be applied in end-staged heart failure patients when hemodynamic state could be maintained by catecholamine before heart transplantation. Mechanical circulatory support included intra-aortic balloon pumping, ventricular assist device, total artificial heart and extra-corporeal cardiopulmonary bypass.
The modern ventricular assist devices can be divided into two main groups - the displacement pumps and the rotary pumps. Between them, the size of the displacement pumps is large and the weight of the control system is also considerable; which together make it a great burden for the patient to move around. On the other hand, the rotary pump is small, light-weighted, portable and easy-of-operation, hence to be preferred for the Asian people.
There are two types of flow rate control for the ventricular assist devices, the pulsatile mode and continuous mode. In the displacement pumps, the pulsatile mode were used, while in the rotary pumps, both modes were implemented. According to the literatures, the rotary pumps using pulsatile mode control were less efficient; besides, the lifespan of the targets was often shorter. Therefore, the continuous mode rotary pumps are still the mainstream in modern clinical applications. However, in most animals’ circulation system, the blood is pulsatile exported from the ventricle, supplies materials the body needs, and work quite efficiently. On this ground, we assumed the existence of a special control mechanism, which can greatly improve the efficiency of the ventricular assist device under pulsatile mode, and make the target in better physiological condition.
In vivo study, a centrifugal rotary left ventricular assist device which developed in National Taiwan University were implanted in 8 calves, which survived more than one month. The mean survival rate was 75± 42 days. The terminations of experiments were mainly due to infection. The average daily free hemoglobulin, platelet and red cell count were 4.8±1.6 mg/dl, 8.4±1.6 mg/dl, 4.50±0.84•105 /μl; and 6.36± 1.01•106 /μl. These indicated less hemolytic damage by pump.
For the rotary pump, the rotation rate should be carefully controlled. When the rate is low, backflow may happen; on the other hand, suction effect occurs at high rotation rate. Hence, parameters such as cardiogram, blood pressure and blood flux should be monitored, and the analysis on the relationship between pump current and rotational rate must be taken. Only when the pump and blood dynamics characteristics are well known, the appropriate and efficient control can be achieved. In the animal experiments, we varied the rotational rate and observed the time-sequential relationship between the ventricular assist device flux and the cardiograph, defined an optimal control method and hope to improve the physiological status of the targets.
In this research, the centrifugal left ventricular assist device was designed and manufactured. It was used to support temporal blood pumping function on experimental targets, and the study of clinical animal experiments, biochemical materials and survival condition were also carried out. The periodic cardiograph, blood stream and blood pressure waveform were analyzed and a meaningful indicator was obtained. The indicator provided valuable results for the control mode of the centrifugal left ventricular assist device, and make possible further applications on human.

Cover
Contents
Chapter 1 Introduction
1.1 Background review
1.2 Optimal control of the rotory centrifugal pum
1.3 Objective
1.4 Organization of the dissertation
Chapter 2 Development of Rotary Centrifugal Blood Pum
2.1 Design concepts
2.2 Streamlined surfaces of impeller
2.3 Major components of T-LVAD
2.4 Electric magnetic coupling driven mode
2.5 Anticoagulation
2.6 Surgical procedure
Chapter 3 In Vitro and In Vitro Study
3.1 In vitro study for hemolysis
3.2 In vivo study for hemolysis, hepatic and renal function
3.3 Performance curve
3.4 Acute physiologic study of Taita No.1 impeller pum
Chapter 4 Optimal Control of T-LVAD
4.1 Physiological signal collection system
4.2 Methodology of control system
4.3 Results
4.4 A Pump control index for reducing suction and backflow effect
Chapter 5 Chronic study
5.1 Long-term survival animal experiments of T-LVAD
5.2 Materials and methods
5.3 Results
5.4 Discussions
Chapter 6 Conclusions and Suggestions for Future Study
References

References:
1.T. Akutsu, and W. J. Kolff, “Permanent substitutes for valves and hearts”, Trans. Am. Soc. Artf. Intern. Organs 4, pp 230-235, 1958.
2.D. Liotta D. A. Cooley, M. E. DeBakey, M. Urquia, and L. Feldman, “Prolonged partial left ventricular bypass by means of an intra thoracic pump implanted in left chest”, Trans. Am. Soc. Artf. Intern. Organs 8, pp 90-99, 1962.
3.D. A. Cooley, D. Liotta, G. L. Hallman, R. D. Bloodwell, R. D. Leachman, and J.D. Milam, “Orthotopic cardiac prothesis for two-staged cardiac replacement”, Am. J. Cardiol. 24, pp 724-730, 1969.
4.T. Murakmi, L.R. Golding, G. Jacobs, and S. Takatani, “Nonpulsatile biventricular bypass using centrifugal blood pumps”, Jap. Soc. Artif. Organs 8, pp 636-639, 1979.
5.L. R. Golding, G. Jacobs, T. Murakami, S. Takasani, F. Valdes, H. Harasaki, and Y. Nose, “Chronic nonpulsatile blood flow in an alive, awake animal 34-day survival”, Trans. Am. Soc. Artif. Intern. Organs 26, pp 438-443, 1980.
6.V. L. Poirer, “Worldwide experience with the TCI HeartMate system: Issues and future perspective”, Thorac Cardiovasc Surg. 47 (suppl), pp 316-320, 1994.
7.S. Murali, “Mechenical circulatory support with Novacor LVAS: Worldwide clinical results”, Thorac Cardiovasc Srug. 47(suppl), pp 321-325, 1999.
8.R.C. Robbins, C.W. Barlow, P.E. Oyer, S.A. Hunt, J.L. Miller, B.A. Teitz, B.E. Stinson, and N.E. Shumay, “Thirty years of cardiac transplantation at Stanford University”, J. Thorac Cardiovasc Srug. 117, pp 939-951, 1999.
9.R. Korfer, A. EI-Banayosy, L. Arosoglu, K. Minsmi, T. Breymann, D. Seifert, and L. Kizner. “Temporary pulsatile ventricular assistant devices and biventricular assistance”, Ann. Thorac Surg. 68(2), pp 678-683, 1999.
10.S. Ohtsubo, E. Tayama, D. Short, G.P. Noon, and Y. Nose, “Clinical comparative study of cardiopulmonary bypass with Nikkiso and BioMedicus centrifugal pumps”, Artif. Organs 20, pp 715-720, 1996.
11.T. Jikuya, T. Sasaki, T. Aizawa, M. Shionio, J.A. Glueck, C.P. Smith, L. Feldman, I. Sakuma, M.E. Sekela, and T. Noda, et. al. “Development of an atraumatic small centrifugal pump for second-generation cardiopulmonary bypass”, Artif. Organs 16, pp 599-606, 1992.
12.Y. Takami, A. Andrade, T. Nakazawa, K. Makinouchi, J. Glueck, R. Benkowski, and Y. Nose, “Eccentric inlet port of the pivot bearing supported Gyro centrifugal pump”, Artif. Organs 21, pp 312-317, 1997.
13.K. Nakazawa, K. Makinouchi, Y. Ohara, S. Ohtsubo, K. Kawahito, K. Tasai, T. Shimono, R. Benkowski, G. Damm, Y. Takami, J. Glueck, G.P. Shimono, and Y. Nose, “Evaluation of the wear of the pivot bearing in the Gyro C1E3 pump”, Artif. Organs 20, pp 523-528, 1996.
14.G. Damm, K. Mizuguchi, R. Bozeman, J. Akkerman, G. Aber, P. Svejkovsky, S. Takatani, Y. Nosr, G. P. Noon, and M.E. DeBakey, “In vitro performance of the Baylor/NASA axial flow pump”, Artif. Organs 17(7), pp 609-613, 1993.
15.G. M. Wieselthaler, H. Schima, A. Lassnigg, R. Pacher, T. Ovsenk, G. Laufer, G. P. Noon, M.E. DeBakey, and E. Wolner, “The DeBakey VAD axial flow pump: first clinical experience with a new generation of implantable, nonpulsatile blood pumps for long-term support prior to transplantation”, Wien Klin Wochenschr 111(16), pp 629-635, 1999. [in German].
16.Y. Takami, G. Ohtsuka, J. Mueller, M. Ebner, E. Tayama, Y. Ohashi, D. Taylor, J. Fernandes, H. Schima, H. Schmalleger, E. Wolner, and Y. Nose. “Current progress in the development of a totally implantable Gyro centrifugal artificial heart”, ASAIO J. 44, pp 207-211, 1998.
17.Y. Nose, K. Kawahito, and T. Nakazawa, “Can we develop a nonpulsatile permanent rotary blood pump? Yes, we can.”, [Review] [28 refs] Artif. Organs 20(6), pp 467-474, 1996.
18.K. Nakata, G. Ohtsuka, M. Yoshikawa, T. Takano, J. Glueck, A. Fujisawa, K. Makinouchi, M. Yokokawa, and Y. Nose, “A new control method that estimates the backflow in a centrifugal pump”, Artif. Organs 23(6), pp 538-541, 1999.
19.T. Akimoto, K. Yamazaki, P. Litwak, K. N. Litwak, O. Tagusari, T. Mori, J. F. Antaki, M. V. Kameneva, M. J. Watach, M. Umezu, J. Tomioka, R. L. Kormos, H. Koyanagi, and B. P. Griffith, “Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension”, ASAIO J. 46(5), pp 596-599, 2000.
20.S. Kawahito, K. Nakata, K. Nonaka, T. Sato, M. Yoshikawa, T. Takano, T. Maeda, J. Linneweber, S. Schulte-Eistrup, D. Flowers, J. Glueck, and Y. Nose, “Analysis of the arterial blood pressure waveform using Fast Fourier Transform technique during left ventricular nonpulsatile assistance: in vitro study”, Artif. Organs 24(7), pp 580-583, 2000.
21.K. I. Nakata, M. Yoshikawa, T. Takano, Y. Sankai, G. Ohtsuka, J. Glueck, A. Fujisawa, K. Makinouchi, M. Yokokawa, S. Nosaka, and Y. Nose, “Control system for an implantable rotary blood pump”, Ann. Thorac & Cardiovasc Surg. 6(4), pp 242-246, 2000.
22.Y. Nose, M. Yoshikawa, S. Murabayashi, and T. Takano, “Development of rotary blood pump technology: past, present, and future”, Artif. Organs 24(6), pp 412-420, 2000.
23.E. Yuhki, M. Hatoh, M. Nogawa, Y. Miura, M. Shimazaki, and S. Takatani, “Detection of suction and regurgitation of the implantable centrifugal pump based on the motor current waveform analysis and its application on optimization of pump flow”, Artif. Organs 23(6), pp 532-537, 1999.
24.K. Affeld, K. Schichl, and A. Yoganathan, “Investigation of the flow in a centrifugal blood pump”, ASAIO Transactions 32(1), pp 269-273, 1986.
25.K. X. Qian, and S. H. Wang, “A fully implantable nonpulsatile impeller pump assists the circulation of the free walking goats”, Progress in Artif. Organs Proc. Of ISAO 85, pp 464-467, 1986.
26.R. K. Wampler, J. C. O. H. Moise, Fraiser, and D. B. Olsen, “In vivo evaluation of a peripheral vascular access axial flow blood pump”, Trans. ASAIO J. 34, pp 450-454, 1988.
27.K. Yamazaki, M. Umezu, and H. Koyanagi, et al. “Development of a miniature intraventricular axial flow blood pump”, Trans ASAIO J. 39, pp 224-230, 1993.
28.J. Hager, F. Brandstaetter, I. Koller, and F. Unger, “The spindle pump--a new concept for a nonpulsatile bloodpump”, Life Support Systems (3), pp 250-253, 1985.
29.Y. K. Reddy, “Optimum vane number and angel of centrifugal pump with a logarithmic vanes”, J. Basic Eng. 93(3), pp 411-425, 1971.
30.K. X. Qian, T. Kitamura, and H. Fukumasu, “Prototype design of a nonpulsatile diagonal pump”, Progress in Artificial Organs Proc. ISAO 83, pp 148-151, 1984.
31.K X. Qian, and G. Z. Zheng, “The comparative testing of index of hemolysis (IH) for new developed artificial heart pump”, Chn. J. Biomed Eng. 6(3), pp 181-182, 1987.
32.E. F. Bernstein, “Factors influencing erythrocyte destruction in artificial organs”, American J. of surgery 114, 1967.
33.P. Grop, “Untersuchung der Bluttraumatisierung durch Blutkreisel pumpen. Dissertation”, Frei. Uni. Berlin, 1983.
34.K. Natio, Y. Miyazoe, K. Mizuguchi, K. Tasai, Y. Ohara, Y. Orime, S. Takatani, G. Noon, and Y. Nose, “Development of Baylor-Nikkiso centrifugal pump with purging system for circulatory support”, Abstr. Book of 39th Annual Meeting of American Society of Artifial Intern Organs, 1993.
35.K. Yamazaki, M. Umezu, and H. Koyanagi, et al. “Development of a miniature intraventricular axial flow blood pump”, ASAIO J. 39(3), pp 224-230, 1993.
36.J. F. Antaki, K. C. Butler, and R. L. Kormos, et al. “In vivo evaluations of the Nimbus axial flow ventricular assist system”, ASAIO J. 39(3), pp 231-236, 1993.
37.P. Litwak, K. C. Butler, D. C. Thomas, L. P. Taylor, M. Macha, K. Yamazaki, H. Konishi, R. L. Kormos, B.P. Griffith, and H.S. Borovetz. “Development and initial testing of a pediatric centrifugal blood pump”, Ann. Thorac Surg. 61, pp 448-451, 1996.
38.K. Nakata, G.. Ohtsuka, M. Yoshikawa, T. Takano, J. Glueck, A. Fujisawa, K. Makinouchi, M. Yokokawa, and Nose Y., “A new control method that estimates the backflow in a centrifugal pump”, Artif. Organs 23(6), pp 538-541, 1999.
39.K. X. Qian, S. S. Wang, and S. H. Chu, “In vivo evaluation of a pulsatile impeller total heart assist”, ASAIO 40, pp 213-215, 1994.
40.S. H. Chu, S.S. Wang, N. K. Chou, and K. X. Qian, ”First assessment of a pulsatile impeller pump as left ventricular assist device in calves”, J. Surg. Assoc. ROC 26, pp 329-332, 1994.
41.K. X. Qian, S. S. Wang, S. H. Chu, “In vivo testing of a pulsatile implantable impeller pump as left ventricular assist device used in calves”, Perfusion 10, pp 257-263, 1995.
42.K. X. Qian, S. S. Wang, S. H. Chu, “In vivo studies of pulsatile implantable assist and toltal hearts”, Artif. Organs 19, pp 328-333, 1995.
43.S. H. Chu, S. S. Wang, N. K. Chou, K.X. Qian, “Left ventricular assist with a pulsatile impeller pump”, Artif. Heart 5, pp 337-340, 1996.
44.S. S. Wang, and S. H. Chu, “Current status of heart assist and replacement in Taiwan”, Artif. Organs 20(12), pp 1325-1329, 1996.
45.S. S. Wang, S. H. Chu, N. K. Chou, and K. X. Qian, “The pulsatile impeller pump for left ventricular assist”, Artif. Organs 20, pp 1310-1313, 1996.
46.K. X. Qian, and M. Zheng, “Realization of a permanent implantable pulsatile impeller heart with magnetically suspended motor”, Artif. Organs 21(7), pp 670-674, 1997.
47.S. S. Wang, Y. S. Lin, N. K. Chou, and S. H. Chu, “Heparin immobilization onto polyurethane surfaces and their characterization”, J. Surg. Assoc. ROC 31, pp 351-356, 1998.
48.S. S. Wang, S. H. Chu, W. J. Ko, Y. S. Chen, N. K. Chou, C. H. Tsai, and F. Y. Lin, “Ventricular assist as a bridge to heart transplantation”, Transplant Proc. 30(7), pp 3401-3402, 1998.
49.Y. Nosé, S. Ohtsubo, and E. Tayama, “Therapeutic and physiological artificial heart:future prospects”, Artif. Organs 21, pp 592-596, 1997.
50.Y. Nosé, K. I. Nakata, M. Yoshikawa, G. V. Letsou, A. Fujisawa, E. Wolner, H. Schima, “Development of totally implantable biventricular bypass centrifugal blood pump system”, Ann. Thorac Surg. 68, pp 775-779, 1999.