False positive head-up tilt: hemodynamic and neurohumoral profile.

OBJECTIVES: This study examined differences in mechanisms of head-up tilt (HUT)-induced syncope between normal controls and patients with neurocardiogenic syncope. BACKGROUND: A variable proportion of normal individuals experience syncope during HUT. Differences in the mechanisms of HUT-mediated syncope between this group and patients with neurocardiogenic syncope have not been elucidated. METHODS: A 30-min 80 degrees HUT was performed in eight HUT-negative volunteers (Group I), eight HUT-positive volunteers (Group II) and 15 patients with neurocardiogenic syncope. Heart rate and blood pressure (BP) were monitored continuously. Epinephrine and norepinephrine plasma levels, as well as left ventricular dimensions and contractility determined by echocardiography, were measured at baseline and at regular intervals during the test. RESULTS: The main findings of this study were the following: 1) All parameters were similar at baseline in the three groups; and 2) During tilt: a) the time to syncope was shorter in Group III than in group II (9.5 +/- 3 vs. 17 +/- 3 min p < 0.05); b) there was an immediate, persisting drop in mean BP in Group III; c) the decrease rate of left ventricular end-diastolic dimensions was greater in Group III than in Group II or Group I (-1.76 +/- 0.42 vs. -0.87 +/- 0.35 and -0.67 +/- 0.29 mm/min, respectively, p < 0.05); d) the leftventricular shortening fraction was greater in Group III than in the other two groups (39 +/- 1 vs. 34 +/- 1 and 32 +/- 1%, respectively, p < 0.05); and e) although the norepinephrine level remained comparable among the groups, there was a significantly higher peak epinephrine level in Group III than in Group II and Group I (112.3 +/- 34 vs. 77.6 +/- 10 and 65 +/- 12 pg/ml, p < 0.05). CONCLUSIONS: Mechanisms of syncope during HUT appeared to be different in normal volunteers and patients with neurocardiogenic syncope. In the latter, there was evidence of an impaired vascular resistance response from the beginning of the orthostatic challenge. Furthermore, in the patients there was more rapid peripheral blood pooling, as indicated by the echocardiographic measurements of left ventricular end-diastolic changes, leading to more precocious symptoms. In syncopal patients, the higher level of plasma epinephrine probably mediated the increased cardiac contractility and possibly contributed to the impaired vasoconstrictive response.

Baroreceptor sensitivity in prehypertensive young adults.

Decreased baroreceptor reflex sensitivity has been implicated in the pathogenesis of hypertension. The purpose of this study is to determine if alterations of baroreceptor function precede the development of hypertension in humans. Baroreceptor function was evaluated in 13 young adult white men with relatively high blood pressures sustained for 12 to 15 years and 12 age-matched men with sustained relatively low blood pressures. High pressure baroreceptor activity was evaluated by measuring change in pulse interval in response to decreases and increases of arterial pressure, induced by graded infusions of nitroprusside and angiotensin II, respectively. In response to both agents, baroreceptor slopes did not differ in the high and low blood pressure groups. Plasma norepinephrine also increased similarly in both blood pressure groups in response to nitroprusside. To study low-pressure baroreceptor function, responses to graded levels of lower-body negative pressure (LBNP) were measured. Comparing both blood pressure groups, there were similar increases of heart rate, total peripheral resistance, and plasma norepinephrine in response to LBNP. Both blood pressure groups also had similar increases of heart rate and blood pressure in response to isometric (handgrip) exercise. Thus, high-pressure and low-pressure baroreceptor function is not altered in prehypertensive young adults. However, continued follow-up will be required to determine if these individuals with sustained relatively high blood pressures are truly prehypertensive.

Effect of increased acceleration on regional pleural pressure in dogs.

The variation of pleural pressure was measured in anesthetized spontaneously breathing dogs subjected to increased acceleration (0-4 G) in a centrifuge. Two groups of animals were studied. In one group, the resultant acceleration was in a direction either ventral-to-dorsal (+Gx) or dorsal-to-ventral (-Gx), with a relatively small residual cranial-to-caudal acceleration. In the other group, the resultant acceleration was either cranial-to-caudal (+Gz) or caudal-to-cranial (-Gz), with a relatively small residual dorsal-to-ventral acceleration. Pleural liquid pressure (Ppl) was measured by two rib capsules that were separated by 7-9 cm and oriented either in the dorsal-to-ventral or cranial-to-caudal direction. At functional residual capacity, Ppl in the nondependent lung region became more negative when the acceleration was in the +Gx or +Gz direction. Thus the lung would be susceptible to damage that results from overexpansion in these acceleration directions. By contrast, acceleration in the -Gx or -Gz direction produced values of Ppl at functional residual capacity that were positive. Thus, in these acceleration directions, the respiratory muscles must provide greater force during inspiration to overcome lung compression before lung ventilation can occur. The Ppl gradients with respect to the acceleration directions increased approximately in proportion to acceleration in the +Gx, -Gx, and -Gz directions but remained relatively constant in the +Gz direction.

Voluntary control of breathing does not alter vagal modulation of heart rate.

Variations in respiratory pattern influence the heart rate spectrum. It has been suggested, hence, that metronomic respiration should be used to correctly assess vagal modulation of heart rate by using spectral analysis. On the other hand, breathing to a metronome has been reported to increase heart rate spectral power in the high- or respiratory frequency region; this finding has led to the suggestion that metronomic respiration enhances vagal tone or alters vagal modulation of heart rate. To investigate whether metronomic breathing complicates the interpretation of heart rate spectra by altering vagal modulation, we recorded the electrocardiogram and respiration from eight volunteers during three breathing trials of 10 min each: 1) spontaneous breathing (mean rate of 14.4 breaths/min); 2) breathing to a metronome at the rate of 15, 18, and 21 breaths/min for 2, 6, and 2 min, respectively; and 3) breathing to a metronome at the rate of 18 breaths/min for 10 min. Data were also collected from eight volunteers who breathed spontaneously for 20 min and breathed metronomically at each subject's mean spontaneous breathing frequency for 20 min. Results from the three 10-min breathing trials showed that heart rate power in the respiratory frequency region was smaller during metronomic breathing than during spontaneous breathing. This decrease could be explained fully by the higher breathing frequencies used during trials 2 and 3 of metronomic breathing. When the subjects breathed metronomically at each subject's mean breathing frequency, the heart rate powers during metronomic breathing were similar to those during spontaneous breathing. Our results suggest that vagal modulation of heart rate is not altered and vagal tone is not enhanced during metronomic breathing.

Endurance training in dogs increases vascular responsiveness to an alpha 1-agonist.

The effects of endurance training on vascular responsiveness to an alpha 1-agonist and the associated changes in baroreflex modulation of heart rate and vascular resistance were studied. Graded dosages of phenylephrine were given to eight treadmill-trained dogs and to eight untrained dogs; both groups were chronically instrumented and were sedated and resting when tested. These dosages were repeated after ganglionic blockade. Aortic pressure, cardiac output, central venous pressure, peripheral resistance, and heart rate were each averaged over 30 s before injection and 90 s after injection. The slope of the peripheral resistance-dose relationship was significantly increased in trained compared with untrained dogs in both the unblocked and blocked cases [unblocked: trained 0.89, untrained 0.47; blocked: trained 4.30, untrained 2.05 (mmHg.l-1.min)/(microgram.kg-1)]. The unblocked resistance slopes were reduced with respect to the blocked slopes by 77 (untrained) and 79% (trained). The slope of the heart rate-aortic pressure response was reduced, but not significantly, by endurance training. We conclude that 6 wk of endurance training in dogs resulted in a doubling of the vascular responsiveness to an alpha 1-agonist, with no significant change in the baroreflex regulation of resistance or heart rate.

Override of spontaneous respiratory pattern generator reduces cardiovascular parasympathetic influence.

We investigated the effects of voluntary control of breathing on autonomic function in cardiovascular regulation. Variability in heart rate was compared between 5 min of spontaneous and controlled breathing. During controlled breathing, for 5 min, subjects voluntarily reproduced their own spontaneous breathing pattern (both rate and volume on a breath-by-breath basis). With the use of this experimental design, we could unmask the effects of voluntary override of the spontaneous respiratory pattern generator on autonomic function in cardiovascular regulation without the confounding effects of altered respiratory pattern. Results from 10 subjects showed that during voluntary control of breathing, mean values of heart rate and blood pressure increased, whereas fractal and spectral powers in heart rate in the respiratory frequency region decreased. End-tidal PCO2 was similar during spontaneous and controlled breathing. These results indicate that the act of voluntary control of breathing decreases the influence of the vagal component, which is the principal parasympathetic influence in cardiovascular regulation.

Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes.

The autonomic nervous system drives variability in heart rate, vascular tone, cardiac ejection, and arterial pressure, but gender differences in autonomic regulation of the latter three parameters are not well documented. In addition to mean values, we used spectral analysis to calculate variability in arterial pressure, heart rate (R-R interval, RRI), stroke volume, and total peripheral resistance (TPR) and measured circulating levels of catecholamines and pancreatic polypeptide in two groups of 25 +/- 1.2-yr-old, healthy men and healthy follicular-phase women (40 total subjects, 10 men and 10 women per group). Group 1 subjects were studied supine, before and after beta- and muscarinic autonomic blockades, administered singly and together on separate days of study. Group 2 subjects were studied supine and drug free with the additional measurement of skin perfusion. In the unblocked state, we found that circulating levels of epinephrine and total spectral power of stroke volume, TPR, and skin perfusion ranged from two to six times greater in men than in women. The difference (men > women) in spectral power of TPR was maintained after beta- and muscarinic blockades, suggesting that the greater oscillations of vascular resistance in men may be alpha-adrenergically mediated. Men exhibited muscarinic buffering of mean TPR whereas women exhibited beta-adrenergic buffering of mean TPR as well as TPR and heart rate oscillations. Women had a greater distribution of RRI power in the breathing frequency range and a less negative slope of ln RRI power vs. ln frequency, both indicators that parasympathetic stimuli were the dominant influence on women's heart rate variability. The results of our study suggest a predominance of sympathetic vascular regulation in men compared with a dominant parasympathetic influence on heart rate regulation in women.

Attenuation of vagal noradrenergic tachycardia by naloxone.

Electrical stimulation of the transected right vagus nerve in anesthetized and atropinized dogs produced tachycardia that was not attenuated by beta-adrenoceptor blockade. Naloxone in intravenous doses of 1 and 4 mg/kg antagonized the tachycardia evoked by nerve stimulation in a dose-dependent manner. However, the attenuation was maximal at approximately 55% of the control response. These results suggest that an endogenous opiate peptide(s) may have a mediator or modulator role in nonadrenergic tachycardia evoked by vagal nerve stimulation in anesthetized and atropinized dogs.

Epinephrine, vasodilation and hemoconcentration in syncopal, healthy men and women.

Healthy young people may become syncopal during standing, head up tilt (HUT) or lower body negative pressure (LBNP). To evaluate why this happens we measured hormonal indices of autonomic activity along with arterial pressure (AP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and measures of plasma volume. Three groups of normal volunteers (n = 56) were studied supine, before and during increasing levels of orthostatic stress: slow onset, low level, lower body negative pressure (LBNP) (Group 1), 70 degrees head up tilt (HUT) (Group 2) or rapid onset, high level, LBNP (Group 3). In all groups, syncopal subjects demonstrated a decline in TPR that paralleled the decline in AP over the last 40 s of orthostatic stress. Ten to twenty seconds after the decline in TPR. HR also started to decline but SV increased, resulting in a net increase of CO during the same period. Plasma volume (PV, calculated from change in hematocrit) declined in both syncopal and nonsyncopal subjects to a level commensurate with the stress, i.e. Group 3 > Group 2 > Group 1. The rate of decline of PV, calculated from the change in PV divided by the time of stress, was greater (p < 0.01) in syncopal than in nonsyncopal subjects. When changes in vasoactive hormones were normalized by time of stress, increases in norepinephrine (p < 0.012, Groups 2 and 3) and epinephrine (p < 0.025, Group 2) were greater and increases in plasma renin activity were smaller (p < 0.05, Group 2) in syncopal than in nonsyncopal subjects. We conclude that the presyncopal decline in blood pressure in otherwise healthy young people resulted from declining peripheral resistance associated with plateauing norepinephrine and plasma renin activity, rising epinephrine and rising blood viscosity. The increased hemoconcentration probably reflects increased rate of venous pooling rather than rate of plasma filtration and, together with cardiovascular effects of imbalances in norepinephrine, epinephrine and plasma renin activity may provide afferent information leading to syncope.

Temperature effects on surface pressure-induced changes in rat skin perfusion: implications in pressure ulcer development.

The effect of varying local skin temperature on surface pressure-induced changes in skin perfusion and deformation was determined in hairless fuzzy rats (13.5+/-3 mo, 474+/-25 g). Skin surface pressure was applied by a computer-controlled plunger with corresponding skin deformation measured by a linear variable differential transformer while a laser Doppler flowmeter measured skin perfusion. In Protocol I, skin surface perfusion was measured without heating (control, T=28 degrees C), with heating (T=36 degrees C), for control (probe just touching skin, 3.7 mmHg), and at two different skin surface pressures, 18 mmHg and 73 mmHg. Heating caused perfusion to increase at control and 18 mmHg pressure, but not at 73 mmHg. In Protocol II, skin perfusion was measured with and without heating as in Protocol I, but this time skin surface pressure was increased from 3.7 to 62 mmHg in increments of 3.7 mmHg. For unheated skin, perfusion increased as skin surface pressure increased from 3.7 to 18 mmHg. Further increases in surface pressure caused a decrease in perfusion until zero perfusion was reached for pressures over 55 mmHg. Heating increased skin perfusion for surface pressures from 3.7 to 18 mmHg, but not for pressures greater than 18 mmHg. After the release of surface pressure, the reactive hyperemia peak of perfusion increased with heating. In Protocol III, where skin deformation (creep and relaxation) was measured during the application of 3.7 and 18 mmHg, heating caused the tissue to be stiffer, allowing less deformation. It was found that for surface pressures below 18 mmHg, increasing skin temperature significantly increased skin perfusion and tissue stiffness. The clinical significance of these findings may have relevance in evaluating temperature and pressure effects on skin blood flow and deformation as well as the efficacy of using temperature as a therapeutic modality in the treatment of pressure ulcers.

Skin perfusion responses to surface pressure-induced ischemia: implication for the developing pressure ulcer.

This study describes alterations in skin perfusion in response to step increases in surface pressure, before and after long-term (5 hr) exposure to pressure-induced ischemia. A provocative test was developed in which surface pressure was increased in increments of 3.7 mmHg until perfusion reached an apparent minimum by a computer-controlled plunger that included a force cell, a laser Doppler flowmeter to determine perfusion, and a thermistor to monitor skin temperature. Force was applied to the greater trochanters of adult male fuzzy rats. Skin perfusion (n=7) initially increased with low levels of surface pressure (up to 13.9+/-1.9 mmHg) and then decreased with further increases in pressure, reaching minimum (zero) perfusion at 58.2+/-3.64 mmHg. After pressure release, reactive hyperemia (3 x normal) was observed, with levels returning to normal within 15-30 min. The provocative test was then applied after a 5-hr ischemic episode (produced by 92 mmHg) and 3 hr of recovery. A comparison of responses between stressed and unstressed skin revealed: elevated (63%) control perfusion levels; loss of the initial increase in perfusion with low levels of increasing pressure; a depression (45%) in the hyperemic response with delayed recovery time; and a decrease (54%) in amplitude of low frequency (<1 Hz) rhythms in skin perfusion. Skin surface temperature gradually increased both during the control period and the period of incremental increases in surface pressure (total DT=3.3 degrees C). The results suggest a compromised vasodilator mechanism(s). The provocative test developed in this study may have clinical potential for assessing tissue viability in early pressure ulcer development.

Microvascular pressure responses of second-generation rats chronically exposed to 2 G centrifugation.

The purpose of thses studies was to compare systemic arterial and microvascular pressures in the second generation of rats reared in a 2-G centrifuge with pressure data from animals subjected to 1 G centrifugation. Systemic arterial pressures were measured in anesthetized animals via carotid catheters and microvascular pressures were measured in mesenteric arterioles by a micropipette servo-null system. Systemic arterial pressures in the 1-G and 2-G groups were not significantly different from each other, but both were considerably higher than those reported for normal rats. In the microcirculation, pressures in the terminal arterioles (20 to 35 micron) were significantly higher in the 2-G animals, but pressures at the level of the smaller (10 to 15 micron) precapillary arterioles were not significantly different between the two groups. The pressure responses to intravenous infusion of norepinephrine were also compared in the two groups and found to be significantly less in the 2-G animals. It is concluded that both 1 G and 2 G chronic centrifugation will elevate arterial blood pressure, and that 2 G, of itself, will affect the pressure distribution in the microcirculation as well as attenuate the pressor effects of norepinephrine.

Comparison of heart rate and arterial pressure spectra during head up tilt and a matched level of LBNP.

Lower Body Negative Pressure (LBNP) can be used to stimulate cardiovascular regulation by inducing blood shifts similar to those produced during head up tilt (HUT). It is unclear, however, whether similar blood shifts produced by these two stresses evoke similar cardiovascular regulatory responses. Hence, we compared the autonomic components of cardiovascular responses to 50 degrees HUT and a matched level of LBNP. A level of LBNP that produced changes in calf circumference similar to those produced during the first 3 min of 50 degrees HUT was considered to be a matched level. Autonomic components of cardiovascular responses were determined by spectral analysis of heart rate and blood pressure. Results from nine subjects showed that in terms of changes in calf circumference at the end of 3 min, 50 degrees HUT and 48 mm Hg LBNP were similar (2.13% and 1.94%). During 20-min exposures to HUT and LBNP, the increase in heart rate during LBNP was greater (+7 bpm) than HUT, while blood pressure increases were similar. For heart rate and blood pressure spectra, power in the respiratory frequency region (0.25 Hz) decreased and power in the low frequency region (0.03 Hz) increased similarly during HUT and LBNP. These results indicated that 50 degrees HUT and a matched level of LBNP evoked similar autonomic responses in cardiovascular regulation, with the autonomic balance shifted toward increased sympathetic and decreased parasympathetic influence.

Control of left ventricular function during acceleration-induced blood volume shifts.

Peripheral pooling of blood was produced in chronically instrumented, sedated dogs (n = 7) by subjecting them to a +2 Gz force (along their spinal axis) for 3 min. The acceleratory force was then quickly removed, thereby mobilizing blood toward the thoracic cavity. Left ventricular volume, calculated from ultrasound measurements of major and minor axes and wall thickness, increased (p less than 0.05) from 21.7 +/- 3.6 ml (diastolic, mean +/- S.E.M.) and 14.1 +/- 3.3 ml (systolic) during the peripheral pooling of blood to 28.2 +/- 4.1 ml (diastolic) and 16.0 +/- 2.9 ml (systolic) as measured at 2 min after release of the acceleratory force. The d(LVP)/dt was essentially unchanged (i.e., from 3415 +/- 482 mm Hg.s-1 to 3536 +/- 249 mm Hg.s-1). The experiment was repeated after total pharmacologic autonomic blockade (propranolol, atropine, phenoxybenzamine). Left ventricular volumes during +2 Gz after blockade were 27.7 +/- 2.5 ml (diastolic) and 21.2 +/- 2.9 (systolic). The acceleration-induced changes in cardiovascular function, including the changes in ventricular volume, were not significantly different from those of the reflexive state. These results, therefore, do not reveal a substantial role for the autonomic nervous system in the regulation of left ventricular volume responses to the sudden cessation of G-induced peripheral blood pooling. Since the cessation of the G force induced essentially identical increases in left ventricular volumes and stroke volumes both before and after the autonomic blockade, it is concluded that the heart relied mainly upon the Frank-Starling mechanism to adapt to the changes in load.

Spectral indices of cardiovascular adaptations to short-term simulated microgravity exposure.

We investigated the effects of exposure to microgravity on the baseline autonomic balance in cardiovascular regulation using spectral analysis of cardiovascular variables measured during supine rest. Heart rate, arterial pressure, radial flow, thoracic fluid impedance and central venous pressure were recorded from nine volunteers before and after simulated microgravity, produced by 20 hours of 6 degrees head down bedrest plus furosemide. Spectral powers increased after simulated microgravity in the low frequency region (centered at about 0.03 Hz) in arterial pressure, heart rate and radial flow, and decreased in the respiratory frequency region (centered at about 0.25 Hz) in heart rate. Reduced heart rate power in the respiratory frequency region indicates reduced parasympathetic influence on the heart. A concurrent increase in the low frequency power in arterial pressure, heart rate, and radial flow indicates increased sympathetic influence. These results suggest that the baseline autonomic balance in cardiovascular regulation is shifted towards increased sympathetic and decreased parasympathetic influence after exposure to short-term simulated microgravity.

Ophthalmologic electronic imaging and data transfer.

A technique has been developed that allows slit lamp images from a patient in a remote locale to be captured by a computer, with the assistance of a non-ophthalmologist, and transmitted at rapid speeds through telephone lines to an ophthalmologist for visualization of relevant clinical information. The results from this study indicate that (1) eye examinations can be performed at the remote site by non-ophthalmologists; (2) objective data can be transferred to a centralized ophthalmologist for expert interpretation; and (3) decisions can be rendered in areas where medical needs are underserved.

Pressor response buffering by beta-adrenergic and cholinergic vasodilation in tranquilized dogs.

Buffering of alpha-receptor-mediated pressor responses by beta-adrenergic or cholinergic vasodilation in tranquilized, chronically instrumented gos was investigated. Increases in aortic pressure were produced in the same animal by intravenous injections of phenylephrine in the control state and in three successive experimental states by 1) pacing the heart to remove the reflex capability to lower heart rate, 2) pacing the heart and beta-blockade to remove beta-adrenergic vascular buffering, and 3) beta-blockade plus atropine to also remove cholinergic vascular buffering. The pressor response in each experimental state was greater than that in the state preceding it. With the combined beta-adrenergic and cholinergic blockade, the pressor response to an alpha-receptor stimulation was three times greater than that of the control state. From an analysis of the components of the pressor response, cardiac output, and peripheral resistance, it is suggested that normal buffering of an alpha-mediated pressor response may include beta-adrenergic and cholinergic vascular dilation in addition to a decrease in heart rate.