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`EXHIBIT 2006
`EXHIBIT 2006
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`Blood Pressure, 2015; Early Online: 1–5
`
` ORIGINAL ARTICLE
`
` Continuous blood pressure measurement using the pulse transit time:
`Comparison to intra-arterial measurement
`
` ANDREAS PATZAK 1 , YURI MENDOZA 2 , HEIKO GESCHE 1 & MARTIN KONERMANN 2
`
` 1 Institut f ü r Vegetative Physiologie, Charit é -Universit ä tsmedizin Berlin, Berlin, Germany, and 2 Department of
`Internal Medicine, Marien-Hospital, Kassel, Germany
`
` Abstract
` Continuous blood pressure (BP) measurement allows the investigation of transient changes in BP and thus may give insights
`into mechanisms of BP control. We validated a continuous, non-invasive BP measurement based on the pulse transit time
`(PTT), i.e. BP PTT , by comparing it with the intra-arterial BP (BP i.a. ) measurement. Twelve subjects (fi ve females and seven
`males) were included. BP i.a. was obtained from the radial artery using a system from ReCor Medical. Systolic and diastolic
`BP were calculated using the PTT (BP PTT , SOMNOscreen ™ ). PTT was determined from the electrocardiogram and the
`peripheral pulse wave. The BP was modulated by application of increasing doses of dobutamine (5, 10, 20 μ g/kg body mass).
`Systolic BP PTT and systolic BP i.a. correlated signifi cantly ( R ⫽ 0.94). The limits of agreement in the Bland—Altman plot
`were ⫾ 19 mmHg; the mean values differed by 1 mmHg. The correlation coeffi cient for the diastolic BP measurements was
` R ⫽ 0.42. The limits of agreement in the Bland—Altman plot were ⫾ 18 mmHg, with a mean difference of 5 mmHg in favour
`of the BP PTT . The study demonstrates a signifi cant correlation between the measurement methods for systolic BP. The results
`encourage the application of PTT-based BP measurement for the evaluation of BP dynamics and pathological BP changes.
`
` Keywords: Blood pressure , pulse transit time , validation
`
` Introduction
`(BP)
` Cuff-based methods of blood pressure
`measurement are widely used and robust. Pathological
`changes in BP can be diagnosed in majority of the
`cases (1,2). Most of these methods work discontinu-
`ously with gaps of some minutes ’ duration between
`consecutive measurements. The sampling rate in
`ambulatory BP monitoring is four times per hour dur-
`ing daytime and two times per hour during night-time.
`However, the detection of transient changes in BP due
`to respiratory events requires BP sampling in the range
`of seconds. Several non-invasive methods have been
`developed with the aim of measuring BP continuously.
`They are mainly based on the principle of Penaz (3,4).
`These cuff-based techniques also have some disadvan-
`tages, which
`limit their application
`in practical
`medicine. The necessity for calibration during the mea-
`surement period, which interrupts the measurement,
`their sensitivity to postural changes and the high price
`hamper their distribution (4,5). A more indirect
`
`method for the determination of BP relies on the
`relation between BP and the pulse wave velocity
`(PWV). Studies have shown a correlation between car-
`diovascular parameters and systolic BP measured using
`the pulse transit time (PTT) in patients with sleep
`apnoea (6,7). Also, a strong correlation between sys-
`tolic BP measured using the PTT and BP measured
`by reference methods was shown in experimental and
`clinical studies (8--10). PWV is a function of arterial
`stiffness, which is affected by several factors including
`BP. Since the arterial vessel status differs individually
`and is infl uenced by vascular age and several diseases
`such as arteriosclerosis, diabetes and other cardiovas-
`cular diseases (11), the determination of absolute BP
`using PTT requires a calibration. Recently, a one-point
`calibration was introduced, which drastically reduces
`the effort of such a procedure in practical medicine
`(8). Although validation studies of the PTT-based
`method have been successfully performed, compari-
`sons of BP determination by PTT with the gold
`
` Correspondence: Prof. Dr. med. A. Patzak, Institut f ü r Vegetative Physiologie, Charit é -Universit ä tsmedizin Berlin, 10117 Berlin, Charit é platz 1, Germany.
`E-mail: andreas.patzak@charite.de
`
` (Received 21 September 2014 ; accepted 10 March 2015 )
`
`ISSN 0803-7051 print/ISSN 1651-1999 online © 2015 Scandinavian Foundation for Cardiovascular Research
`DOI: 10.3109/08037051.2015.1030901
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`A. Patzak et al.
`
`standard of BP measurements are rare (9). We there-
`fore conducted a study where the PTT-based method
`with one-point calibration was validated in comparison
`to intra-arterial measurements. The results suggest the
`applicability of this method for clinical investigations.
`
` Methods
`
` Subjects
`
` Twelve subjects, seven male and fi ve female, aged
`between 21 and 53 years were included in the study
`(Table I). The local ethics committee approved the
`study. The subjects gave written informed consent
`before the test.
`
` Protocol
`
` Measurements were performed in a lying position.
`The BP of the subject was increased by intravenous
`administration of dobutamine into the non-dominant
`arm. Dobutamine was applied in cumulative doses
`of 5, 10 and 20 μ g/kg body mass by changing the
`infusion rate of the infusion solution (125 mg dobu-
`tamine/50 ml NaCl 0.9%). Intra-arterial pressure
`was monitored using a 20-gauge catheter, which was
`inserted in the radial artery of the non-dominant
`arm. The catheter was connected by fl uid-fi lled tub-
`ing to a transducer, which was placed at the height
`of the heart. Transducer signals (ReCor Medical,
`Palo Alto, CA, USA) were transferred via an optical
`coupler to a SOMNOscreen ™ device.
` Simultaneously with the intra-arterial measure-
`ment, BP was determined by measuring the PTT using
`the SOMNOscreen. The electrocardiogram (ECG)
`and the fi nger plethysmography curve (dominant arm)
`were recorded with the SOMNOscreen polysomnogra-
`phy device (SOMNOmedics, Randersacker, Germany).
`The determination of PTT and calculation of PWV
`and BP were performed with DOMINO software (sup-
`plied with the SOMNOscreen). A modifi ed lead after
`
`Nehb was applied to obtain the ECG. Two bipolar elec-
`trodes were fi xed parasternally, at the second right
`intercostal space and fi fth left intercostal space. Another
`electrode was affi xed to the lower arm and served as
`the electrical ground. The plethysmography signal was
`obtained using a probe for fi nger plethysmography/ p O 2
`(SOMNOmedics, Randersacker, Germany).
`
` Data processing
`
` Recording and storage of the BP transducer together
`with ECG and plethysmography signal allowed an
`exact temporal alignment of the time series. Systolic
`and diastolic BP values from the intra-arterial record-
`ing were defi ned as the maximum and minimum
`values of the BP waveform following the last detected
`R-peak. Data pairs for systolic and diastolic BP PTT
`and BP i.a. were obtained for each minute of investiga-
`tion. The duration of the protocol was 9 min, result-
`ing in nine data pairs for each subject. PTTs were
`averaged for fi ve cycles to reduce the infl uence of
`respiration on the signal.
`
` Principle of blood pressure detection using pulse transit
`time
`
` PTT is defi ned as the time that a pulse wave needs
`to travel from the left ventricle to a certain site of the
`arterial system. In the present study, PTT results
`from the period between the R-wave of the ECG and
`the appearance of the pulse wave of the same cardiac
`beat at the site of the fi nger plethysmography. PWV
`is calculated as the quotient of the distance (from the
`midline of the breast bone to the fi nger, determined
`using the body correlation factor) and the PTT. The
`DOMINO software calculates the BP on the base of
`a PWV-BP relation and by application of the one-
`point calibration (8). The calibration was performed
`immediately before starting the data collection in
`each patient under resting conditions.
`
` Table I. Characteristics of the subjects and correlation coeffi cients (CC) for systolic (Syst.) and diastolic (Diast.) blood pressure.
`
`Subject no. Gender
`
`Age years) Height (cm)
`
`Body mass (kg)
`
`BMI (kg/m 2 )
`
`CC Syst.
`
`CC Diast. No. of data pairs
`
`1
`M
`23
`2
`M
`21
`3
`F
`25
`4
`M
`27
`5
`F
`37
`6
`M
`53
`7
`F
`27
`8
`F
`33
`9
`M
`29
`10
`F
`26
`11
`M
`23
`12
`M
`22
` M, male; F, female; BMI, body mass index.
`
`191
`180
`187
`177
`161
`169
`185
`173
`163
`183
`183
`163
`
`72
`72
`70
`87
`87
`72
`64
`62
`74
`50
`83
`70
`
`24.1
`22
`22.9
`28.4
`24.9
`23.2
`23.2
`21.0
`23.4
`19.8
`25.6
`22.6
`
`0.959
`0.934
`0.620
`0.912
`0.926
`0.781
`0.872
`0.799
`0.932
`0.937
`0.984
`0.966
`
`0.945
`0.685
`0.666
`0.810
`–0.672
`0.204
`0.679
`0.037
`–0.125
`0.367
`0.852
`0.012
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` Pulse transit time and blood pressure
`
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` Figure 1. Effect of dobutamine on (a) systolic blood pressure and (b) diastolic blood pressure measured intra-arterially (BP i.a., open
`boxes) and using the pulse transit time (BP PTT, grey boxes) presented as box-and-whisker plots: 5th, 25th, 50, 75th and 95th percentiles
`with outliers (dots). Doses 1–3 correspond to 5, 10 and 20 μ g/kg body mass. * Signifi cant difference compared to BP i.a.
`
` Statistics
`
` Data are presented as presented as box-and-whisker
`plots showing 5th, 25th, 50th, 75th and 95th percen-
`tiles, including outliers. The effect of dobutamine on
`the BP was tested using the Kruskal—Wallis test. The
`Mann—Whitney U test was used to test the differ-
`ences between the BP measured by the two methods
`for different doses of dobutamine. The linear rela-
`tionship between BP measured by both methods was
`analysed using Pearson correlation and tested with
`the t distribution. A value of p ⬍ 0.05 was considered
`signifi cant. The Bland—Altman plot was applied for
`investigation of the agreement between the two
`methods.
`
` Results
` Dobutamine treatment increased the systolic and
`diastolic BP i.a. in a dose-dependent manner. Median
`systolic BP rose from 126 mmHg (25th percentile:
`114 mmHg, 75th percentile: 154 mmHg) to 140
`mmHg (123.5 mmHg, 158.5 mmHg) and diastolic
`BP from 63 mmHg (59 mmHg, 70 mmHg) to 66
`mmHg (61.5 mmHg, 70.5 mmHg) in all patients for
`dose 1. The dobutamine doses 2 and 3 further
`elevated systolic BP to 159 mmHg (131 mmHg, 181
`
`mmHg) and 167 mmHg (147 mmHg, 170 mmHg),
`respectively. The values for the diastolic BP i.a. were
`64 mmHg (60 mmHg, 69 mmHg) and 64 mmHg
`(61 mmHg, 67 mmHg), respectively. BP measured
`by PTT changed similarly. The diastolic BP readings
`for doses 1 and 2 were signifi cantly greater than for
`BP i.a. (Figure 1).
` Figure 2(a) shows the scatterplot of systolic BP i.a.
`versus systolic BP PTT for all values measured. The data
`correlated signifi cantly. The correlation coeffi cient was
` R ⫽ 0.947 ( p ⬍ 0.01) and the regression coeffi cient
` R 2 ⫽ 0.896 ( n ⫽ 107) (Figure 2a). Individual correlation
`coeffi cients are given in Table I. The mean difference of
`the systolic BP of both methods was 0.78 mmHg in
`favour of systolic BP PTT and the limits of agreement
`were ⫾ 18.9 mmHg (Bland—Altman plot; Figure 2b).
` Diastolic BP obtained by the two methods cor-
`related less than the systolic BP data. The correlation
`coeffi cient was R ⫽ 0.419 ( p ⬍ 0.01) and the regres-
`sion R ⫽ 0.176 ( n ⫽ 108) (Figure 3a). The individual
`correlation coeffi cients differed clearly (Table I). The
`mean difference between BP i.a. and BP PTT was 4.78
`mmHg, i.e. the BP PTT was greater in the average
`of all measurements. The limits of agreement, also
`depicted in the Bland—Altman plot, were ⫾ 18.05
`mmHg (Figure 3b).
`
` Figure 2. (a) Scatterplot of systolic blood pressure measured i.a. (BPsyst i.a.) versus systolic blood pressure calculated from the pulse
`transit time (BPsyst PTT) for all subjects and measurements. (b) Bland—Altman plot of the systolic blood pressure (BP) data of all
`subjects and measurements ( n 107). The limits of agreement ( ⫾ 1.96 SD) were ⫾ 18.9 mmHg; the mean difference between the methods
`was 0.78 mmHg.
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`A. Patzak et al.
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`BPdiast PTT (mmHg)
`
`BPdiast i.a. (mmHg)
` Figure 3. (a) Scatterplot of diastolic blood pressure measured intra-arterially (BPdiast i.a.) versus diastolic blood pressure calculated from
`the pulse transit time (BPdiast PTT) for all subjects and measurements. (b) Bland—Altman plot of the diastolic blood pressure (BP) data
`of all subjects and measurements (n ⫽ 108). The limits of agreement ( ⫾ 1.96 SD) were ⫾ 18.05 mmHg; the mean difference between the
`methods was 4.78 mmHg.
`
` Discussion
` This study showed that systolic BP measured using
`the PTT and BP measured intra-arterially correlate
`signifi cantly. In the Bland—Altman plot, limits of
`agreement were about 18 mmHg. The correlation of
`diastolic BP values between the methods was
`signifi cant, but clearly smaller compared with the
`systolic BP. Limits of agreement were similar to those
`of the systolic BP in the Bland—Altman plot.
` Non-invasive and continuous BP monitoring
`have attracted increasing attraction because of the
`option to obtain complete time series with high time
`resolution and the ability to access to more informa-
`tion about the BP control systems. Transient changes
`in BP related to respiratory or central nervous system
`events are important for sleep medicine and sleep
`research (12). Fast and transient changes in BP
`cannot be obtained by traditional cuff-based, discon-
`tinuously working methods.
` Based on the fi nding of Moens and Korteweg,
`that the velocity of a longitudinal pressure wave is
`related to the elasticity of the arterial vessel and to
`the vessel dimension (both infl uenced by BP) (13),
`equipment for the indirect measurement of BP has
`been developed. Recent validation studies showed
`encouraging results regarding the applicability of this
`method in medicine (7,9,10,14–16). An important
`aspect in the application of this principle for BP mea-
`surement is the requirement to calibrate the measur-
`ing system (17,18). This is due to the individual
`mechanical properties of the vascular wall, modifi ed
`also by remodelling and arteriosclerosis, which infl u-
`ence the measurement (19–22). To circumvent the
`relevant effort of calibration, which does not fi t the
`clinical situation, a suitable one-point calibration has
`been recently introduced and validated in some stud-
`ies (8–10). However, there is only one study available
`in patients in which the gold standard (intra-arterial
`measurement of BP) was used as the reference method
`(9). In this study, the BP was not actively modulated
`in the subjects. Thus, the relatively small range of BP
`values may limit the signifi cance of the data. The aim
`
`of the present study was to validate the PTT-based
`BP measurement including one-point calibration
`using intra-arterial BP as a reference. The BP was
`elevated by application of dobutamine, which is a
`sympathomimetic,
`inotropic
`agent
`stimulating
` β 1 -receptors (23). It has been shown that dobutamine
`infl uences the cardiovascular system in a similar way
`to physical stimulation (exercise) (17).
` Dobutamine (5, 10 and 20 μ g/kg body mass)
`increased the median systolic BP in all subjects from
`about 126 mmHg to 167 mmHg; individual values
`were between 100 mmHg and 200 mmHg, giving a
`wide range of BP values. Remarkably, the average
`diastolic BP for all subjects changed much less,
`refl ecting the situation of physical load.
` Correlation analysis revealed a highly signifi cant
`relation between systolic BP i.a. and systolic BP PTT . This
`confi rms
`the observations of other
`studies
`(7,8,10,22,24). The mean values differed negligibly
`between the methods. The limits of agreement were 18
`mmHg in the Bland—Altman plot. These observations
`also agree with results from validation studies per-
`formed in healthy volunteers and patients, using the
`same PTT-based method (9). A signifi cant relationship
`between PTT and BP stimulated by dobutamine was
`also observed in anaesthetized mongrel dogs (17).
` The average diastolic BP PTT differed from BP i.a.
`(7.5 mmHg) and the correlation between the meth-
`ods was clearly smaller compared to the situation for
`systolic BP. Correlations varied considerably when
`comparing individuals. Small changes in diastolic BP,
`combined with a variability in BP measurement and
`determination, may be the reason. One can speculate
`that individual factors such as the pattern of the
`plethysmographic curve differ between subjects and
`that this resulted in a higher variability in the obtained
`PTT and PWV. However, this has not been system-
`atically investigated. Greater differences between
`diastolic BP i.a. and diastolic BP PTT have been dem-
`onstrated in a study using the same technique as in
`the present study (9). Both studies also coincide in
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`transit
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`the observation of limits of agreement of the
`Bland—Altman plot in the range of 18–20 mmHg.
` Strengths of the present study are the intra-arte-
`rial BP measurement as a reference and the pharma-
`cological modulation of the BP. However, this study
`also has some limitations. The small number of sub-
`jects constrains the signifi cance of the results. The
`volunteers were relatively young and did not suffer
`from cardiovascular diseases. More validation in
`patients with different diagnoses should be performed
`before the introduction of the method into clinical
`use. Furthermore, the time-frame of measurement in
`the present study is relatively short, which does not
`allow long-term investigation of the BP PTT .
` In conclusion, the present study demonstrates
`that measurement of BP using PTT offers a method
`for monitoring the systolic BP under clinical condi-
`tions. The systolic BP PTT shows a very good correla-
`tion with the gold standard of BP measurement.
`Furthermore, mean values did not differ and the lim-
`its of agreement in the Bland—Altman plot encour-
`age further optimization of the PTT-based method
`with one-point calibration.
`
`interest: A. Patzak advises
` Declaration of
`SOMNOmedics in development of methods for
`blood pressure measurement and has received hono-
`raria and travel support. The study was not supported
`by funding.
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`In Press
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