Intracardiac Impedance to Determine Sympathetic Activity in Rate Responsive Pacing M. SCHALDACH and H. HUTTEN* From the Zentralinstitut fur Biomedizinische Technik, Universitat Erlangen-Nrnberg, Erlangen, Germany, and the *Institut fur Elektro- und Biomedizinische Technik, Universitat Graz, Graz, Austria SCHALDACH, M., ETAL.: Intracardiac Impedance to Determine Sympathetic Activity in Rate Responsive Pacing. Modern pacemaker technology renders possible the adaptation of pacing rate ta hemodynamic requirements. The most ambitious approach aims at restoration of the physioIagicaJ cJosed-Joop system by utiJizing the in/ormation supplied by the autonomic nen^ous system fANSjand extracted/rommyocardiaJ contractiJe performance. Measurement is accomplished by the impedance method using the stimulation eJectrode as the measuring eJectrode. The ventricuiar inotropic parameter (VIP) has been identified as an ANS dependent parameter. A special detection algorithm, regional effective slope quantity (RQJ, with high ANS sensitivity has been developed. Rate adaptation has been achieved by using an individually adjustable inotropic index (II}. The concept has been evaluated in a multicenter study using a standardized exercise protocol. The results in patients with AV hlock demonstrate excellent agreement between spontaneous sinus rhythm and the ANS-controlJed stimulation rate during different forms of exercise. Measurement of mean arterial blood pressure (MABP) supports the physiological approach of adapting the pacing rate to various types of hemodynamic challenges. [PACE, Vol. 15, November, Part II 1992}
autonomic nervous system pacing, intracardiac impedance, closed-loop pacing
Introduction The heart is an autonomous organ with its basic actions being impulse generation, impulse propagation, electromechanical coupling, and contraction. The proper adjustment of its pumping performance to short-term challenges, i.e., physical exercise, postural changes, and temperature changes, is mainly controlled by the autonomous nervous system [ANS) as shown in Figure la. The arterial baroreceptor reflex with its negative feedback via the medullary circulation center is a typical example of a multi-input, multi-output control system. The controlled variable is the mean arterial blood pressure (MABP), which is measured by baroreceptors in the aortic arch and the carotid sinus. The most relevant controlling variable is cardiac output (CO), itself determined by stroke
Address for reprints; M. Schaldach, Zentralinstitut fiir Biomedizinische Technik Universitat Erlangen-Niirnberg. Turnstrape 5, D-8520 Erlangen, Germany.
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volume (SV], heart rate (HR), and total peripheral resistance (TPR). A decrease in MABP causes increased sympathetic activity, thereby raising SV, HR, and TPR, and reduced parasympathetic activity, which augments the sympathetic effect on HR. The closed-loop control system consists of the baroreceptors, the efferent pathway to the medulla oblongata, the medullary circulation control center, the efferent pathway via the ANS (i.e., sympathetic and vagal), the heart as servo-element for CO, and the peripheral circulation as servo-element for TPR. Higher effects as well as other effects are considered in the medullary circulation control center. In patients with chronotropic insufficiency, e.g., sick sinus syndrome, myocardial contraction is initiated by artificial pacing. Although this therapy is life supporting, it does not face up to hemodynamic challenges as well as the physiological system. The most restrictive deficiency of VVI pacemakers is the incapability of adjusting the pacing rate to the hemodynamic and metabolic requirements.
November, Part II 1992
PACE, Vol. 15
SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
highar affacU
1
cortex
hypothalamus
circulation control center medulla oblongata
Autonomic Nervous System
C)
InotropJc State
Systolic Tims Intervals
Ventricular Inotraplc Parameter
Stroke Volume
PEP
Figure 1. fa) Schematic diagram of the physiological controJ syslem fors mean arterial blood pressure (MABPJ with regard to short-term chaiJenges. (b) Block diagram for ANS-controUed rate adaptive pacing in patients with chronotropic insufficiencies, (c) The efferent part of the sympathetic nervous system, with its inotropic influence on the myocardial muscle modulates the contractility, which is reflected in the stroke volume (SVJ, systoJic time intervals, and the ventricular inotropic parameter. CO = cardiac output; HR = heart rate; LVET = Je/t ventricular ejection time; PEP = preelection period; TPR = total peripheral resistance.
Progress in pacemaker technology has permitted the development of programmahle, reliahle systems suitable for long-term implantation.^'^ For some years, pacemakers have been available that offer rate modulation features in an open-loop approach, e.g., hy sensing physical activity, venous hlood temperature, and respiratory parameters.^"^ The aim, however, should he rate adaptation, which reestablishes a closed-loop function. The ANS-controlled pacemaker utilizes a physiological approach by supplying the implanted pacemaker with hemodynamically-relevant ANS information (Fig. lb).^
Methods Hypotheses and Experimental Approach In patients with chronotropic incompetence, the ANS information is remains availahle in the
PACE, Vol. 15
heart, especially in myocardial contractile function. There are several variables that reflect the inotropic modulation by the ANS {Fig. lc). Stroke Voiume This parameter has not been considered for two reasons: (1) Sufficiently accurate measurement of SV is not guaranteed for long-term applications. Although the multielectrode impedance method in the left ventricle allows the monitoring of changes in intraventricular volume, it cannot be reliably used in the right ventricle hecause of its odd geometric shape.^^'^^ (2) There is strong interdependency hetween SV and HR since both ANS dependent variables determine CO and, thus, MABP and ANS activity. If an increased SV is used to increase HR without
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affecting CO, the resulting increase in HR must be compensated hy a decrease in SV. Therefore, this approach requires additional conditions in order to ensure stability. Systolic Time Intervals (STI) The most relevant ANS modulated variables among STI are the QT interval, the left ventricular ejection time (LVET), and the preejection period (PEP).^^-^^ The QT interval must be discarded despite the simplicity of its measurement since it depends on tbe sympathetic tone and on HR. An increase in HR reduces the length of the QT interval, causing the risk of positive feedback. The same argument is valid for LVET. PEP is the time interval between the onset of ventricular electrical activity as marked by the Q wave of the ECG and the beginning of the ejection period, i.e., the opening of the semilunar valves. This time interval therefore includes the electromechanical delay and the isovolumic contraction phase. Since PEP does not depend on HR, the risk of positive feedback is excluded. In patients with artificially stimulated heart action, the pacemaker spike marks the beginning of PEP. The main problem, however, is to determine tbe end of PEP with sufficient accuracy by a measuring feature integrated in tbe implanted pacemaker. For this reason, PEP was discarded for the final ANS concept. Ventricular Inotropic Parameter (VIP) ANS activity influences the inotiopic state of the heart, i.e., the strength of contraction.^'^^ For practical purposes, the VIP must meet several requirements: (1) The risk of positive feedback must be excluded. (2) The relation between ANS tone and VIP must be unequivocal. (3) Despite individual differences, the parameter must be easily detectable and applicable to rate adaptation during rest and different stages of hemodynamic challenges. (4) The measuring method for this parameter must not impair the safety of cardiac pacing as well as that of the pacemaker, especially witb regard to its sensing features and the battery drain.
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Impedance Measurement Tbe multielectrode impedance metbod has been used to determine left ventricular volume changes by assuming certain regular geometric shapes for the ventricle.^*^"^^ Due to its thin palmate shape and rather irregular geometric anatomy, this volumetric method cannot be successfully applied to the right ventricle. It has been proven, however, that the impedance (or conductance) signal measured by a unipolar electrode in the right ventricuiar cavity against the pacemaker housing as counter electrode, reflects the transient state of the beart during systole and diastole, as well as the ANS influence on the contractile state.^'^^ The conductance measurement is performed by injecting a 4-kHz square wave constant current of 40 \xA through the tip of the implanted stimulation electrode for a short period of time following the application of the stimulation pulse or the detection of ventricular depolarization (Fig. 2a). Since this conductance signal is accompanied by artifacts from ventilation, motion, and other causes, thorough signal processing, including phase demodulation and filtering, is required. Signal distortion is minimized by using a Bessel bandpass filter with corner frequencies at 0.3 and 40 Hz, resulting in a signal-to-noise ratio above 36 dB.^ The extracted signal is digitized by an 11bit analog-to-digital converter, which provides a minimal resolution of at least six bits. Tbe conversion rate of 128 Hz gives a resolution time of 8 msec. The typical shape of such an intraventricular unipolar conductance measurement during rest and moderate exercise is show^n in Figure 2b. Exercise Protocol Tbe patients who participated in the multicenter clinical study performed a standardized exercise protocol taking into account their individual physical capabilities. The protocol included changes in position (orthostatic challenges), followed by an incremental increase in workload on a bicycle ergometer. Bicycle exercise was performed either in the sitting or supine position up to the patient's maximum performance capacity. Tbe exercise was followed by a 5- to 10-minute recovery period during which the patient was either in a seated or supine position at his own discretion. During the exercise protocol, ECG, HR, and blood
November, Part II 1992
PACE, Vol. 15
SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
Conductance (relative units) 50 40
\
Exercise
30
\
V
20
\
Inotropic 1ndex (active rec
Rest
\
10
\
0
\ \
-10
\ -20
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-RQrest
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"
\
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-\
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-70
s
-80
96
48
72
96
128 144 168 192 216 240 264 288
Time (ms)
c)
b)
Time (ms)
Figure 2. (a) Block diagram of the ANS-con trailed pacemakers for single and dual chamber pacing (Biotronik Neos-PEP, Biotronik Diplos-PEP). fb] Typical shape of conductance curves. The shaded area indicates the time intervaJ for RQ evaluation, (c) Possible windows (A, B, and CJ for the optimal app]icatian of the RQ algorithm in comparison to the opening phases of the aortic and the pulmonic vaJves.
pressure were monitored. Echocardiography was utilized to monitor the different phases of cardiac action and the position of cardiac valves in order to determine early systolic time intervals and to independently verify the reliability of the VIP information. Exercise was performed in a manner to avoid additional emotional stress that might affect the sympathetic response. Regional Effective Slope Quantity (RQ) Algorithm
The conductance curves [Fig. 2h) were analyzed by an appropriate algorithm meeting the following requirements: (1) The algorithm must be easily adjustable to individual shapes of the conductance curves during rest.
PACE, Vol. 15
(2) The algorithm must be adaptive in a manner that considers only the ANS dependent changes of the conductance curves caused by different types and stages of physical exercise. (3) The algorithm must be insensitive to ANS independent changes of the conductance curves, especially against beat-to-beat fluctuations. The most qualified among the algorithms tested has been RQ. The evaluation of this algorithm has shown that it can most favorably be applied at three different periods ("windows"), each with a 24-msec width during the cardiac cycle (Fig. 2c). In some patients, the early window A might be overlapped by a minor poststimulation repoiarization effect. In these patients, window A should be discarded. Window B coincides with the opening phase of the pulmonic valves at rest
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(i.e., with the right ventricular PEP during rest). This is usually the preferred window. Window C is associated with the rapid ejection phases of the right and left ventricles. The sensitivity of the RQ algorithm is usually smaller for window C than for window B. However, since the RQ algorithm is based neither on the determination of an STI nor on the measurement of a volume, tbere is no conflict between rate adaptation and the measured variable (i.e., there is no risk for positive feedback). Tbe ANS information expressed by the changes in the shape of the conductance curves and detected by the RQ algorithm can be directly applied to the individual adjustment of the stimulation rate. This individual adaptation characteristic is achieved by the inotropic index (II), a normalizing variable that adequately considers the RQ value at rest (RQo), the RQ value at the maximum performance limit of each individual ), and the actual RQ value 11 = (RQactual - RQo)/(RQmax " RQo] Obviously, II = 0 for RQactuai = RQo, and II = 1 for RQactuai =
Tbe heart rate (HR) can be calculated from: HR = BSR + II (MSR - BSR) with BSR = basal stimulation rate (at rest), and MSR = maximal stimulation rate (at the individually-limited safety level for maximum performance). It follows from II = 0 that HR = BSR, and from II = 1 that HR = MSR. The patient is protected from overpacing by limiting II to values < 1. Results Unipolar Impedance Measurement Eighty-two patients with chronically implanted unipolar stimulation electrodes in the right ventricular cavity participated in the first clinical study. These patients did not perform the entire exercise protocol. Type, position, and implant date of the chronically implanted unipolar electrodes varied widely. There was a wide range for the basic impedance from about 500 to 1,500
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ohms. The impedance fluctuations, due to cardiac action at rest, ranged from about 4 to 25 ohms. Figure 3c shows that the changes in impedance were correlated with the basic impedance (r = 0.76). The increase in impedance during the ejection period, combined with a weak correlation, indicates that tbe decrease in intraventricular volume is the dominant, but not the only, influence on impedance. Comparison of the impedance changes during rest and exercise showed a correlation (r = 0.81), but nearly on the line of identity (Fig. 3c). This demonstrates that the applied unipolar impedance method cannot be used for volumetric measurements. A theoretical investigation of this problem reveals that the electrode primarily measures the impedance in its surrounding, i.e., in a volume of about 1 mL. In the second series, 158 patients participated and received a Biotronik Neos-PEP VVIR pulse generator (Biotronik, Lake Oswego, OR, USA) as a replacement for a depleted W I pacemaker. This modified version of a standard Biotronik Neos device offered the following additional features^: (1) unipolar system with the electrode serving as stimulator electrode and multimode sensor for spontaneous pacing events, stimulated cardiac actions, and sympathetic response; (2) an integrated conductance measurement system; (3) sufficient memory capacity for tbe storage of conductance signals obtained during several hundreds of cardiac cycles; (4) a signal processing circuit for filtering, RQ application, and rate adjustment; and (5) interrogation features for bidirectional communication with an external programmer to transfer and process data, providing high algorithmic flexibility. These patients participated in the standardized exercise program. In most of the patients of the second group, PEP was measured and correlated with the results obtained from the conductance curves after application of different evaluation algorithms. The RQ algorithm with its unique features is the most important result of this study. It was demonstrated tbat the RQ algorithm can be easily adjusted to individually-registered conduc-
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PACE, Vol. 15
SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
HR (1/min)
T
I j:
1 .....v.v...v:-:.:->:;;
©
©
/ I
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(min)
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Pariuaiofi dlaturbancv Vaacular apaam
c)
d) Figure 3. (a) ANS-controlled pacing during different kinds of exercise, (h) Twenty-four hour monitoring of paced heart rate (HB). (c) Comparison of basic impedance data with its changes during cardiac action at rest (upper part), and comparison of the impedance changes during rest and exercise (lower partJ. (dJ New concepts in the electrotherapy of the heart,
tance curves and their changing shapes during different stages of exercise and orthostatic load. Rate Adaptation During Exercise
In a third ongoing clinical study, the acute performance of the ANS-controlled pacemaker, i.e., the Biotronik Neos-PEP VVIR pacemaker with its integrated impedance measuring feature and signal processing capability with regard to VIP sensing, RQ evaluation, and II adjustment, is under investigation. Other aims of this study are the long-term stability of the rate adaptive therapy and its clinical consequences. This study is primarily limited to patients with sick sinus syn-
PACE, Vol. 15
drome and/or third-degree AV block. Some of the patients have Chagas' disease. As of October 1991, 105 patients in four countries (ranging in age from 20 to 90 years, 71% male) received the Biotronik Neos-PEP VVIR pulse generator with the RQ ANS detection feature. Figure 4 shows the efficiency of ANS-controlled, rate adaptive pacing in a patient during bicycle ergometry. In this patient, the spontaneous sinus rhythm (SR) can be compared with the ANScontrolled pacing rate (HR) (Fig. 4a). The time courses of both rates are in excellent agreement during all phases of the exercise protocol, including the recovery period (Fig. 4b). The minor deviations at the beginning when the patient starts pe-
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f *dno b l * Ippm)
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*
1
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10
12
14
15
18
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Time (min)
a)
b)
140
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RECCWERY
EXERCISE
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100
-
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8
c)
10
12
14
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Time (min)
SOW
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TSW 1 100 W
Figure 4. [a] ANS-controIIed pacing rate and spontaneous sinus rate in a patient with AV bJock during bicycle ergomefry with correct ad|usfnient of ihe RQ aJgorithm with ventricular inotropic parameter fVIP) defection, [h] Quality o/ ANS-controlJed pacing, [c] Misadjustment of the RQ aJgorithm wiXhouX VIP detection, fdj Time course of ANS-controJJed pacing rote and mean arterial blood pressure during exercise and recovery.
daling without load might indicate that HR responds much faster to a decrease in parasympathetic than to an increase in sympathetic drive. The patient can sustain 75 watts for nearly 2 minutes at a HR of 110 beats/min. In Figure 4c, the results are illustrated for the same patient when the ANS detection was misadjusted. There was only a slight increase in HR during the exercise period, which continued during the recovery period. SR increases much more, to about 140 heats/ min. The actual HR, however, is too slow to meet the real hemodynamic requirements. This hehavior can be compared with an open-control circuit in which the feedback of the controlling variahle
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to the controlled variahle is interrupted. As a consequence of this misadjustment, the patient can tolerate only 56 watts for about 2 minutes. The efficacy of ANS-controlled pacing in restoring the closed-loop system is demonstrated in Figure 4d. This 70-year-old male patient performed a graded exercise protocol on a bicycle ergometer. The maximum stimulated HR was limited to 110 beats/min, and during the exercise and recovery period, showed the typical time course. MABP was kept nearly constant during the entire period with a slight increase at the beginning of the exercise. Such behavior is typical for a control system with a proportionally acting controller.
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SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
Figure 3a shows the ambulatory adaptive pacing performance by a 81-year-old male patient recorded with the pacemaker's trend monitor. The patient was exposed to different daily routine exercise conditions as indicated. It is obvious that the rate adaptation occurs in accordance with the effort expended by the patient. The patient did not exhibit any symptoms of underpacing or overpacing during the entire exercise protocol. The monitoring can be extended to 24 hours as seen in Figure 3b. Again, HR correlates well with the daily activities.
Discussion The physiological system for the adaptation of HR to short-term hemodynamic challenges can be described as a control system with MABP as the controlled quantity. In patients with chronotropic incompetence, only one part of the whole system, the autonomous timer "sinus node" with the modulating influence from the controlling unit "medullary circulation center," is defective. All other parts of the system, i.e., the sensors, the afferent pathway to the controlling unit, the efferent pathway to myocardial muscle, and, in the absence of myocardial insufficiency, the cardiac muscle, are still functioning. In developing the ANS concept, the main difficulty was to define the ANS dependent parameter that would "close the loop." With VIP and its measurement by the unipolar impedance method, this problem has been solved. The results obtained during an extended clinical study demonstrate the unique features of this concept. The time course of the stimulation rate coincides well with the spontaneous SR in patients with AV hlock who were measured during different types of physical exercise. In patients with sick sinus syndrome, the transition of the stimulated HR at the beginning of the exercise as well as during the recovery period shows a typical physiological behavior. There is a clear indication that ANS-controlled rate adaptation also works for changes in posture and even for emotional reactions. The ongoing clinical study focuses on longterm stability and the influence of medication. The experience available for some months demonstrates excellent long-term stability if the rate ad-
PACE. Vol. 15
aptation is adjusted properly to each individual. Since rate adaptation during exercise provides protection against myocardial overstressing, most of the patients supplied with the ANS-controUed Biotronik Neos-PEP VVIR and Biotronik DiplosPEP DDDR generator felt so comfortable that they became more active in daily life.
Conclusions Access to the flow of cardiac ANS information opens new avenues for cardiac electrotherapies. Figure 3d depicts many of these new therapies. On the left are the rhythm, myocardial performance, and perfusion disturbances. On the right are the therapies improved through the use of cardiac ANS information. At the upper right, the cardiac ANS signal is being used to control the chronotropic pacing therapy in response to physiological demand. Physiological pacing avoids episodes of chronotropic insufficiency and, thus, prevents the occurrence of excessively high inotropic excitation of the myocardium. Avoiding high inotropic states serves to directly prevent many ventricular arrhythmias. The second block shows that early detection of an incipient arrhythmia or an acute imbalance between sympathetic and parasympathetic tone can be used to trigger and control arrhythmia suppression therapies. The third block shows that the cardiac ANS signal can be used to modulate ventricular assist systems including cardiomyoplasties, which would further protect tne myocardium from acute stress. The fourth block describes circulatory disorders triggered by pain. In such cases, acute pain leads to a systemic sympathetic response triggering angina pectoris. The patient may be equipped with a neurostimulator to block on demand or automatically the painful sensory stimulus. The neurostimulator delivers corrective therapy by applying epidural neurostimulation to block nociception, thus interrupting conditions leading to the emergence of angina pectoris. In cardiology, and specifically in the field of electrotherapy, medical progress by continuous technological improvements in many disciplines has been made. These advances are leading to simpler, physiological, and more versatile pacing therapies.
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References
10.
11.
12. 13. 14.
Schaldach M. Present state and future trends in electrical heart stimulation. Med Prog Technol 1987; 13:85-102. Schaldach M. Microelectronics in implantable cardiovascular devices. Proc IEEE Eng Med Biol 1991; 13:2120-2122. Hubmann M, Weikl A, Hardt R, et al. Bewegungsenergie als Steuergr6(3e fiir die Anpassung der Stimulationsfrequenz. Biomed Technik 1989; 34: 191-196. Schaldach M. Compensation of chronotropic incompetence with temperature-controlled rateadaptive pacing. Biomed Technik 1988; 33; 286-294. Schaldach M. Herzschrittmacher mit temperaturgesteuerter Frequenzanpassung. Herzschrittmacher 1989; 9:5-14. Stangl K, Wirtzfeld A, Heinze R, et al. A new multisensor pacing system using stroke volume, respiratory rate, mixed venous oxygen saturation, and temperature, right atrial pressure, right ventricular pressure, and dP/dt, PACE 1988; 11:712-724. Stangl K, Heuer H, Wirtzfeld A. Frequenzadaptive Herzschrittmacher. Darmstadt, Steinkopff Verlag, 1990. Wirtzfeld A, Goedel-Meinen L, Bock T, et al. Central venous oxygen saturation for the control of automatic rate-responsive pacing. Circulation 1981; 64(Suppl. IV):299. Schaldach M. Hutten H, A physiological approach to different concepts of rate-adaptive cardiac pacing. Med Prog Technol 1990; 16;235-246. Boheim G. Intrakardiale Impedanzmessung zur frequenzadaptiven Stimulation des Herzens. Engineering Science Thesis, University of Erlangen, 1988. Boheim C, Schaldach M. Frequenzadaption eines kiinstlichen Herzschrittmachers iiber einen Volumenregelkreis. Biomed Technik 1988; 33; 100-105. Chirife R. The pre-ejection period; An ideal physiologic variable for closed-loop rate-responsive pacing. PACE 1987; 10:425. Chirife R. Physiological principles of a new method for rate responsive pacing using the preejection interval. PACE 1988; ll[Pt I);154. Niederlag W, Rentsch W, Wunderlich E, et al. 1st die Anspannungszeit ein brauchbarer Parameter fur die frequenzadaptierte Herzstimulation. Biomed Technik 1989; 34(EB):62-65.
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15. Rentsch W, Niederlag W, Foelske H, et al. Zur physiologischen Frequenzanpassung von Herzschrittmachern mlttels systolischer Zeitintervalle. Z gesamte inn Med 1987; 42:386-389. 16. Schaldach M. Systolic time intervals as a control of rate-adaptive pacing. 11th Annual Conference. Proc IEEE Eng Med Biol 1989; 1407-1410. 17. Schaldach M. Electrotherapy of the Heart. Berlin, Heidelberg, New York, Springer-Verlag, 1992. 18. Spodick DH, Doi YL, Bishop RL, et al. Systolic time intervals reconsidered. Reevaluation of the preejection period absence of relation to heart rate. Am I Cardiol 1984; 53;1667-1670. 19. Hutten H, Schaldach M. Rate-adaptive cardiac pacing considering closed-loop control. Proc IEEE Eng Med Biol 1991; 13[5/5);2111-2113. 20. Baan I, Aouw long TT, Kerkof PLM, et al. Continuous intraventricular measurement of stroke volume and cardiac output and estimation of regional wall motion. Digest Comb Meet XII Int Conf Med Biol Eng V int Conf Med Phys (lerusalem) 1979; (Pt II):29.3. 21. Baan I, van der Velde ET, Stenndijk P, et al. Calibration and application of the conductance catheter for ventricular volume measurement. In ME Valentinuzzi (ed.): Intracardiac Conductance Volumetry. Automedica 11. New York, Gordon & Breach, Science Publishers Inc., 1989, pp. 357-365. 22. Geddes LA, Hoff HE, Mello A, et al. Continuous measurement of ventricular stroke volume by electrical impedance. Cardiovasc Res Center Bull (Houston) 1966; 4;118-130. 23. Herrera MC, Clavin OE, Spinelli IC et al. Multichannel tetrapolar admittance meter (MY) for intracardiac volume measurements in animals. Med Prog Technol 1986; 11:43-49. 24. McKay RG, Spears IR, Aroesty JM, et al. Instantaneous measurement of left and right ventricular volume and pressure-volume relationships with an impedance catheter. Circulation 1984; 69: 703-710. 25. Schaldach M, Rentsch W, Rentsch HW. Advances in intracardiac impedance plethysmography. Proc IEEE Eng Med Biol 1990; 12(2);711-713. 26. Spinelii JC, Valentinuzzi ME. Conductivity and geometrical factors affecting volume measurements with an impedancimetric catheter. Med Biol Eng Comput 1986; 27:25-32.
November, Part n 1992
PACE, Vol. 15
autonomic nervous system pacing, intracardiac impedance, closed-loop pacing
Introduction The heart is an autonomous organ with its basic actions being impulse generation, impulse propagation, electromechanical coupling, and contraction. The proper adjustment of its pumping performance to short-term challenges, i.e., physical exercise, postural changes, and temperature changes, is mainly controlled by the autonomous nervous system [ANS) as shown in Figure la. The arterial baroreceptor reflex with its negative feedback via the medullary circulation center is a typical example of a multi-input, multi-output control system. The controlled variable is the mean arterial blood pressure (MABP), which is measured by baroreceptors in the aortic arch and the carotid sinus. The most relevant controlling variable is cardiac output (CO), itself determined by stroke
Address for reprints; M. Schaldach, Zentralinstitut fiir Biomedizinische Technik Universitat Erlangen-Niirnberg. Turnstrape 5, D-8520 Erlangen, Germany.
1778
volume (SV], heart rate (HR), and total peripheral resistance (TPR). A decrease in MABP causes increased sympathetic activity, thereby raising SV, HR, and TPR, and reduced parasympathetic activity, which augments the sympathetic effect on HR. The closed-loop control system consists of the baroreceptors, the efferent pathway to the medulla oblongata, the medullary circulation control center, the efferent pathway via the ANS (i.e., sympathetic and vagal), the heart as servo-element for CO, and the peripheral circulation as servo-element for TPR. Higher effects as well as other effects are considered in the medullary circulation control center. In patients with chronotropic insufficiency, e.g., sick sinus syndrome, myocardial contraction is initiated by artificial pacing. Although this therapy is life supporting, it does not face up to hemodynamic challenges as well as the physiological system. The most restrictive deficiency of VVI pacemakers is the incapability of adjusting the pacing rate to the hemodynamic and metabolic requirements.
November, Part II 1992
PACE, Vol. 15
SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
highar affacU
1
cortex
hypothalamus
circulation control center medulla oblongata
Autonomic Nervous System
C)
InotropJc State
Systolic Tims Intervals
Ventricular Inotraplc Parameter
Stroke Volume
PEP
Figure 1. fa) Schematic diagram of the physiological controJ syslem fors mean arterial blood pressure (MABPJ with regard to short-term chaiJenges. (b) Block diagram for ANS-controUed rate adaptive pacing in patients with chronotropic insufficiencies, (c) The efferent part of the sympathetic nervous system, with its inotropic influence on the myocardial muscle modulates the contractility, which is reflected in the stroke volume (SVJ, systoJic time intervals, and the ventricular inotropic parameter. CO = cardiac output; HR = heart rate; LVET = Je/t ventricular ejection time; PEP = preelection period; TPR = total peripheral resistance.
Progress in pacemaker technology has permitted the development of programmahle, reliahle systems suitable for long-term implantation.^'^ For some years, pacemakers have been available that offer rate modulation features in an open-loop approach, e.g., hy sensing physical activity, venous hlood temperature, and respiratory parameters.^"^ The aim, however, should he rate adaptation, which reestablishes a closed-loop function. The ANS-controlled pacemaker utilizes a physiological approach by supplying the implanted pacemaker with hemodynamically-relevant ANS information (Fig. lb).^
Methods Hypotheses and Experimental Approach In patients with chronotropic incompetence, the ANS information is remains availahle in the
PACE, Vol. 15
heart, especially in myocardial contractile function. There are several variables that reflect the inotropic modulation by the ANS {Fig. lc). Stroke Voiume This parameter has not been considered for two reasons: (1) Sufficiently accurate measurement of SV is not guaranteed for long-term applications. Although the multielectrode impedance method in the left ventricle allows the monitoring of changes in intraventricular volume, it cannot be reliably used in the right ventricle hecause of its odd geometric shape.^^'^^ (2) There is strong interdependency hetween SV and HR since both ANS dependent variables determine CO and, thus, MABP and ANS activity. If an increased SV is used to increase HR without
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affecting CO, the resulting increase in HR must be compensated hy a decrease in SV. Therefore, this approach requires additional conditions in order to ensure stability. Systolic Time Intervals (STI) The most relevant ANS modulated variables among STI are the QT interval, the left ventricular ejection time (LVET), and the preejection period (PEP).^^-^^ The QT interval must be discarded despite the simplicity of its measurement since it depends on tbe sympathetic tone and on HR. An increase in HR reduces the length of the QT interval, causing the risk of positive feedback. The same argument is valid for LVET. PEP is the time interval between the onset of ventricular electrical activity as marked by the Q wave of the ECG and the beginning of the ejection period, i.e., the opening of the semilunar valves. This time interval therefore includes the electromechanical delay and the isovolumic contraction phase. Since PEP does not depend on HR, the risk of positive feedback is excluded. In patients with artificially stimulated heart action, the pacemaker spike marks the beginning of PEP. The main problem, however, is to determine tbe end of PEP with sufficient accuracy by a measuring feature integrated in tbe implanted pacemaker. For this reason, PEP was discarded for the final ANS concept. Ventricular Inotropic Parameter (VIP) ANS activity influences the inotiopic state of the heart, i.e., the strength of contraction.^'^^ For practical purposes, the VIP must meet several requirements: (1) The risk of positive feedback must be excluded. (2) The relation between ANS tone and VIP must be unequivocal. (3) Despite individual differences, the parameter must be easily detectable and applicable to rate adaptation during rest and different stages of hemodynamic challenges. (4) The measuring method for this parameter must not impair the safety of cardiac pacing as well as that of the pacemaker, especially witb regard to its sensing features and the battery drain.
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Impedance Measurement Tbe multielectrode impedance metbod has been used to determine left ventricular volume changes by assuming certain regular geometric shapes for the ventricle.^*^"^^ Due to its thin palmate shape and rather irregular geometric anatomy, this volumetric method cannot be successfully applied to the right ventricle. It has been proven, however, that the impedance (or conductance) signal measured by a unipolar electrode in the right ventricuiar cavity against the pacemaker housing as counter electrode, reflects the transient state of the beart during systole and diastole, as well as the ANS influence on the contractile state.^'^^ The conductance measurement is performed by injecting a 4-kHz square wave constant current of 40 \xA through the tip of the implanted stimulation electrode for a short period of time following the application of the stimulation pulse or the detection of ventricular depolarization (Fig. 2a). Since this conductance signal is accompanied by artifacts from ventilation, motion, and other causes, thorough signal processing, including phase demodulation and filtering, is required. Signal distortion is minimized by using a Bessel bandpass filter with corner frequencies at 0.3 and 40 Hz, resulting in a signal-to-noise ratio above 36 dB.^ The extracted signal is digitized by an 11bit analog-to-digital converter, which provides a minimal resolution of at least six bits. Tbe conversion rate of 128 Hz gives a resolution time of 8 msec. The typical shape of such an intraventricular unipolar conductance measurement during rest and moderate exercise is show^n in Figure 2b. Exercise Protocol Tbe patients who participated in the multicenter clinical study performed a standardized exercise protocol taking into account their individual physical capabilities. The protocol included changes in position (orthostatic challenges), followed by an incremental increase in workload on a bicycle ergometer. Bicycle exercise was performed either in the sitting or supine position up to the patient's maximum performance capacity. Tbe exercise was followed by a 5- to 10-minute recovery period during which the patient was either in a seated or supine position at his own discretion. During the exercise protocol, ECG, HR, and blood
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SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
Conductance (relative units) 50 40
\
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30
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-70
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96
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128 144 168 192 216 240 264 288
Time (ms)
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Figure 2. (a) Block diagram of the ANS-con trailed pacemakers for single and dual chamber pacing (Biotronik Neos-PEP, Biotronik Diplos-PEP). fb] Typical shape of conductance curves. The shaded area indicates the time intervaJ for RQ evaluation, (c) Possible windows (A, B, and CJ for the optimal app]icatian of the RQ algorithm in comparison to the opening phases of the aortic and the pulmonic vaJves.
pressure were monitored. Echocardiography was utilized to monitor the different phases of cardiac action and the position of cardiac valves in order to determine early systolic time intervals and to independently verify the reliability of the VIP information. Exercise was performed in a manner to avoid additional emotional stress that might affect the sympathetic response. Regional Effective Slope Quantity (RQ) Algorithm
The conductance curves [Fig. 2h) were analyzed by an appropriate algorithm meeting the following requirements: (1) The algorithm must be easily adjustable to individual shapes of the conductance curves during rest.
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(2) The algorithm must be adaptive in a manner that considers only the ANS dependent changes of the conductance curves caused by different types and stages of physical exercise. (3) The algorithm must be insensitive to ANS independent changes of the conductance curves, especially against beat-to-beat fluctuations. The most qualified among the algorithms tested has been RQ. The evaluation of this algorithm has shown that it can most favorably be applied at three different periods ("windows"), each with a 24-msec width during the cardiac cycle (Fig. 2c). In some patients, the early window A might be overlapped by a minor poststimulation repoiarization effect. In these patients, window A should be discarded. Window B coincides with the opening phase of the pulmonic valves at rest
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(i.e., with the right ventricular PEP during rest). This is usually the preferred window. Window C is associated with the rapid ejection phases of the right and left ventricles. The sensitivity of the RQ algorithm is usually smaller for window C than for window B. However, since the RQ algorithm is based neither on the determination of an STI nor on the measurement of a volume, tbere is no conflict between rate adaptation and the measured variable (i.e., there is no risk for positive feedback). Tbe ANS information expressed by the changes in the shape of the conductance curves and detected by the RQ algorithm can be directly applied to the individual adjustment of the stimulation rate. This individual adaptation characteristic is achieved by the inotropic index (II), a normalizing variable that adequately considers the RQ value at rest (RQo), the RQ value at the maximum performance limit of each individual ), and the actual RQ value 11 = (RQactual - RQo)/(RQmax " RQo] Obviously, II = 0 for RQactuai = RQo, and II = 1 for RQactuai =
Tbe heart rate (HR) can be calculated from: HR = BSR + II (MSR - BSR) with BSR = basal stimulation rate (at rest), and MSR = maximal stimulation rate (at the individually-limited safety level for maximum performance). It follows from II = 0 that HR = BSR, and from II = 1 that HR = MSR. The patient is protected from overpacing by limiting II to values < 1. Results Unipolar Impedance Measurement Eighty-two patients with chronically implanted unipolar stimulation electrodes in the right ventricular cavity participated in the first clinical study. These patients did not perform the entire exercise protocol. Type, position, and implant date of the chronically implanted unipolar electrodes varied widely. There was a wide range for the basic impedance from about 500 to 1,500
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ohms. The impedance fluctuations, due to cardiac action at rest, ranged from about 4 to 25 ohms. Figure 3c shows that the changes in impedance were correlated with the basic impedance (r = 0.76). The increase in impedance during the ejection period, combined with a weak correlation, indicates that tbe decrease in intraventricular volume is the dominant, but not the only, influence on impedance. Comparison of the impedance changes during rest and exercise showed a correlation (r = 0.81), but nearly on the line of identity (Fig. 3c). This demonstrates that the applied unipolar impedance method cannot be used for volumetric measurements. A theoretical investigation of this problem reveals that the electrode primarily measures the impedance in its surrounding, i.e., in a volume of about 1 mL. In the second series, 158 patients participated and received a Biotronik Neos-PEP VVIR pulse generator (Biotronik, Lake Oswego, OR, USA) as a replacement for a depleted W I pacemaker. This modified version of a standard Biotronik Neos device offered the following additional features^: (1) unipolar system with the electrode serving as stimulator electrode and multimode sensor for spontaneous pacing events, stimulated cardiac actions, and sympathetic response; (2) an integrated conductance measurement system; (3) sufficient memory capacity for tbe storage of conductance signals obtained during several hundreds of cardiac cycles; (4) a signal processing circuit for filtering, RQ application, and rate adjustment; and (5) interrogation features for bidirectional communication with an external programmer to transfer and process data, providing high algorithmic flexibility. These patients participated in the standardized exercise program. In most of the patients of the second group, PEP was measured and correlated with the results obtained from the conductance curves after application of different evaluation algorithms. The RQ algorithm with its unique features is the most important result of this study. It was demonstrated tbat the RQ algorithm can be easily adjusted to individually-registered conduc-
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SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
HR (1/min)
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d) Figure 3. (a) ANS-controlled pacing during different kinds of exercise, (h) Twenty-four hour monitoring of paced heart rate (HB). (c) Comparison of basic impedance data with its changes during cardiac action at rest (upper part), and comparison of the impedance changes during rest and exercise (lower partJ. (dJ New concepts in the electrotherapy of the heart,
tance curves and their changing shapes during different stages of exercise and orthostatic load. Rate Adaptation During Exercise
In a third ongoing clinical study, the acute performance of the ANS-controlled pacemaker, i.e., the Biotronik Neos-PEP VVIR pacemaker with its integrated impedance measuring feature and signal processing capability with regard to VIP sensing, RQ evaluation, and II adjustment, is under investigation. Other aims of this study are the long-term stability of the rate adaptive therapy and its clinical consequences. This study is primarily limited to patients with sick sinus syn-
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drome and/or third-degree AV block. Some of the patients have Chagas' disease. As of October 1991, 105 patients in four countries (ranging in age from 20 to 90 years, 71% male) received the Biotronik Neos-PEP VVIR pulse generator with the RQ ANS detection feature. Figure 4 shows the efficiency of ANS-controlled, rate adaptive pacing in a patient during bicycle ergometry. In this patient, the spontaneous sinus rhythm (SR) can be compared with the ANScontrolled pacing rate (HR) (Fig. 4a). The time courses of both rates are in excellent agreement during all phases of the exercise protocol, including the recovery period (Fig. 4b). The minor deviations at the beginning when the patient starts pe-
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f *dno b l * Ippm)
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Figure 4. [a] ANS-controIIed pacing rate and spontaneous sinus rate in a patient with AV bJock during bicycle ergomefry with correct ad|usfnient of ihe RQ aJgorithm with ventricular inotropic parameter fVIP) defection, [h] Quality o/ ANS-controlJed pacing, [c] Misadjustment of the RQ aJgorithm wiXhouX VIP detection, fdj Time course of ANS-controJJed pacing rote and mean arterial blood pressure during exercise and recovery.
daling without load might indicate that HR responds much faster to a decrease in parasympathetic than to an increase in sympathetic drive. The patient can sustain 75 watts for nearly 2 minutes at a HR of 110 beats/min. In Figure 4c, the results are illustrated for the same patient when the ANS detection was misadjusted. There was only a slight increase in HR during the exercise period, which continued during the recovery period. SR increases much more, to about 140 heats/ min. The actual HR, however, is too slow to meet the real hemodynamic requirements. This hehavior can be compared with an open-control circuit in which the feedback of the controlling variahle
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to the controlled variahle is interrupted. As a consequence of this misadjustment, the patient can tolerate only 56 watts for about 2 minutes. The efficacy of ANS-controlled pacing in restoring the closed-loop system is demonstrated in Figure 4d. This 70-year-old male patient performed a graded exercise protocol on a bicycle ergometer. The maximum stimulated HR was limited to 110 beats/min, and during the exercise and recovery period, showed the typical time course. MABP was kept nearly constant during the entire period with a slight increase at the beginning of the exercise. Such behavior is typical for a control system with a proportionally acting controller.
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SYMPATHETIC ACTIVITY IN RATE RESPONSIVE PACING
Figure 3a shows the ambulatory adaptive pacing performance by a 81-year-old male patient recorded with the pacemaker's trend monitor. The patient was exposed to different daily routine exercise conditions as indicated. It is obvious that the rate adaptation occurs in accordance with the effort expended by the patient. The patient did not exhibit any symptoms of underpacing or overpacing during the entire exercise protocol. The monitoring can be extended to 24 hours as seen in Figure 3b. Again, HR correlates well with the daily activities.
Discussion The physiological system for the adaptation of HR to short-term hemodynamic challenges can be described as a control system with MABP as the controlled quantity. In patients with chronotropic incompetence, only one part of the whole system, the autonomous timer "sinus node" with the modulating influence from the controlling unit "medullary circulation center," is defective. All other parts of the system, i.e., the sensors, the afferent pathway to the controlling unit, the efferent pathway to myocardial muscle, and, in the absence of myocardial insufficiency, the cardiac muscle, are still functioning. In developing the ANS concept, the main difficulty was to define the ANS dependent parameter that would "close the loop." With VIP and its measurement by the unipolar impedance method, this problem has been solved. The results obtained during an extended clinical study demonstrate the unique features of this concept. The time course of the stimulation rate coincides well with the spontaneous SR in patients with AV hlock who were measured during different types of physical exercise. In patients with sick sinus syndrome, the transition of the stimulated HR at the beginning of the exercise as well as during the recovery period shows a typical physiological behavior. There is a clear indication that ANS-controlled rate adaptation also works for changes in posture and even for emotional reactions. The ongoing clinical study focuses on longterm stability and the influence of medication. The experience available for some months demonstrates excellent long-term stability if the rate ad-
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aptation is adjusted properly to each individual. Since rate adaptation during exercise provides protection against myocardial overstressing, most of the patients supplied with the ANS-controUed Biotronik Neos-PEP VVIR and Biotronik DiplosPEP DDDR generator felt so comfortable that they became more active in daily life.
Conclusions Access to the flow of cardiac ANS information opens new avenues for cardiac electrotherapies. Figure 3d depicts many of these new therapies. On the left are the rhythm, myocardial performance, and perfusion disturbances. On the right are the therapies improved through the use of cardiac ANS information. At the upper right, the cardiac ANS signal is being used to control the chronotropic pacing therapy in response to physiological demand. Physiological pacing avoids episodes of chronotropic insufficiency and, thus, prevents the occurrence of excessively high inotropic excitation of the myocardium. Avoiding high inotropic states serves to directly prevent many ventricular arrhythmias. The second block shows that early detection of an incipient arrhythmia or an acute imbalance between sympathetic and parasympathetic tone can be used to trigger and control arrhythmia suppression therapies. The third block shows that the cardiac ANS signal can be used to modulate ventricular assist systems including cardiomyoplasties, which would further protect tne myocardium from acute stress. The fourth block describes circulatory disorders triggered by pain. In such cases, acute pain leads to a systemic sympathetic response triggering angina pectoris. The patient may be equipped with a neurostimulator to block on demand or automatically the painful sensory stimulus. The neurostimulator delivers corrective therapy by applying epidural neurostimulation to block nociception, thus interrupting conditions leading to the emergence of angina pectoris. In cardiology, and specifically in the field of electrotherapy, medical progress by continuous technological improvements in many disciplines has been made. These advances are leading to simpler, physiological, and more versatile pacing therapies.
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References
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