Author + information
- Received March 17, 2004
- Revision received July 26, 2004
- Accepted July 29, 2004
- Published online November 2, 2004.
- Salvatore M. Romano, PhD* (, )
- Chiara Lazzeri, MD,
- Marco Chiostri, MD,
- Gian Franco Gensini, MD and
- Franco Franchi, MD
- ↵*Reprint requests and correspondence:
Dr. Salvatore M. Romano, Department of Critical Care, School of Medicine, University of Florence, Viale Morgagni 85, I-50134 Florence, Italy
Objectives The aim of this study was to noninvasively define the hemodynamic profile characterizing the early response to tilting.
Background The mechanisms causing orthostatic intolerance have not been fully elucidated. Usually, patients undergoing tilt test are studied in a time-consuming way. Moreover, the test can cause discomfort to the patient and even be potentially hazardous.
Methods Nineteen orthostatic intolerant patients (OIP), compared with 22 healthy subjects (HS), performed head-up tilt test while their arterial pressure waveform was noninvasively recorded. We elaborated data using the Pressure Recording Analytical Method to obtain hemodynamic parameters, then analyzing the variables by discriminant analysis.
Results Compared with HS, OIP showed lower stroke volume index (SVI) values even in baseline conditions associated with higher values of systemic vascular resistance (SVR) and heart rate (HR). From the third minute of the tilted position and until symptoms appeared, patients exhibited lower values of blood pressure (BP) and SVI and higher HR values but no difference in SVR. At termination, patients showed a further significant reduction in BP and SVI and a persistent increase in HR.
Conclusions This investigation underlines: 1) the possibility of beat-to-beat monitoring of hemodynamic changes during tilting; 2) the cardiovascular profile of OIP at rest, characterized by lower SVI and higher SVR and HR; 3) the maladaptive response to postural challenge of OIP mainly identifiable in impaired vascular regulation; and 4) the possibility of detecting parameters that enable prompt identification of the positive response to tiltingin these patients, thus guiding the duration of the test.
We have studied patients with orthostatic intolerance (OIP) or postural tachycardia syndrome, which is characterized by symptoms such as lightheadedness, palpitations, fatigue, blurred vision, dizziness, and occasionally syncope (1–3). These symptoms usually occur after upright posture is assumed and are associated with rapid development of tachycardia. Though the pathophysiologic background of chronic orthostatic intolerance is still unclear, it is generally accepted that autonomic dysfunction can be a pathogenetic hallmark of the disease and that chronic orthostatic intolerance may constitute part of a spectrum of disorders of orthostatic cardiovascular homeostasis, including the neuromediated syncope and perhaps the chronic fatigue syndrome (4).
In patients with chronic orthostatic intolerance, autonomic dysfunction appears to comprise a hyperadrenergic state during supine rest and a blunted sympathetic vasoconstrictor response of muscle blood vessels to standing, accompanied by an augmented cardiac sympathetic response (5). Though the autonomic profile in these patients has been extensively studied (5–7), several questions remain unresolved, especially concerning hemodynamic response to orthostasis. In particular, is cardiac output increased as would be expected given the faster heart rate (HR)?
Insights into disorders of orthostatic homeostasis have been enhanced by the advent of tilt table testing (8), which allows simulation of standing in carefully monitored and controlled conditions. The continuous, noninvasive measurement of blood pressure (BP) and pulse pressure wave morphology has attained widespread use.In particular, the Finapres device (Ohmeda, Englewood, Colorado) has provided a useful alternative for continuous intra-blood measurement in a variety of situations, including short-lasting orthostatic stress (9–11). Moreover, employment of the Modelflowor Pulse Contour Method (PCM) has enabled researchers to compute continuous noninvasive (finger) measurements of the stroke volume in healthy subjects (HS) (12) as well as in patients affected by chronic autonomic failure (13). This methodology is limited by the need for calibration (i.e. by thermodilution) to perform reliable measures of cardiac output, able to reflect its physiologic and pathologic variations (14). However, without calibration, the calculation of arterial impedance and thereafter of stroke volume can be obtained only by extrapolation, using values referring to a previously studied population (matched for age, gender, and anthropometric data) (14).
The aim of the present investigation is to test the usefulness of a beat-to-beat evaluation of stroke volume and related parameters during head-up tilt test in OIP, with the aid of the new, noninvasive, Pressure Recording Analytical Method (PRAM). This method, different from PCM, is based on the change of the pressure wave morphology, without any precalculated parameter or external calibration (15).
Nineteen consecutive patients (11 males, 8 females; age 36 ± 17 years, range 22 to 64 years) with debilitating symptoms consistent with orthostatic intolerance and 22 HS as controls (13 males, 9 females; age 47 ± 12 years, range 20 to 72 years) gave their informed consent to participate in the study. Patients referred to our laboratory for investigation of symptoms of chronic orthostatic intolerance were included in this study if they met the following criteria: 1) sustained increase in HR of at least 30 beats/min or HR more than 120 beats/min during active standing; 2) absence of orthostatic hypotension (declines in the ratio of systolic blood pressure [SBP] to diastolic blood pressure [DBP]during active standing lower than 10 mm Hg); 3) duration of symptoms longer than three successive months; and 4) daily occurrence of at least two of the following symptoms: palpitations, abnormal sweating, lightheadedness or dizziness, blurred vision, and presyncope or faintness sensation during upright posture (5,16). Chronic fatigue, nausea, vomiting, headache, and syncope were less frequent, as previously described (16,17). Their clinical features are presented in Table 1.In none of our patients was the onset of symptoms attributed to earlier viral infection.No differences were observed in body surface area between patients and control subjects (patients: 1.71 ± 0.16 m2; control subjects: 1.73 ± 0.11 m2, p = NS). The protocol was in accordance with the Declaration of Helsinki (1989) of the World Medical Association and has been approved by the ethical committee of our department.
All patients included in the study underwent a complete medical evaluation, including electrocardiogram, 24-h Holter recording, chest X-ray, electroencephalography, Doppler echocardiography, complete neurologic examination, and serum blood tests (glucose, creatinine, electrolytes, aminotransferase, ethanol, thyroid hormones, cortisol and aldosterone, platelet count, hematocrit, red blood cell count, white cell count), to exclude secondary causes of orthostatic intolerance or other illnesses such as heart failure, diabetes mellitus, neuropathy, coronary heart disease, mitral valve prolapse, blood hypertension, and any other disease (e.g., adrenal insufficiency) that could affect the autonomic nervous system. The HS had no history of faintness and had normal echocardiogram, exercise test tolerance, neurologic and laboratory findings. Neither patients nor control individuals were taking any medication in the two weeks before or during the study period. Patients younger than 16 years, elite athletes, and sports professionals were excluded.
All subjects included in the study underwent a tilting test which was performed between 2 pmand 4 pmin a dedicated laboratory with subdued lighting and ambient temperature of 20°C to 22°C. Subjects were required to have fasted for 4 h before tilt. They remained supine for half an hour and were then tilted to a 60° angle for 45 min or until they developed presyncopal or syncopal symptoms. The motorized tilt table achieved 60° of tilt over 20 s. During the test, subjects were restrained by two Velcro straps placed around the legs and waist, and any conversation other than reporting symptoms was discouraged.
Continuous and noninvasive beat-to-beat HR and BP measurements were recorded. After a 30-min resting period (equilibrium), data were obtained for a supine resting period of 2 min (baseline condition) throughout the tilted period (3 min, 5 min, and every 5 min afterwards until 45 min or symptom appearance, and for 2 min after return to the supine position, i.e. post tilting period). The BP measurements were achieved by digital photoplethysmography (Finapres), a method previously described during tilt testing (18,19).
We have, in real time, performed continuous recordings and computation of stroke volume by PRAM of the systemic BP waves from the finger, as described in a previous report (15,20). The computed values of stroke volume PRAM were displayed in real time by the dedicated software. The corresponding waves were recorded and stored for subsequent check of the data. An event marker on the pressure recordings was used to identify the start of each clinical symptom.
The noninvasive pressure signals were acquired at 1,000 Hz by means of an analogic-digital multifunction card (DAQ Card-700; National Instruments Corp., Austin, Texas). All the signals were recorded on a personal computer (Acer, TravelMate 507-DX, Taipei Hsien, Taiwan, Republic of China).
The data from each subject were reviewed and edited manually to remove artifacts (which consisted of the calibration intervals, devoid of pressure signal). Data from pressure signals were evaluated averaging 1-min periods at baseline, during up-tilting, down-tilting, the post-tilting, and throughout the 60°-tilted position: in particular at the 3rd, 5th, 10th, 15th, 20th, and 25th (or until symptoms supervened) minute from the up-tilted position, by averaging 30 s before and 30 s after the selected time (21).
The following parameters were calculated:
1. Heart rate (beats/min);
2. SBP, DBP, and dicrotic blood pressures (DICBP) (mm Hg). Dicrotic pressure was computed from the second derivative of the pressure curve in the time domain. In fact, the dicrotic notch is the point in which the forces generated by the blood physical properties overcome cardiac stroke output, causing aortic valve closure. Therefore, DICBP may approximate the left ventricular end-systolic pressure (21,22);
3. Pulse pressure (mm Hg), as the difference between SBP and DBP. Its peripheral amplification is a well-established hemodynamic pattern in cardiovascular physiology (23);
4. Stroke volume index (SVI) (ml/m2);
5. Systemic vascular resistance (SVR), as mean systemic arterial pressure/cardiac output (dynes·s·cm−5);
6. Ratio between stroke volume and pulse pressure (stroke volume/pulse pressure, ml/mm Hg) as an estimate of overall vascular compliance (24);
7. Cardiac index (ml/min/m2).
The PRAM is based on the principle that, in any given vessel, volume changes occur mainly because of radial expansion in response to variations in pressure. This process involves the interplay of several physical parameters including force of left ventricular ejection, arterial impedance counteracting the pulsatile blood inflow, arterial compliance, and peripheral, small vessel resistance. These variables are tightly interdependent and simultaneously evaluated by PRAM. Thus, any kind of flow that is perceived at the peripheral arterial level, whether pulsatile or continuous as in physiologic conditions, can be evaluated. A similar approach to the pulsatile evaluation of flow has been studied by several authors in the course of three decades and has led to the development of clinical applications such as the PCM. Different from PRAM, however, PCM requires retrospective calibration based on independent measurements of flow and/or pre-calculated parameters (14).
The PRAM technique, based on the analysis of the peripheral artery waveform morphology, has been extensively described elsewhere (15). The PRAM is based on software that analyzes the pressure signal obtained via the analogic card by a routine that identifies the characteristic points of the pressure wave during each beat (diastolic, systolic, dicrotic, and resonant points pressure during the systolic and end-diastolic phases). The morphologic analysis of the beat allows the determination of the stroke volume.
For statistical analysis, we used the Statistical Package for Social Science (Version 11.5, SPSS Inc., Chicago, Illinois). Values are expressed as mean values ± 1 SD. Differences in the mean values between the two groups were compared using an unpaired ttest (p < 0.05 was considered statistically significant). Forward stepwise discriminant analysis was used to assess: 1) the reliability of a short-lasting test, and 2) the variables to consider in order to predict with the best agreement the test outcome (25,26).
All control subjects were clinically healthy and showed no symptoms during head-tilt. As depicted in Figures 1and 2,in comparison with baseline, up-tilting induced a slight increase in DBP, DICBP, and HR as well as an increase in SVR in the first 15 min of the tilted position. In the same period, stroke volume and pulse pressure showed a progressive decline. Thereafter, the considered parameters showed stable and still higher values throughout the tilted position, at termination, and during down-tilting. At the end of the test, BP values, HR, SVI, SVR, and pulse pressure were comparable to those at the beginning.
As depicted in Figures 1and 2, in OIP, unlike HS, up-tilting induced within the first 3 min a sharp increase in HR, despite the lack of changes in SBP and DBP values.The DICBP and SVI showed a trend toward lower values.
Afterward, in the first 15 min of tilted position, OIP showed a progressive increase in HR associated with a progressive decrease in DICBP but with only a trend toward lower values of SBP and DBP. Thereafter, and until presyncopal (and rarely syncopal) symptoms supervened, SBP, DBP, DICBP, and SVI progressively declined, SVR manifested a trend toward a progressive decrease, whereas HR remained at higher levels (5,13,19). In nine patients BP reached values lower than 80 mm Hg at the end of the procedure. Only in five patients did a true syncopal event occur. The mean time of symptoms appearance was 17 ± 5.4 min from up-tilting.
In concomitance with symptoms, patients showed a further reduction in SBP, DICBP, DBP, as well as SVI and pulse pressure in the presence of a persistent increase in HR and unchanged values of SVR. The down-tilting induced a reduction in HR, a tendency to higher values of BP and SVR, and a slight increase in SVI. At the end of the procedure, hemodynamic parameters became comparable to those observed at baseline. An example of the hemodynamic profile of patients who developed syncope during head-up tilt is depicted in Figure 3.
Comparison between HS and OIP
As shown in Table 2,at baseline, in the resting position, OIP showed lower values of SBP, pulse pressure, and SVI, whereas they exhibited higher values of HR and SVR. No significant differences in stroke volume/pulse pressure ratio were found between the two groups. During up-tilting and in comparison to HS, OIP showed lower values of SBP, DICBP, and SVI but no changes in SVR and stroke volume/pulse pressure.
From the third minute of tilted position and until symptoms appeared (test termination is “Stop” in Table 2and Fig. 2), patients exhibited lower values of SBP, DBP, DICBP, SVI, and pulse pressure and higher values of HR but no difference in SVR or stroke volume/pulse pressure. At termination, patients showed a further significant reduction in BP values, pulse pressure, and SVI and a persistent increase in HR. No significant differences between the two groups were observed in SVR or in stroke volume/pulse pressure ratio. At the end of the procedure, OIP showed lower values of SBP and SVI, without any difference in the other variables.
To examine whether an early termination of the head-up tilt test was feasible, we applied forward stepwise discriminant analysis (F to enter and F to remove, p = 0.05 and 0.10, respectively) on the entire set of variables: first considering all time intervals up until 15 min (DA-15) and then stopping our analysis at 3 min (DA-3), that is, an overall number of six and three parameters,respectively. The DA-15 found seven variables (SVI baseline, DBP-DICBP up, DICBP-DBP 3 min, SVR 3 min, SVR 5 min, SVR 10 min, SVR 15 min), and the agreement was approximately 95%. The DA-3 found three variables (SVI baseline, DICBP-DBP 3 min, SVR 3 min) and total agreement was 92%.
The main finding of the present investigation is that individuals with orthostatic intolerance have a lower stroke volume and higher SVR at rest than age-matched healthy control individuals. This hemodynamic profile can be viewed as a maladaptive response to postural challenge related to impaired vascular regulation. In this context, the discriminant analysis allowed the identification of some parameters (mainly SVI and SVR) able to quickly characterize the response to tilting in OIP, thus making the prompt termination of the test feasible.
In OIP, several factors can account for the decreased SVI in the recumbent position. The first such factor is hypovolemia, either absolute or relative, probably the result of a different distribution of blood among the various vascular districts and further confirmed by the higher values of SVR and HR in patients compared with HS. The finding of lower values of SVI throughout the whole test strongly suggests the failure of all compensatory mechanisms physiologically involved in counteracting the hemodynamic changes induced by posture. Our data partially disagree with those by Furlan et al. (5), who observed that central venous pressure was similar in the supine position and decreased by the same extent during tilt in both OIP and control subjects. However, in OIP, absolute values of central venous pressure showed a trend toward lower values, though not statistically significant. Besides, central venous pressure is an indirect estimate of volume status (27), whereas stroke volume is a direct measure of cardiac performance that in HS strictly correlates with left ventricular filling as well as with afterload, myocardial contractility, and relaxation.
Secondly, deconditioning cannot be ruled out as a contributing factor to the reduced SVI. In fact, head-down tilt bed rest causes hemodynamic effects clearly different from those of acute hypovolemia, and in particular it induces ventricular remodeling, leading to reduced supine left ventricular end-diastolic volume and compromised ventricular filling (28). Deconditioning has also been suggested to explain the marked decrease in stroke volume in response to head-up tilt of women with chronic fatigue syndrome (29). Finally, the reduced SVI could probably explain previously published data by others who found that a therapeutic strategy directed at either volume expansion with saline or increasing peripheral vasoconstriction with the alpha1-agonists midodrine or phenylepinephrine is far more effective than one directed at blunting the hyperadrenergic state using clonidine or esmolol (7,16).
The behavior of SVR in OIP deserves some comments. These patients showed higher values of SVR in comparison to HS at baseline, as previously described by Stewart and Weldon (30). However, differently from HS, SVR did not exhibit any significant change throughout the test, despite the postural challenge and, more importantly, despite the higher HR (i.e., a sympathetic activation index). Bush et al. (31) found that changes in forearm vascular resistance (calculated as mean arterial pressure/brachial artery blood velocity ratio) were even less in patients with postural tachycardia syndrome during head-up tilt. Again, the lack of increase in SVR can be viewed as the patients' failure to face the progressive reduction in stroke volume that follows a decrease in venous return and strongly suggests an abnormal regulation of vascular tone in these patients.
In our investigation, pulse pressure and SBP also showed a peculiar hemodynamic profile throughout the test in OIP. In fact, in comparison to HS, we suppose that OIP may show lower values of pulse pressure despite an adrenergic activation as indicated by the higher HR. On the contrary, Laurent et al. (32) observed that the increase in HR was able to induce an increase in pulse pressure both in HS and in hypertensive patients. The discrepancy between our data (present investigation and Romano et al. ) and those by Laurent et al. (32) strongly suggests an abnormal regulation of peripheral vascular tone in OIP, as described in previous studies (5,30,33,34). In fact, Stewart (33) and Jacob et al. (34)observed that patients with orthostatic intolerance show a blunted arterial vasoconstriction which may produce passive redistribution of blood within peripheral venous capacitance beds and accounts for symptoms in these patients. Stewart and Weldon (30)and Jacob et al. (34) described a decrease in norepinephrine spillover in the lower limbs and an abnormal peripheral vascular physiology, respectively, in idiopathic orthostatic intolerance. Also Furlan et al. (5) described a blunted sympathetic vasoconstrictor response to standing of muscle blood vessels in OIP as part of their selective autonomic dysfunction.
In our findings, OIP showed lower values of SBP at rest, and symptom appearance after prolonged tilting was associated with a further reduction in BP together with an increased, though not compensatory, HR. This phenomenon can probably be related to the fact that our patients were submitted to increased stimulus intensity, such as prolonged tilt test. However, in patients with orthostatic intolerance SBP behaves differently from hypotension to hypertension. Indeed, whereas some patients develop symptoms in the absence of any significant BP reduction (5), others show a trend to hypotension (4) or even a hypertensive response to standing (3). In other words, the hemodynamic response to orthostatic challenge in OIP appears to share common characteristics both in patients with neuromediated syncope (who more frequently show a hypotensive response) and in those with chronic fatigue syndrome (who usually show no change in BP). It has therefore been speculated that chronic orthostatic intolerance may constitute part of a spectrum of disorders of orthostatic cardiovascular homeostasis, including the neuromediated syncope and chronic fatigue syndrome (4), and that postural tachycardia syndrome and neurocardiogenic presyncope or syncope both can be considered forms of dysautonomia, differing in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreased release in the latter (13). Thus, the diagnostic categorization for a given patient is often mainly determined by the initial presentation (35).
A possible limitation of the study is that enrolled patients were selected on clinical grounds to have chronic orthostatic intolerance. Furthermore, the possibility that some of our patients may have inappropriate sinus tachycardia cannot be ruled out, because these two syndromes exhibit overlapping features and a clear distinction between the two of them is arbitrary both in quantitative and qualitative terms (36).
In conclusion, the present study underlines the following topics: 1) the cardiovascular profile of OIP at rest, characterized by lower SVI and higher SVR and HR; 2) the maladaptive response to postural challenge in OIP may be mainly identifiable in impaired peripheral arterial tone regulation; 3) the significance of measuring SVI and SVR in quickly identifying the positive response to tilting to optimize the timing of the test and the therapeutic strategy.
Dr. Romano is the owner of the Italian patent for the PRAM technique.
- Abbreviations and acronyms
- blood pressure
- diastolic blood pressure
- dicrotic blood pressure
- heart rate
- healthy subjects
- orthostatic intolerant patients
- Pulse Contour Method
- Pressure Recording Analytical Method
- systolic blood pressure
- stroke volume index
- systemic vascular resistance
- Received March 17, 2004.
- Revision received July 26, 2004.
- Accepted July 29, 2004.
- American College of Cardiology Foundation
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