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(Hypertension. 1996;28:238-243.)
© 1996 American Heart Association, Inc.
Articles |
Noninvasive Assessment of Baroreflex Control in Borderline Hypertension
Comparison With the Phenylephrine Method
the Lown Cardiovascular Research Foundation, Brookline, Mass, and Duke University, Department of Psychiatry, Durham, NC.
Correspondence to Dr Paul Grossman, Lown Cardiovascular Research Foundation, 21 Longwood Ave, Brookline, MA 02146. E-mail pgrossman@bics.bwh.harvard.edu.
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Abstract |
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In this study, we examined the sensitivity of two recently developed noninvasive baroreflex measurement techniques to assess baroreflex control in hypertension. We assessed baroreflex sensitivity noninvasively from covariations of systolic pressure and RR interval using spectral analysis and sequence detection. The noninvasive estimates of baroreflex control were compared with estimates derived from phenylephrine-induced increases in systolic pressure and RR interval in normotensive subjects (n=27) and borderline hypertensive subjects (n=15). Baroreflex sensitivity was significantly reduced in the borderline hypertensive group relative to the normotensive group when assessed with the use of either the noninvasive or invasive methods to index baroreflex control. In addition, estimates obtained from the noninvasive methods were significantly correlated with baroreflex sensitivity assessed with the phenylephrine method (spectral: r=.48, P<.001; sequence: r=.50, P<.001). These findings suggest that spectral analysis and the sequence method provide viable alternatives to the pharmacological approach for estimation of baroreflex sensitivity in hypertension.
Key Words: baroreflex • hypertension, borderline • phenylephrine • spectrum analysis • heart rate • blood pressure
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Introduction |
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Advances in beat-by-beat blood pressure (BP) monitoring technology have now made possible noninvasive estimation of baroreflex sensitivity from the RR interval changes associated with spontaneous fluctuations in BP. This new methodology offers clear advantages over traditional techniques of assessing baroreflex control with neck suction or intravenous injections of vasoactive pharmacological agents.1 2 3 Specifically, the noninvasive nature of these new methods simplifies the test procedure, minimizes the risk, and permits measurement under a broad range of natural conditions, making these methods more appropriate in many research settings.
Noninvasive estimates of baroreflex sensitivity are obtained from beat-by-beat BP and heart rate recordings by one of two methods to extract concordantly changing systolic BP (SBP) and RR interval. Power spectral analysis provides a baroreflex estimate based on the RR interval changes associated with rhythmic BP oscillations over a range of frequencies reported to be associated with baroreflex functioning.4 5 Baroreflex sensitivity estimates obtained by spectral analysis are significantly correlated with estimates of baroreflex control obtained from phenylephrine-induced increases in SBP and RR interval.6
In contrast to this frequency-domain-based estimation of baroreflex sensitivity, a second recently developed method extracts covarying pressure and RR interval based on the magnitude of the changes occurring across sequential beats.7 8 In this technique, beat-by-beat BP and RR interval recordings are scanned for sequences in which SBP and RR interval concurrently increase or decrease for at least three consecutive beats. Baroreflex sensitivity is then assessed from the relationship between SBP and RR interval across these sequences. Significant positive correlations have been reported between baroreflex estimates obtained by the sequence method and from pharmacological manipulations of BP and RR interval.9 10
One disease process in which abnormal baroreflex control has been consistently documented is hypertension. Studies have shown that baroreflex sensitivity is negatively correlated with BP status,3 11 12 with stepwise reductions in sensitivity reported in the transition from borderline to established hypertension.13 In the present study, we compared baroreflex sensitivity in normotensive control and borderline hypertensive subjects using the phenylephrine method, the spectral method, and the sequence method to assess baroreflex sensitivity. Our primary objective was to assess whether the three techniques are equally sensitive at detecting reductions in baroreflex sensitivity in borderline hypertension. Second, we sought to validate the two noninvasive techniques, using the phenylephrine method of baroreflex assessment as a standard for comparison.
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Methods |
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Subjects
Fifty-eight normotensive and borderline hypertensive male and female volunteers, aged 25 to 44 years, were recruited by regional postings and newspaper advertisements. Recruitment criteria excluded individuals with any history of antihypertensive medication. Individuals who were greater than 30% above ideal body weight according to the 1983 Metropolitan Life Insurance tables were also excluded. All subjects read and signed a consent form approved by the Duke University Medical Center Institutional Review Board. On each of three screening sessions, scheduled at 1-week intervals, resting seated BPs were taken in triplicate by a trained technician using a stethoscope, mercury sphygmomanometer, and occlusion cuff of appropriate size. Subjects were accepted for study if their average screening SBP was 160 mm Hg or less and their average screening diastolic BP was 99 mm Hg or less. The present study sample included subjects with normal BP (<130/85 mm Hg) and with borderline high BP (130 to 159/85 to 99 mm Hg). The borderline high BP group was composed of subjects with high normal BP (130 to 139/85 to 89 mm Hg) and stage 1 (mild) hypertension (140 to 159/90 to 99 mm Hg) according to the most recent criteria set forth by the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure.14 Demographic characteristics of subjects according to BP category are presented in Table 1
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Baroreceptor Reflex Assessment Procedures
All measurements were taken while subjects were in a supine posture and at least 6 hours after they had last consumed caffeine. BP was measured continuously by the Finapres (Ohmeda) noninvasive BP monitor, with the appropriately sized cuff applied to the middle finger of the left hand. This instrument, which uses the vascular unloading technique to measure SBP, diastolic BP, and mean BP on a beat-by-beat basis, has been validated against intra-arterial measures under various conditions, including pressor responses to phenylephrine.8 15 Specifically, these studies8 15 showed that phenylephrine-derived baroreflex slopes assessed with SBP values from the Finapres were highly correlated (r=.92) with the phenylephrine slopes assessed with intra-arterially measured SBP, supporting the use of finger BP in the study of arterial baroreflex. The arm was supported at or close to the level of the heart, with precise placement chosen to equate Finapres mean arterial pressure with mean arterial pressure in the brachial artery measured by the auscultatory technique. An electrocardiogram was recorded with three disposable electrocardiographic chest electrodes, permitting measurement of RR interval as the time interval between successive R waves.
Spontaneous Fluctuations in Arterial Pressure and RR Interval
After subjects had rested 20 minutes in the supine position, 5 minutes of continuous BP and RR interval measurements were recorded for noninvasive assessment of baroreflex sensitivity. The automatic servo-adjustment option of the Finapres was disabled for the 5-minute recording period. The spontaneous fluctuations in SBP and RR interval were analyzed with the following two methods for indexing baroreceptor sensitivity.
Spectral Technique
Beat-by-beat SBP and RR interval were edited for artifacts, interpolated, and sampled at a frequency of 4 Hz to obtain equally spaced events. Power spectra were estimated with the Welch algorithm.16 Specifically, a fast Fourier transform was applied to the data after detrending and application of a Hanning filtering window. Power spectra were derived as the average of 60-second data segments, overlapping by half. For each 60-second segment, 256 points were analyzed, which included 240 sampled points with zero padding. Typical beat-by-beat SBP and RR interval recordings, together with the respective power density spectra, are shown in Fig 1.
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SBP oscillations in the frequency range between 0.070 and 0.129 Hz represent rhythmic fluctuations in vasomotor activity, also known as Mayer waves. These BP waves most often show a 10-second periodicity and are substantially reduced after pharmacological blockade of 
-adrenergic receptors,17 suggesting an underlying involvement of sympathetic vasomotor activity. RR interval oscillations at this frequency range result primarily from baroreflex-mediated adjustments in sympathetic and parasympathetic control of heart rate17 18 and are reduced after sinoaortic denervation.19 20
We performed cross-spectral analysis to assess the magnitude of the RR interval changes associated with SBP oscillations. Coherence between the changes in SBP and RR interval was required to be at least 0.5 for acceptance of points as baroreflex estimates. Baroreflex sensitivity was estimated from the modulus of the cross spectrum of RR interval and SBP for frequencies ranging from 0.070 to 0.129 Hz.
Fig 2 shows the coherence and cross spectra of RR interval and SBP for one representative subject. Note that the coherence between RR interval and SBP is high across the 0.10-Hz frequency band as well as across the respiratory frequency band (in this subject, the respiratory frequency band occurs at 0.2 Hz). Although the transfer function relating respiratory-related oscillations in SBP and RR interval may describe baroreflex sensitivity,21 22 this remains to be unequivocally demonstrated. (The fact that parasympathetic blockade abolishes respiratory-related variations in heart rate without reducing respiratory-related variations in BP23 suggests that the respiratory-related heart rate oscillations are baroreflex-mediated responses to direct mechanical effects of respiration on BP.) We therefore report findings related to the respiratory-based transfer function as separate ancillary analyses.
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Sequence Technique
Command language written for use with SAS (SAS Institute) was used for scanning of 5-minute recordings of BP and RR interval for sequences in which SBP and the subsequent RR interval progressively increased or decreased over three consecutive beats. Sequences were selected if successive pressure pulses differed by at least 1.0 mm Hg and successive RR intervals differed by at least 5.0 milliseconds. Linear regressions relating RR interval to SBP were plotted for each sequence, and the slope of the function was used as an estimate of baroreflex sensitivity. Slopes derived from all sequences were pooled so one measure of baroreflex sensitivity was obtained for each individual.
Pharmacological Manipulation of Arterial Pressure
A 21-gauge butterfly needle was inserted into an antecubital vein of the right arm and attached to a three-way stopcock with a 20-mL syringe containing heparinized saline connected to the main port. Tuberculin syringes were prepared containing phenylephrine hydrochloride solutions at 25, 50, 100, 200, 400, 600, and 800 µg. All phenylephrine doses were prepared at a constant volume of 0.5 mL. Each phenylephrine dose was administered as a bolus by attaching the tuberculin syringe to the secondary port of the stopcock. The 0.5-mL bolus of phenylephrine solution was displaced into the infusion tubing of the butterfly needle (total tubing volume=0.7 mL). The 0.5-mL phenylephrine bolus was pushed into the vein by injection of 2 mL saline over approximately 1 second. The first dose injected was 25 µg, with each higher dose in the series injected after at least 5 minutes of recovery or until mean arterial pressure had returned to resting levels, usually within 5 to 10 minutes. In this test, no further doses were administered when a given dose in the series produced an increase in mean arterial pressure of 25 mm Hg or greater. Only doses that produced an increase in SBP of at least 15 mm Hg were used for derivation of baroreflex sensitivity. Fig 3 shows typical BP and RR interval responses to phenylephrine. Segments were selected for analysis starting at the beginning of the SBP increase and ending just before the peak change in SBP as originally described.2 Linear regressions were applied to the values, with SBP used as the independent variable and RR interval as the dependent variable (Fig 4); only regressions with a correlation coefficient greater than .80 were considered. Baroreflex sensitivity was estimated for each individual from the average of all qualified regression coefficients (on average, two doses met criteria for pressure change and correlation). In some instances, a secondary increase in pressure occurred 10 to 15 seconds after the peak of the initial pressor response. These delayed responses were not included in the regression analyses.
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Statistical Analyses
ANOVA tests were used for evaluation of the effects of BP category (normotensive/borderline hypertensive) on the three baroreflex sensitivity measures (pharmacological/sequence/spectral). Regression analyses were also used for comparison of the baroreflex sensitivity measures obtained by the three different techniques.
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Results |
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Of the 58 subjects recruited for the study, the data from 16 could not be used because of the following reasons. Phenylephrine-derived baroreflex slopes could not be obtained in 7 subjects because of difficulties with the use of this technique (eg, signal artifact, difficulties with the intravenous line, poor correlation between RR interval and SBP, outlier data). Spectral analysis-derived estimates of baroreflex sensitivity could not be obtained in 9 subjects because of either movement or ectopic-related artifacts creating a nonstationary time series or because of poor coherence between pulse interval and SBP. (In 5 of these subjects, spectral analysis could have been performed on smaller segments of the 5-minute recording; however, a shorter time series may have adversely affected the accuracy of the sequence method-derived baroreflex slopes.)
Table 2 shows baroreflex sensitivity estimated with the phenylephrine method, the spectral method, and the sequence method. Baroreflex sensitivity measured with each method was significantly lower in the borderline hypertensive group than the control group. The mean hypertensive-normotensive difference was comparable for each method. Specifically, baroreflex sensitivity was attenuated by approximately 35% in the borderline hypertensive group compared with the normotensive group.
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As shown in Figs 5 and 6, both the spectral estimates and the sequence method estimates of baroreflex sensitivity were significantly correlated with the baroreflex estimates derived from phenylephrine-induced changes in SBP and RR interval (spectral estimate: n=42, r=.48, P<.001; sequence estimate: n=42, r=.50, P<.001). (Significant correlations were also observed between phenylephrine-derived baroreflex estimates and spectral analysis-derived baroreflex estimates uncorrected for coherence [n=42, r=.48, P<.001].) Both regressions revealed slopes substantially less than 1 (Spectral Estimate=4.16+0.27xPhenylephrine Estimate; Sequence Estimate=7.45+0.39xPhenylephrine Estimate). The spectral-derived and sequence-derived estimates were more strongly correlated with each other than with the pharmacological method estimates (n=42, r=.76, P<.001; Fig 7); in addition, the regression analysis revealed slopes not different from 1 (Sequence Estimate=4.86+1.05xSpectral Estimate).
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; n=27) and borderline hypertensive subjects (
; n=15); Spectral Estimate=4.16+0.27xPhenylephrine Estimate. Frequency range for spectral estimates: 0.070 to 0.129 Hz.
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Ancillary Findings
Comparisons of correlation coefficients indicated that the sequence-derived baroreflex estimates were significantly more highly correlated (P<.005) with the transfer function estimates derived over the respiratory frequency (r=.94, P<.0001) than with the spectral baroreflex estimate derived across the 0.10-Hz frequency band (r=.76, P<.001).
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Discussion |
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This study provides evidence that spectral analysis and the sequence method are viable alternatives to the conventional method of measuring baroreflex control by pharmacological manipulation of BP. Both of the noninvasive methods accurately track the reduction in baroreflex sensitivity described by earlier studies to be present in borderline hypertensive subjects when assessed by phenylephrine-induced increases in pressure and RR interval.13 As reported previously,13 baroreflex sensitivity measured by either the phenylephrine technique or the two noninvasive techniques was reduced by approximately 35%.
Although the phenylephrine method is widely used for examination of baroreflex sensitivity, it is limited in several respects. First, there is little standardization of the phenylephrine procedure. In most cases, two or three bolus doses of phenylephrine, sufficient to increase SBP by 15 to 20 mm Hg, are used. However, sometimes phenylephrine is infused over several minutes. Whether phenylephrine is given as a bolus or an infusion is important because the mode of administration influences both the baroreflex estimate magnitude and the autonomic effectors underlying the reflex bradycardic response.24 The phenylephrine method is also limited in that it describes only reflex bradycardic responses. A full description of baroreflex sensitivity requires evaluation of the reflex tachycardic arm of the baroreflex arc. Administration of multiple bolus doses of phenylephrine in conjunction with a depressor agent, such as nitroprusside, is a preferred pharmacological approach to baroreflex estimation because this method allows generation of a complete range of points that can be used in composing a baroreflex curve, which supplies additional information regarding the range of operation for the baroreceptor-heart rate response.
In addition to the methodological limitations of the phenylephrine method, the exogenous nature of the phenylephrine stimulus may affect the estimation of baroreflex sensitivity. For instance, phenylephrine-induced changes in venous compliance and venous return may affect baroreflex control of heart rate.25 More importantly, phenylephrine activates baroreceptor pathways independently of the pressor effects of phenylephrine. Specifically, phenylephrine activates 1-adrenergic receptors in the smooth muscle of the aortic arch and carotid sinus, which increase baroafferent discharge and sensitize baroafferent responses to changes in pressure.26 27 Furthermore, phenylephrine produces direct effects on preganglionic and postganglionic cardiac parasympathetic nerves, which may alter the derived index of baroreflex sensitivity.28 29
The present findings of higher levels of baroreflex sensitivity with the phenylephrine method relative to the two noninvasive methods may be attributable to the exogenous effects of phenylephrine (ie, direct activation of baroafferents).26 27 It is unlikely that the larger baroreflex estimates result from the added contribution of cardiac sympathetic nerve activity to the reflex bradycardic response because blockade of cardiac sympathetic control does not reduce the reflex bradycardic response to bolus phenylephrine.30 31
The noninvasive assessment of baroreflex sensitivity by spectral analysis and the sequence method offers several advantages over the vasoactive drug method of baroreflex assessment. First and foremost, these noninvasive methods provide equivalent information with less risk and discomfort to the patient. Although the risk associated with vasoactive drug injection is minimal in young healthy individuals, risk may be increased in individuals with certain types of cardiovascular disease. In addition, the maintenance of patent intravenous lines and the injection process itself can be associated with increased anxiety in some patients. This increased anxiety is a potential confounder because increased levels of stress have been associated with reduced levels of baroreflex sensitivity.32 33 Second, because the noninvasive methods of baroreflex sensitivity assessment require only 5 minutes of BP and RR interval recording, these techniques are more practical than the pharmacological methods and can be performed under a broad range of research settings. Furthermore, the noninvasive methods provide a less restricted representation of baroreflex control than the phenylephrine method because they describe reflex tachycardic as well as reflex bradycardic responses.
Previous studies have reported high correlations between pharmacologically derived baroreflex estimates and baroreflex estimates derived by spectral analysis (r=.94, n=8)6 or by the sequence method (r=.96, n=8).9 The present study extends these earlier findings by showing that the pharmacological method and the noninvasive methods are significantly correlated in a larger population sample. The fact that the correlations found by the present study (spectral analysis versus phenylephrine: r=.48, n=42; sequence method versus phenylephrine: r=.50, n=42) are smaller than those previously reported may reflect the greater heterogeneity of the sample examined in the present study (mixed sex, race, and BP status) compared with the earlier studies (all normotensive male subjects).
The findings that both the spectral and sequence methods describe equivalent reductions in baroreflex sensitivity with hypertension and are highly intercorrelated (r=.76) with a regression coefficient of unity suggest that these noninvasive measures provide similar information regarding baroreflex sensitivity. The choice of noninvasive baroreflex method (ie, spectral versus sequence) will therefore depend primarily on accessibility to computer software. The two noninvasive techniques differ, however, in the number of data-processing steps and in the amount of supplemental information supplied. For instance, spectral analysis involves not only editing for artifacts; beat-by-beat data are also typically interpolated, sampled at a constant frequency, detrended, and filtered so that a suitable input file for Fourier transform and cross-spectral analysis can be obtained. In contrast, the linear regression analysis of sequences with covarying SBP and RR interval is relatively more straightforward. However, spectral analysis offers the advantage of providing estimates of vasomotor tone and respiratory sinus arrhythmia from the 0.10-Hz Mayer wave SBP frequency band and from the separate respiratory-related RR interval variations, respectively. Spectral analysis also permits a more in-depth analysis of differences in baroreflex sensitivity over time or between subjects, given that differences in baroreflex sensitivity can be dissected into variations in the magnitude of BP Mayer waves as well as variations in the magnitude of concordant RR interval oscillations. Knowledge of which of these changes are responsible for alterations in baroreflex sensitivity is likely to provide important information about the specific autonomic mechanisms involved.
The present findings of a strong, positive correlation between the sequence estimate and the spectral transfer function assessed across the respiratory band strengthen increasing evidence supporting the baroreflex nature of the transfer function relating RR interval to SBP at the respiratory frequency.21 22 23 34 This close correlation also shows that the sequence method reflects baroreflex control at the respiratory frequency more closely than baroreflex control estimated over the frequency range associated with the 10-second cardiovascular rhythms. Further studies are needed to test whether the occurrence of sequences of covarying SBP and RR interval is linked to cyclic inspiratory influences.35
In conclusion, recently developed noninvasive methods provide valid means of baroreflex sensitivity assessment. Both spectral analysis and the sequence method accurately describe the attenuation of baroreflex control associated with borderline hypertension and are significantly correlated with phenylephrine-derived baroreflex estimates. Noninvasive assessment of baroreflex control is easily accomplished through analysis of beat-by-beat variations in SBP and RR interval and is associated with minimal discomfort and risk. Future studies are needed to clarify whether these new noninvasive methodologies will also be comparable with the phenylephrine method in the stratification of individual patients at increased risk of mortality associated with cardiovascular disease.36 37
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Acknowledgments |
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This study was supported by funds from the Lown Cardiovascular Research Foundation; by National Institutes of Health grant HL-49427; and by M01-RR-30, National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health. The authors acknowledge the helpful comments of Dr Peter Sleight and the anonymous reviewer. The authors are also grateful to Kristy Johnson and Tamara Green for technical support.
Received October 11, 1995;
first decision November 24, 1995; first decision February 27, 1996;
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 L. J. Badra, W. H. Cooke, J. B. Hoag, A. A. Crossman, T. A. Kuusela, K. U. O. Tahvanainen, and D. L. Eckberg Respiratory modulation of human autonomic rhythms Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2674 - H2688. [Abstract] [Full Text] [PDF]
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K. Sevre, J. D. Lefrandt, G. Nordby, I. Os, M. Mulder, R. O. B. Gans, M. Rostrup, and A. J. Smit Autonomic Function in Hypertensive and Normotensive Subjects : The Importance of Gender Hypertension, June 1, 2001; 37(6): 1351 - 1356. [Abstract] [Full Text] [PDF]
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G. Nollo, A. Porta, L. Faes, M. Del Greco, M. Disertori, and F. Ravelli Causal linear parametric model for baroreflex gain assessment in patients with recent myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1830 - H1839. [Abstract] [Full Text] [PDF]
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 K. D Monahan, F. A Dinenno, H. Tanaka, C. M Clevenger, C. A DeSouza, and D. R Seals Regular aerobic exercise modulates age-associated declines in cardiovagal baroreflex sensitivity in healthy men J. Physiol., November 15, 2000; 529(1): 263 - 271. [Abstract] [Full Text] [PDF]
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L. L. Watkins, P. Grossman, R. Krishnan, and J. A. Blumenthal Anxiety Reduces Baroreflex Cardiac Control in Older Adults With Major Depression Psychosom Med, May 1, 1999; 61(3): 334 - 340. [Abstract] [Full Text] [PDF]
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L. Rudas, A. A. Crossman, C. A. Morillo, J. R. Halliwill, K. U. O. Tahvanainen, T. A. Kuusela, and D. L. Eckberg Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1691 - H1698. [Abstract] [Full Text] [PDF]
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M. V. Pitzalis, A. Passantino, F. Massari, C. Forleo, C. Balducci, G. Santoro, F. Mastropasqua, G. Antonelli, and P. Rizzon Diastolic Dysfunction and Baroreflex Sensitivity in Hypertension Hypertension, May 1, 1999; 33(5): 1141 - 1145. [Abstract] [Full Text] [PDF]
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P. van de Borne, S. Heron, H. Nguyen, P. Unger, M. Leeman, J. L. Vincent, and J. P. Degaute Arterial Baroreflex Control of the Sinus Node During Dobutamine Exercise Stress Testing Hypertension, April 1, 1999; 33(4): 987 - 991. [Abstract] [Full Text] [PDF]
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 J. Freitas, S. Pereira, P. Lago, O. Costa, M.J. Carvalho, and A. FalcaO de Freitas Impaired arterial baroreceptor sensitivity before tilt-induced syncope Europace, January 1, 1999; 1(4): 258 - 265. [Abstract] [PDF]
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 M. V. Pitzalis, F. Mastropasqua, F. Massari, A. Passantino, R. Colombo, A. Mannarini, C. Forleo, and P. Rizzon Effect of respiratory rate on the relationships between RR interval and systolic blood pressure fluctuations: a frequency-dependent phenomenon Cardiovasc Res, May 1, 1998; 38(2): 332 - 339. [Abstract] [Full Text] [PDF]
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 M. V. Pitzalis, F. Mastropasqua, A. Passantino, F. Massari, L. Ligurgo, C. Forleo, C. Balducci, F. Lombardi, and P. Rizzon Comparison Between Noninvasive Indices of Baroreceptor Sensitivity and the Phenylephrine Method in Post–Myocardial Infarction Patients Circulation, April 14, 1998; 97(14): 1362 - 1367. [Abstract] [Full Text] [PDF]
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 P. B. Persson Spectrum analysis of cardiovascular time series Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1997; 273(4): R1201 - R1210. [Abstract] [Full Text] [PDF]
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H. L. Ristuccia, P. Grossman, L. L. Watkins, and B. Lown Incremental Bias in Finapres Estimation of Baseline Blood Pressure Levels Over Time Hypertension, April 1, 1997; 29(4): 1039 - 1043. [Abstract] [Full Text]
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