Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemakers Alar Kuusik, Raul Land, Mart Min, Toomas Parve, Gustav Poola Tallinn University of Technology, Tallinn, Estonia ABSTRACT: A method of highly accurate measurement of intracardiac bioimpedance usable in implantable rate adaptive pacemakers and portative cardiomonitors based on lock-in signal processing and bipolar pulse waveform signals is proposed ICE2004, Kyoto, June 27–July 1, 2004

a) b) c) d) Time variant The three-element The two-component Phasor diagram of bioimpedance Ż of equivalent circuit of (R=ReŻ and X=ImŻ) the time variant a biological object the bioimpedance Ż serial equivalent of Ż bioimpedance Ż=R+jX In the multiple-element equivalent circuit (b) variations of resistive elements r ext and r int can cause changes in the imaginary part X=ImŻ, and variations of the capacitive element C can cause changes in the real part R=ReŻ. Depending on frequency, these contradictory changes in ReŻ and ImŻ can be more or less significant. But because of this phenomenon unexpectedly high accuracy of mea- surement of R and X is needed to allow to calculate by them the values for r ext, r int, and C. ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 2 EQUIVALENT CIRCUITS AND PHASOR DIAGRAM FOR THE ELECTRICAL BIOIMPEDANCE

SHAPES OF SIGNALS (a) Conventional solution of pulse wave excitation signal for using in intracardiac impedance measurement. (b) Novel solution of pulse wave excitation and reference signals for lock-in signal conversion in measurement of the intracardiac EBI. ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 3

ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 4 THE NOVEL LOCK-IN EBI MEASUREMENT SYSTEM Block diagram of the novel lock-in EBI measurement system based on application of the shortened pulse signals. Note: In comparison with the common solution modifications are introduced in SDs, Formator, and Sequencer. The Sequencer contains more triggers and 15 times higher clock frequency f c is needed.

Circuit diagram of the synchronous detector (SD) operating with shortened pulse. Very little changes are needed - in the Mux the third position with grounded input is introduced. ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 5 THE LOCK-IN EBI MEASUREMENT SYSTEM (continued)

18º 30º The 1 st harmonic t/T The coinciding harmonics Relative magnitude of harmonic Order of harmonics Spectra of the rectangular waveforms with shortened pulses Rectangular waveforms with pulse shortening by 18° and 30° ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 6 THE SHAPES AND SPECTRA OF THE SIGNALS

X R ^ X ^ R  max  = ± 4. 1  max  = 23% corresponds to sine wave true vector measured vector ZZ   corresponds to rectangular wave XX RR X R ^X ^X ^ R  max   = ± 1  max  = ±2. 4 % corresponds to sine wave corresponds to the SDC wave   a) ordinary rectangular waveformsb) rectangular waveforms with shortened pulses ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 7 THE PHASOR ERRORS Trajectories of the tip of impedance phasor Ż = R + jX for the two cases of estimating the phasor from the results of measurement R and X using rectangular waveform signals instead of the sine-waves (giving an arc of a cycle) in the case of a purely resistive reference and variable time delay used as the phase shift (the systematic magnitude error  Z and phase error  are shown).

 ° Relative magnitude error ΔZ/Z, %  ° Relative magnitude error ΔZ/Z, %  ° Phase error Δ Φ, °  ° Phase error Δ Φ, ° Relative magnitude error ΔZ/Z, % a) ordinary rectangular waveformsb) rectangular waveforms with shortened pulses ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 8 THE PHASOR ERRORS (Cont.1) Systematic magnitude error  Z and phase error  in case of applying rectangular waveform signals instead of the sine-wave signals to a purely resisitive element.

Z, R 0 Φ f, kHz ΔZ R 0 ΔΦ f, kHz t/T The 1 st harmonic All the harmonics are coinciding Relative magnitude of harmonic Order of harmonics The frequency response characteristics of the typical equivalent circuit achieved using ordinary rectangular waveforms as excitation and reference signals. The phasor errors can reach 5 deg and 10%. 200ohm 500ohm 1.75nF ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 9 THE PHASOR ERRORS (cont.2) Equivalent of a tissue segment ( myocardium ) used.

Z, R0Z, R0 Φ f, kHz ΔZ R 0 ΔΦ 18º 30º The 1 st harmonic t/ T The coinciding harmonics Relative magnitude of harmonic Order of harmonics The frequency response characteristics of the typical equivalent circuit achieved using rectangular waveforms with shortened pulses as excitation and reference signals. The phasor errors do net exceed 0.2 deg and 0.3%. 200ohm 500ohm 1.75nF ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 10 THE PHASOR ERRORS (cont.3) Equivalent of a tissue segment ( myocardium ) used.

Proposed lock-in signal conversion techniques on the basis of rectangular waveforms with shortened pulses is sufficiently simple and power efficient to be used in implantable biomedical devices. Despite its simplicity, it ensures acceptable estimates of the real (Re) and imaginary (Im) parts of the electrical bioimpedance. Obtained estimations are trustable for determination of the beat- to-beat stroke volume and duration of systolic and diastolic intervals, which are playing an important role in the adaptive adjustment of pacing rate, and in maintaining of the required level of myocardium's energy supply. ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 11 CONCLUSIONS

Acknowledgments This work is supported by Estonian Science Foundation, grants 5892, 5897, and 5902, and partially by Japan Society for the Promotion of Science (JSPS) 2003 postdoctoral fellowship program. REFERENCES J.G. Webster (Ed.), Design of Cardiac Pacemakers A rate adpative pacemaker. Internat. patents PCT WO and PCT WO 00/57954, M. Min, A. Kink and T. Parve S. Grimnes and Ų.G. Martinsen, Bioimpedance and Bioelectricity Basics M. Min, O. Märtens and T. Parve, - Measurement. 27, no.1, 21 (2000). M. Min, T. Parve, V. Kukk and A. Kuhlberg, - IEEE Trans. Instrum. & Meas., 51, 674 (2002). A. Kuusik, R. Land, M. Min and T. Parve. - Internat. Journ. of BioElectroMagnetism, 5, 1, 23 (2003). A method and a device for measuring electrical bioimpedance. International patent application PCT/EE03/00006, filed , M. Min, A. Kink, R. Land, T. Parve. Thank you for your attention! ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 12 Resuscitation of an animal (pig) heart Resuscitation of an animal (pig) heart in the Laboratory of Bionics at the Chair of Electronic Measurements, Department of Electronics, Tallinn University of Technology, ESTONIA

Using of intracardiac electrical bioimpedance (EBI) for pacing rate control requires trustable measurements. Usually, the short (<1ms) and low level (10  A) excitation pulses are used to get the response characterizing the impedance. Unfortunately, the response is weak and spread over the frequency range, and it is difficult to interpret the measurement results. In our novel approach, the excitation energy is concentrated at the frequency of interest, and reliable determination of both, the real (Re) and imaginary (Im) parts of the impedance is achieved at selected frequencies. Different bipolar pulse waveforms are used for excitation and for lock-in demodulator. Obtained EBI-based information is trustable for determination of the beat-to-beat stroke volume and duration of systolic and diastolic intervals, used for adaptive adjustment of the pacing rate, and for maintaining required myocardium’s energy supply level. 1. Introduction Pacing rate control, based on information extracted from the measurement of intracardiac electrical bioimpedance (EBI) is safe only when the measurement results are trustable [1]. This is not an easy task, particularly in case of implantable pacemakers, which have to operate for years without any service. Usually, therefore the simplest methods of EBI measurement are exploited, which work properly for determining the parameters of breathing activity and the cardiac activity [1]. In general, the EBI comprises more information, e.g., on the status of cardiac muscle (myocard) [1, 2]. This information can not be easily obtained from the results of pulse based EBI measurement, as it usually is based on analysis of the transient response processes. Typically, a short (<1ms) and low level (10μA) excitation pulses (Fig.1a) are used to get the response, which is used to determine the impedance [1]. Unfortunately, the response to a short pulse is spread over a wide frequency range and reflection of the certain components of the equivalent circuit in the response signal is weak. So it is difficult to interpret the measurement results, even if the simplest three- element equivalent circuit is used [3]. For three-element equivalent circuit, both the transient response and the frequency response measurement can be used. But in the case of real EBI, which in fact has a much more complicated equivalent circuit, it is quite complicated or even impossible to perform, because only limited computing resources are available in the implanted devices. 2. Method As the pulse form signals are very suitable for the implantable devices, it is of the interest to obtain the EBI measurement method, where the pulse form signals are used, though the term of complex impedance has been defined for the sine wave signals. But it is still possible to measure directly only the active and reactive components R and X of the complex impedance Ż = R + jX (or G and B of the complex admittance Y = G + jB), which are mutually in quadrature [3, 4, 5]. To avoid excessive mathematical conversion errors, R and X (or G and B) must be measured with required uncertainty, which is hardly achievable in the implantable devices. In our novel approach, the pulse waves are successfully used for high precision EBI measurements thanks to using of the lock-in approach, where the excitation energy as well as measurement sensitivity are concentrated at the frequency of interest, and reliable determination of both, the real (Re) and imaginary (Im) parts of the impedance is achieved at selected frequencies [6]. The block diagram of the lock-in EBI measurement system based on application of the novel pulse waveform signals in Fig. 2, where traditional lock-in system is modified without introducing significant complexity. Essential is to reduce the higher odd harmonic content of the excitation signal, and to decrease the sensitivity of the switching-type synchronous detectors to the lower order of harmonics of the excitation signal. The simplest appropriate approximation of the sine wave is shortening of the rectangular signal pulses and introducing zero-level intervals, yielding spectrum, given by: (1) where - a is the magnitude value of the pulse signal, b characterises the shortening of pulses, and is equal to the duration of the signal’s zero value segment within half period (b = 0…  /2). According to Eq.(1), from all of the easy-to-generate waveform pairs with maximally different harmonic content, the best one is consisting of waveforms having 30° (  /6) and 18° (  /10) pulse shortening, which removes the harmonics 3(2n+1) and 5(2n+1) correspondingly from the signal spectra. As different bipolar pulse waveforms are used for excitation, and for lock-in demodulation (Fig.1b), the errors caused by higher odd harmonics are reduced significantly [6]. In the case of typical three-element equivalent circuit the systematic error of determining the frequency response of impedance is reduced to a level not exceeding 0.3% (against 10% in the case of using common rectangular waveforms). In Fig. 3 a block diagram of the modified synchronous detector is shown, which is modified in comparison with the conventional switching type SD. The operating mode with shortened pulses is achieved by introducing the third, zero-gain phase of the synchronous detector [7]. ICE2004, Kyoto, June 27-July 1, 2004 Measurement of Intracardiac Bioimpedance in Rate Adaptive Pacemaker A. Kuusik, R. Land, M. Min, T. Parve, G. Poola ( Tallinn University of Technology, Tallinn, Estonia ) 13