A novel external counterpulsation system for coronary artery disease and heart failure: pilot studies and initial clinical experiences

A novel external counterpulsation system for coronary artery disease and heart failure: pilot studies and initial clinical experiences
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  ORIGINAL ARTICLE A novel external counterpulsation system for coronary arterydisease and heart failure: pilot studies and initial clinicalexperiences Tsuyoshi Shimizu  • Shunei Kyo  • Kazuhito Imanaka  • Kohei Nakaoka  • Etsuji Nishimura  • Takahiro Okumura  • Masaaki Ishii  • Motoyuki Hisagi  • Takashi Nishimura  • Noboru Motomura  • Minoru Ono  • Shinichi Takamoto Received: 2 March 2010/Accepted: 19 July 2010/Published online: 25 August 2010   The Japanese Society for Artificial Organs 2010 Abstract  External counterpulsation (ECP) is a beneficialand noninvasive treatment for coronary artery disease orheart failure; however, it still has a lot of limitations. Weused a novel ECP system, Compact CP, the main feature of which is the double-lumen cuff that reduces the impact of cuff inflation and the size of the air compressor. The firstlumen was a contact cuff that was attached to the legs witha constant pressure (8 kPa). The second lumen was a maincuff that was inflated and deflated with a driving pressureand synchronized to the cardiac cycle. In this report, wedescribe the results of four pilot studies in a total number of 39 healthy volunteers and initial clinical experiences of thissystem in three patients. The pilot studies demonstratedthat the ECP system provided significant diastolic aug-mentation and systolic unloading. It also achieved a satis-factory diastolic/systolic pressure ratio (1.00  ±  0.06) witha high comfort level at a driving pressure of 40 kPa. Higherpressure (50–70 kPa) increased the assist performance butdecreased the comfort level. ECP was also applied with apatient with chronic refractory angina and two patientswith postoperative heart failure following cardiac surgery.The clinical conditions improved. No adverse effect wasobserved. Our novel ECP system is safe, effective, andpromising in the treatment of coronary artery disease orheart failure. Further clinical investigations are needed tosupport the significance of this system. Keywords  External counterpulsation    Angina pectoris   Ischemic heart disease    Heart failure Introduction External counterpulsation (ECP) is a noninvasive methodthat uses sequential inflation of pressure cuffs on the legs toaugment diastolic pressure and increase coronary flow.Simultaneous cuff deflation at the onset of systole decreasesleft-ventricular (LV) afterload by systolic unloading (SU).These actions produce hemodynamic effects similar tothose of intra-aortic balloon pumping (IABP). An ECPsystem (the CardiAssist, Cardiomedics Inc., CA, USA) wasfirst approved by the USA Food and Drug Administration(FDA) in 1987 to treat angina, acute myocardial infarction,and cardiogenic shock, and congestive heart failure wasadded as an indication in 2002. Another system (enhanced T. Shimizu ( & )    S. Kyo ( & )    M. Ishii    M. Hisagi   T. NishimuraDepartment of Therapeutic Strategy for Heart Failure,Graduate School of Medicine, The University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japane-mail: Kyoe-mail: ImanakaDepartment of Cardiovascular Surgery,Saitama Medical Center, Saitama, JapanK. Nakaoka    E. NishimuraNishimura Kikai Co. Ltd, Tokyo, JapanT. OkumuraSchool of Biomedical Engineering,Faculty of Health and Medical Care,Saitama Medical University, Saitama, JapanN. Motomura    M. OnoDepartment of Cardiac Surgery,The University of Tokyo, Tokyo, JapanS. TakamotoDepartment of Cardiovascular Surgery,Mitsui Memorial Hospital, Tokyo, Japan  1 3 J Artif Organs (2010) 13:161–169DOI 10.1007/s10047-010-0511-2  external counterpulsation, EECP, Vasomedical Inc., NY,USA) was cleared by the FDA in 1995. Since then, ECP hasbeen widely recognized as a safe, beneficial, low-cost, andnoninvasive therapy for treating patients with coronaryartery disease [1–3], especially those who are unsuitable for coronary revascularization or refractory to conventionalpharmacological treatment [4]. However, ECP therapy isstill on the way to worldwide use. A standard treatmentcourse consists of 35 1-h sessions over a 7-week period.This isone ofthe major limitations ofECP therapy. The sizeof a system may be another limitation [5]. Leg pain and skinabrasion are complications of ECP [6]. Furthermore, thereis no commercially available ECP system in Japan.We used a new ECP system, Compact CP, developed inJapan for the first time [7, 8]. The main feature of this system is the double-lumen cuff that reduces the impact of cuff inflation to achieve a more comfortable treatment. Thesystem has been designed for home battery use. Down-sizing the ECP system may allow bedside, ambulance, oreven home use. In this report, we describe the results of pilot studies in healthy volunteers and the clinical experi-ence of this system in three patients with chronic refractoryangina or postoperative heart failure after cardiac surgery. Materials and methods ECP systemA prototype of a Compact CP (Nishimura Kikai Co. Ltd,Japan) was developed in 2006. The Compact CP compriseda driving console (475  9  650  9  930 mm, 105 kg, AC100 V, 12 A, 1 kW), which included an air compressor anda computer console, and a set of cuffs. Before treatment, thecuffs were wrapped around the feet, calves, thighs andbuttocks of the patient. This system had double-lumen cuffs(Fig. 1). The first lumen was a contact cuff that was tightlyattached to the legs with a constant pressure (adjustablebetween 0 and 10 kPa). The second lumen was a main cuff that was inflated with a driving pressure (adjustablebetween 20 and 80 kPa) and deflated in a sequence that wassynchronized to the patient’s cardiac cycle [electrocardio-gram (ECG) R-wave trigger] at a beat ratio of 2:1 or 1:1(basically 2:1). The driving pressure was applied sequen-tially from the feet to the buttocks, starting in early diastole.At the end of the diastole, the compressed air of the maincuff was released simultaneously, whereas the contact cuff remained inflated with a constant pressure. After the firstpilot study, the response of cuff inflation and deflation wasimproved by modifying the tubing between the cuff and theair compressor. The timing of cuff inflation and deflationwas more accurately adjusted using this model (NCP-001,Nishimura Kikai). After the first series of ECP therapy, thefoot cuff was removed because it did not significantlyimprove diastolic augmentation (DA) and SA. Removal of the foot cuff saved compressor air. The second generationof the Compact PC, model NT-CCP series (Nishimura Ki-kai and the University of Tokyo, Tokyo, Japan) wasdeveloped in August 2008. The software of the system hasbeen substantially improved since the introduction of thismodel. The noninvasive radial artery pressure wave formwas obtained by pressure tonometry (BP-608, Omron ColinCo. Ltd, Tokyo, Japan), except in patients with the radialartery pressure line. System settings are shown in Fig. 2. LegLeg The main cuff The main cuff The Contact cuff The Contact cuff Inflation of the contact cuff Deflation and inflation of the main cuff  Table Leg Leg Fig. 1  Mechanismofdouble-lumensystem.Thefirstlumenisacontactcuff attached to the legs tightly with a constant pressure (adjustablebetween 0 and 10 kPa). The contact cuff pressure is basically set at8 kPa. The second lumen is a main cuff inflated with a driving pressure(adjustable between 20 and 80 kPa). The driving pressure is generallystarted at 20 kPa and gradually increased to 40 kPa. It can be increasedmore than 40 kPa depending on patients’ condition Fig. 2  Settings of the external counterpulsation (ECP) system. Cuffsare wrapped around the patient’s calves, thighs, and buttocks and areconnected to an air compressor with tubes. A sensor of radial arterypressure tonometry is attached to the right wrist, and a blood pressurecuff is wrapped around the right upper arm. ECG monitor cables areattached to the chest (in this case, a wireless ECG monitor system isused). A pulse oximeter is occasionally put on the fingertip162 J Artif Organs (2010) 13:161–169  1 3  The timing of the main cuff inflation and deflation can beadjusted according to the arterial pressure wave form. Peak or average systolic and diastolic pressure were obtainedusing wave-form-analysis software (Multi Trace CC,MedicalTrySystem Co. Ltd, Tokyo, Japan); percent DA(%DA), percent systolic unloading (%SU), and diastolic/ systolic pressure ratio (D/S) were calculated using theequations shown in Fig. 3.Methods of pilot studies for healthy volunteersIn pilot study I, 16 healthy men were studied using aprototype of a Compact CP. The contact cuff pressure wasset at 8 kPa and driving pressure was at 40 kPa. Aug-mentation delay time was constant and set at approximately500 ms in all participants. Cuff inflation time was set at550 ms and increased by 50 ms every 10 min up to750 ms. In pilot study II, 11 healthy men were studiedusing type NCP-001. Timing of cuff inflation and deflationwas adjusted according to arterial pressure wave forms.The ECP effect was assessed in three pressure conditions ineach individual: condition A (contact cuff pressure 8 kPa;driving pressure 40 kPa), condition B (contact cuff pres-sure 0; driving pressure 40 kPa), condition C (contact cuff pressure 8; driving pressure 20 kPa). In pilot study IV, sixhealthy men were studied using type NT-CCP. Contact cuff pressure was set at 8 kPa. Every healthy individualunderwent ECP with a driving pressure of 50, 60, and70 kPa. The pressure ware form characteristics were ana-lyzed in study I, II and IV. In pilot study III, six healthymen were studied using type NT-CCP. Every healthyindividual underwent four 1-h ECP sessions, one daily,with four different driving pressures: 40, 50, 60, and70 kPa. During each ECP treatment, the comfort level wasestimated every 10 min (Table 1).Clinical studiesAccording to the standard course of treatment [1, 9], ECP was applied in 1-h sessions, once or twice daily, over aperiod of 18–35 days to provide a total of 35 h of treatmentfor a patient with chronic refractory angina. Contact cuff pressure was set at 8 kPa. Driving pressure was set at40 kPa and occasionally increased up to 70 kPa dependingon the effect of the ECP and the patient’s conditions(Table 1). Contraindications included aortic aneurysm ordissection, severe peripheral arterial disease, venous dis-ease (varicose vein, phlebitis, stasis ulcers, prior or currentdeep vein thrombosis), moderate or severe aortic valveregurgitation, severe hypertension ( [ 180/110 mmHg),early postoperative or unhealed surgical wound at thelower leg, arrhythmias that may interfere with the trig-gering of ECP, and decompensated heart failure. The ethicscommittee approved our study, and written informedconsent was obtained from each patient.Statistical analysisWe calculated means  ±  standard deviation (SD) for con-tinuous variables and compared them using Student’s  t   testor analysis of variance (ANOVA). A  p  value of  \ 0.05 wasconsidered to indicate statistical significance. % DA mean =(DP1 mean -DP2 mean )/DP2 mean =(SP1 SP2 )/SP1 % SU mean =(SP1 mean -SP2 mean )/SP1 mean D/S mean =DP1 mean  /SP2 mean % DA peak  =(DP1 peak  -DP2 peak  )/DP2 peak  SP1 peak  DP1 peak  SP2 peak p p p p % SU peak  =(SP1 peak  -SP2 peak  )/SP1 peak  D/S peak  =DP1 peak   /SP2 peak  DP2 peak  SP1 mean DP1 mean SP2 mean DP2 mean Fig. 3  Calculation of pressure parameters assessing external count-erpulsation (ECP) effect and system performance. ECP is appliedwith 2:1 assist mode. An  arrow  shows inflation of the main cuff.  SP1 systolic pressure without counterpulsation,  DP1  diastolic pressurewith counterpulsation,  SP2  systolic pressure with counterpulsation(just after cuff deflation),  DP2  diastolic pressure without counterpul-sation,  SP mean  or  DP mean  systolic or diastolic mean pressure,  SP  peak   or  DP  peak   systolic or diastolic peak pressure,  %DA  percent diastolicaugmentation,  %SU   percent systolic unloading,  D/S   diastolic/systolicpressure ratioJ Artif Organs (2010) 13:161–169 163  1 3  Results Pilot studiesIn pilot study I (Table 2), significant DA [diastolic pressurewith counterpulsation vs. diastolic pressure without count-erpulsation (DP1 vs. DP2:  p \ 0.0001)] with %DA of 21  ±  8 and significant SU [systolic pressure withoutcounterpulsation vs. systolic pressure with counterpulsa-tion(SP1 vs.SP2:  p  =  0.012)] with %SU of 2  ±  3 wereprovidedwiththeoptimalcuffinflationtime(644  ±  77 ms).The averaged D/S ratio was 0.96  ±  0.08 in this condition.All healthy individuals underwent ECP under comfortableconditions without any complications. In pilot study II(Table 2),%DAandD/Sratioweresignificantly(  p \ 0.001)betterinconditionAthaninconditionBorC.SignificantDA(DP1 vs. DP2:  p \ 0.001) and SU (SP1 vs. SP2:  p \ 0.001)were provided in all three conditions. Percent SU in condi-tion A was significantly better than that in pilot study I(  p  =  0.0004). All healthy individuals underwent ECP undercomfortable conditions without any complications. In pilotstudy III (Table 3), the comfort level remained high with a Table 1  Studied subjectsStudy or patient number I II III IV 1 1 2 3Year 2006 2007 2009 2009 2007 2008 2008 2008Participant Volunteers Volunteers Volunteers Volunteers Patient Patient Patient PatientModel Prototype NCP-001 NT-CCP NT-CCP NCP-001 NCP-001 a NCP-001 a NT-CCPNumber of subjects 16 11 6 6 1 1 1 1Gender Male Male Male Male Male Male Male MaleAge (years old) 36  ±  10 35  ±  11 41  ±  14 41  ±  14 65 66 73 64BSA (m 2 ) 1.77  ±  0.12 1.80  ±  0.13 1.83  ±  0.18 1.86  ±  0.13 1.58 1.59 1.39 1.65Assist ratio 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1Contact cuff pressure (kPa) 8 0 or 8 8 8 8 8 8 8Driving pressure (kPa) 40 20 or 40 40–70 50–70 40 45–70 50–70 60–70Total driving time 50 min 30 min 4 h 30 min 35 h 35 h 18 h 5 h a Without foot cuffs  BSA  body surface area Table 2  External counterpulsation (ECP) effects in pilot studies I and IIGroup I II-A II-B II-CStudy number I II II IIPressure condition A A B CContact cuff pressure (kPa) 8 8 0 8Driving pressure (kPa) 40 40 40 20Augmentation delay Fixed Adjustable Adjustable AdjustableInflation time (ms) 644  ±  77 a 555  ±  104 555  ±  104 555  ±  104Heart rate (/min) 69  ±  14 64  ±  11 64  ±  10 65  ±  11Mean pressure (mmHg)SP1 117  ±  13* 114  ±  17** 112  ±  19** 115  ±  15**DP1 109  ±  14 b 106  ±  14 b,c 96  ±  16 b 102  ±  12 b SP2 114  ±  14 105  ±  14 108  ±  20 109  ±  15DP2 91  ±  14 87  ±  15 d 87  ±  18 92  ±  15%DA mean  21  ±  8 22  ±  8 c,d 10  ±  6 12  ±  7%SU mean  2  ±  3 a 7  ±  4 c 4  ±  2 d 6  ±  2D/S mean  0.96  ±  0.08 1.00  ±  0.06 c,d 0.89  ±  0.04 0.94  ±  0.06Unpaired  t   tests;  a \ 0.001 vs. group II-A SP1  systolic pressure without counterpulsation,  DP1  diastolic pressure with counterpulsation,  SP2  systolic pressure with counterpulsation (justafter cuff deflation),  DP2  diastolic pressure without counterpulsation,  %SU   percent systolic unloading,  D/S   diastolic/systolic pressure ratioPaired  t   tests: *  p \ 0.05 vs. SP2, **  p \ 0.001 vs. SP2,  b  p \ 0.001 vs. DP2,  c  p \ 0.05 vs. II-B,  d  p \ 0.05 vs. II-C164 J Artif Organs (2010) 13:161–169  1 3  pressure of 40 kPa but decreased with increasing drivingpressure and treatment time (  p \ 0.001). In pilot study IV(Fig. 4), %DA, %SU, and D/S ratio were increased(  p  =  0.0003, 0.0021, and 0.018, respectively) with anincrease in the driving pressure.A patient with chronic refractory anginaThe patient was a 65-year-old man who underwent coronaryartery bypass at the age of 50 years, now presenting withgrade III angina. His coronary angiography revealed diffuseleft coronary artery stenosis and bypass graft occlusion.Neither coronary artery bypass nor percutaneous coronaryintervention was indicated. He underwent the first course(35 h) of ECP treatment for 7 weeks between February andMarch 2007. ECP was applied with a driving pressure of 40 kPa. Whereas exercise stress test and myocardial per-fusion scan showed no significant improvement, chestsymptoms dramatically improved. The first ECP treatmentwas also described in the previous report [7]. One year afterthe first ECP treatment, this patient underwent the secondcourse (35 h) between March and April 2008 because of recurrent grade III angina. The ECP was applied with adriving pressure between 45 and 70 kPa and provided theaveraged D/S ratio of 0.91 in the first 12 h. The average D/Sratio was significantly (  p \ 0.001) increased to 0.99 in thelast 12 h. Percent DA was also improved (  p \ 0.0001)during the second treatment (Table 4). Since the secondcourse of treatment, he has been nearly asymptomatic anddoing well with grade I angina. Stress myocardial perfu-sion imaging revealed partial resolution of reversibleredistribution.Two patients with postoperative heart failure followingcardiac surgeryTwo patients underwent ECP in 2008 in the intensive careunit after cardiac surgery for postoperative heart failurepossibly due to prolonged cardioplegic cardiac arrest. Onepatient was a 72-year-old man who underwent aortic rootreplacement using a homograft for prosthetic valve endo-carditis. Hypoperfusion of the right coronary artery systemwas another possible cause of postoperative heart failure.IABP was performed for a few weeks, but it was ceasedbecause of infection. After removal of the IABP, ECP wasperformed once or twice daily for 2 weeks (total 18 h). Theother patient was a 64-year-old man who underwent doublevalve and ascending aortic replacement. He underwentECP for several days (total 5 h) 1 month after operation.Both patients were intubated and sedated. ECP provided Table 3  Driving pressure and comfort level during 1-h externalcounterpulsation (ECP) treatment in pilot study IIIDrivingpressure(kPa)Treatment time (min) Overall10 20 30 40 50 6040 4.3 4.3 4.2 4.2 4.2 4.2 4.250 4.0 3.7 3.5 3.5 3.2 3.0 3.560 3.0 2.7 2.7 2.7 2.3 2.3 2.670 2.3 2.2 2.2 2.2 2.0 2.0 2.1Data are average comfort levels: level 5 very comfortable, level 4comfortable, level 3 intermediate, level 2 uncomfortable, level 1painful or ceased. Comfort level was decreased with driving pressureand treatment time (  p \ 0.001) Fig. 4  Driving pressure and external counterpulsation (ECP) effect inpilot study III. Contact cuff pressure was set at 8 kPa in allindividuals. Percent diastolic augmentation (%DA), percent systolicunloading (%SU), and diastolic/systolic pressure (D/S) ratio wereincreased with an increase in driving pressure. *  p \ 0.05, **  p \ 0.01 Table 4  External counterpulsation (ECP) effect in the second courseof a patient with chronic refractory anginaFirst 12 h Middle 11 h Last 12 hContact cuff pressure 8 kPa 8 kPa 8 kPaDriving pressure 68  ±  6 kPa 67  ±  5 kPa 69  ±  4 kPaAssist ratio 2:1 2:1 2:1Heart rate (/min) 49  ±  5 48  ±  4 52  ±  3**Peak pressure (mmHg)SP1 113  ±  10 117  ±  9 111  ±  5DP1 99  ±  8 108  ±  9* 106  ±  6*SP2 109  ±  9 111  ±  8 107  ±  5DP2 78  ±  6 80  ±  8 72  ±  4* , **%DA peak   28  ±  5 38  ±  6* 49  ±  8* , **%SU peak   3  ±  2 6  ±  3* 3  ±  2**D/S peak   0.91  ±  0.07 0.98  ±  0.07* 0.99  ±  0.05* SP1  systolic pressure without counterpulsation,  DP1  diastolic pres-sure with counterpulsation,  SP2  systolic pressure with counterpulsa-tion (just after cuff deflation),  DP2  diastolic pressure withoutcounterpulsation,  SP mean  or  DP mean  systolic or diastolic mean pres-sure,  %DA peak   peak percent diastolic augmentation,  %SU  peak  peak percent systolic unloading,  D/S  peak   peak diastolic/systolic pressureratio*  p \ 0.05 vs. first 12 h, **  p \ 0.05 vs. middle 11 hJ Artif Organs (2010) 13:161–169 165  1 3
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