Evaluation of parasympathetic nervous system function Author Roy Freeman, MD Section Editor Jeremy M Shefner, MD, PhD Deputy

Editor John F Dashe, MD, PhD Disclosures Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Mon Jun 22 00:00:00 GMT 2009 (More) INTRODUCTION The laboratory evaluation of the parasympathetic nervous system includes measures of heart rate variation at rest and in response to deep respiration, a Valsalva maneuver, postural changes, and apneic facial immersion. These tests primarily provide an index of vagal cardiac function [1]. The technical aspects of heart rate variability and its clinical applications are discussed separately. (See "Heart rate variability: Use after myocardial infarction" and "Heart rate variability: Uses other than after myocardial infarction" and "Heart rate variability: Technical aspects".) SHORT-TERM MEASURES OF HEART RATE VARIABILITY Respiration The beat to beat variability in heart rate accompanying respiration at normal respiratory rates is predominantly mediated by the vagus nerve and is reduced or abolished by vagotomy, vagus nerve cooling, and muscarinic blockade. The determinants of the respiratory fluctuations in heart rate include a stretch reflex from the lungs and thoracic wall, changes in cardiac filling, arterial baroreceptor responses to blood pressure changes, changes in baroreflex sensitivity with respiratory phase, and respiratory center activity overflow to medullary vasomotor neurons [1]. Despite these multiple mechanisms that involve several reflex arcs, respiratory sinus arrhythmia has provided a valuable window for determining autonomic nervous system control of cardiovascular function and an important index of autonomic nervous system pathology. Use of the amplitude of the beat-to-beat variation with respiration as a clinical measure of autonomic nervous system function was first suggested in the 1970s [2,3]. In the ensuing years, additional measures have been proposed including the standard deviation of the R-R interval [4], the mean square successive difference [5], the mean successive difference [4], the expiratory-inspiratory ratio (E:I ratio) [3], and the mean circular resultant [6,7]. Although the mean circular resultant has not attained widespread use, it was the sole test of heart rate variability with respiration used to assess parasympathetic function in the Diabetes Control and Complications Trial [8]. The laboratory or bedside tests of heart rate variability with deep breathing are usually performed in the supine position where vagal tone is greatest. However, some authors have advocated the seated position. Typically, the test is performed over six respiratory cycles with a respiratory rate of six breaths per minute, although other paradigms are also used [1]. The amplitude of the beat-to-beat variation with respiration (ie, the maximum minus minimum heart rate difference measured in beats per minute) and the E:I ratio are generally regarded as the simplest and most reliable measures of heart rate variability in

response to deep respiration. The maximum heart rate variation in response to deep breathing is a sensitive and specific index of autonomic function. This test is the best noninvasive test to assess cardiac vagal innervation. The standard deviation of the R-R interval or instantaneous heart rate is the most widely used statistical measure of heart rate variability. This measure is more frequently used to assess heart rate variability over longer periods (five minutes to 24 hours), although it can be used to assess heart rate variability in the smaller segments more typically obtained during clinical testing. (See "Heart rate variability: Technical aspects".) Other commonly used statistical approaches are based upon the hypothesis that successive differences in the R-R intervals, ie, the actual differences between adjacent R-R intervals, would be more sensitive than the standard deviation to short-term fluctuations in heart rate. The mean square successive difference (MSSD) is the average of the square of the differences between successive beats [5], the rMSSD is its square root [9], the mean successive difference (MSD) [4] is the average of the differences between successive beats, while the SDSD is the standard deviation of the successive differences [10]. Unlike the standard deviation, these measures are dependent upon the sequence of RR intervals. The measurements are theoretically robust against gradual trends in heart rate over time and are independent of mean heart rate in most [11] but not all studies [12]. They are, however, sensitive to ectopic beats such as ventricular premature beats, ie, a short interval followed by a long compensatory pause [11]. There are a number of factors that influence respiratory mediated heart rate variability. Respiratory sinus arrhythmia is dependent on the both the frequency and depth of respiration; that is, the magnitude of change in heart rate at a given respiratory rate is dependent on the tidal volume and, for a specific tidal volume, the magnitude of heart rate variability is dependent on the breathing frequency. Several time and frequency domain studies have suggested that the amplitude of the heart rate increase is maximal at respiratory rates between 5 to 10 breaths per minute [13]. Smaller changes in heart rate occur at lower and higher respiratory rates for a given tidal volume [14,15]. The maximal heart rate response in subjects with an autonomic neuropathy occurs at lower respiratory rates [13,16]. Other potential confounders that may reduce respiratory mediated heart rate variability include hypocapnia (that may occur with hyperventilation) [17] and increased sympathetic outflow [18]. There is a well established relationship between age and heart rate variability. This relationship has been expressed in most studies as a linear decline in the heart rate response to deep breathing with increasing age [19]. These studies suggest a decline in heart rate variability of 3 to 5 beats per minute per decade in control subjects. The diagnostic discrimination of this test is reduced by the use of a single normal value for all ages, which may lead to false-negative test results in younger patients and false-positive results in older patients. As examples of the age-related decline in the maximum minus minimum heart rate difference with deep respiration, the fifth percentile cut off is as follows: 14 beats per minute (bpm) in 10 to 29-year-old males and females 12 bpm in 30 to 39-year-olds 10 bpm in 40 to 49-year-olds

9 bpm in 50 to 59-year-olds 7 bpm in 60 to 79-year-olds [19]

Valsalva maneuver The Valsalva maneuver provides a measure of sympathetic, vagal, and baroreceptor function. The maneuver is typically performed by blowing through a mouthpiece connected to a mercury manometer for 15 or 20 seconds. The mercury column of the manometer is maintained at 40 mmHg. There should be a small air leak in the system to prevent closing of the glottis. An expiratory pressure of 40 mmHg appears to result in an optimal response; lower levels do not provide an adequate stimulus, while higher levels result in poor reproducibility. This test should be repeated several times to ensure a reproducible response [20]. The normal Valsalva maneuver has four phases: Phase 1 consists of a transient rise in arterial pressure and an associated decrease in heart rate Phase 2, during the expiratory phase of the maneuver, is characterized by a gradual fall in blood pressure followed by a recovery; an increase in heart rate accompanies this phase Phase 3 consists of a sudden brief fall in blood pressure with an accompanying increase in heart rate occurring with the cessation of straining. Phase 4 is characterized by an increase in blood pressure above the resting value (the "overshoot") and by bradycardia.

Phases 1 and 3 most likely reflect mechanical factors, while phases 2 and 4 are a consequence of sympathetic, vagal, and baroreflex interactions [21-25]. The heart rate change in response to this maneuver is a widely used indirect, sensitive, specific, and reproducible measure of autonomic function. The Valsalva ratio, the ratio of the shortest RR interval (the tachycardia) during or after phase II of the maneuver to the longest RR interval (the bradycardia) in phase IV of the maneuver, is the most commonly used measure derived from the maneuver. Other statistical measures of the heart rate response to the maneuver include the tachycardia ratio, the ratio of the shortest RR interval during the maneuver to the longest RR interval before the maneuver, which may be more reproducible but more dependent on resting heart rate than the Valsalva ratio [22,23,26,27]. Variables that influence the Valsalva ratio include age [28] and the duration and magnitude of expiratory effort [20]. In addition, when sympathetic outflow is deficient, parasympathetic activity cannot be adequately assessed because blood pressure during phase IV does not increase and there is therefore no stimulus to increase vagal activity [29]. When these variables are properly controlled, the heart rate response to the Valsalva maneuver is a sensitive and specific test of cardiac vagal innervation. Age and gender-based norms should be used for the Valsalva ratio. As an example, the fifth percentile Valsalva ratio cut-off point is as follows [19]: 1.59 for males and 1.46 for females ages 10 to 29 1.52 for males and 1.50 for females ages 30 to 39

1.44 for males and 1.51 for females ages 40 to 49 1.36 for males and 1.47 for females ages 50 to 59 1.29 for males and 1.39 for females ages 60 to 69

Assumption of upright posture Moving from the supine to upright posture results in the translocation of 300 to 800 cc of blood from the central intravascular compartment to dependent regions in the legs, buttocks, pelvis, and splanchnic circulation. This orthostatic stress evokes a sequence of compensatory cardiovascular responses to maintain homeostasis. Analysis of the heart rate response to the upright posture provides a measure of the sympathetic nervous system, the parasympathetic nervous system, and baroreceptor function. Active standing results in an abrupt increase in heart rate that peaks at approximately 3 seconds followed by a more gradual increase that peaks at approximately 12 seconds. The initial increase in heart rate is mediated by sudden inhibition of vagal tone, while the more gradual increase is due to further vagal inhibition and sympathetic activation. The initial heart rate increase is most likely an "exercise reflex" evoked by the integration of afferent signals from contracting muscle with signals from higher brain centers such as the insula and cingulate cortex (central command). This results in a response that is proportional to the intensity of the physical activity or perceived requirement for the physical activity [30]. Baroreflex activation due to transient hypotension causes the later increase in heart rate [31,32]. The heart rate and blood pressure return to a new baseline after approximately 30 seconds. The "30:15 ratio" assesses this physiologic response by measuring the ratio of the heart rate increase that occurs at approximately 15 seconds after standing to the relative bradycardia that occurs at approximately the 30 seconds after standing [33,34]. When cardiovagal function is deficient, the bradycardia does not occur. This ratio provides a measure of cardiac vagal function [31]. One report dissected the components of the heart rate response to passive tilting by measuring the acceleration index (the shortest R-R interval after standing minus the baseline R-R interval, all divided by the baseline R-R interval) and the brake index (the longest R-R interval after standing minus the shortest R-R interval, all divided by the baseline R-R interval). It was suggested that the acceleration index provides a measure of baroreceptor-mediated vagal withdrawal, while the brake index assesses the vagal response to the sympathetic-mediated increase in peripheral resistance [35]. However, others have suggested that R-R interval lengthening does not occur after passive tilting [31,33]. There is a low correlation between indices of the heart rate response to postural change and those of heart rate variability provoked by deep breathing (r = 0.14) suggesting different physiological mechanisms are involved [36]. Typical normal values for the 30:15 are as follows [12]: 1.15 1.12 1.10 1.08 to to to to 1.12 1.10 1.08 1.07 in in in in 20 31 41 51 to to to to 30-year-olds 40-year-olds 50-year-olds 60-year-olds

Lying down A related test measures the heart rate response to assuming the supine position. After lying down, there is a decrease in the R-R interval that is maximal around the third or fourth beat, which is followed by an increase in the R-R interval value (greater than the resting value) at approximately the 25th to 30th beat. Autonomic blockade studies with atropine and propranolol have suggested that the initial R-R interval shortening is mediated by the vagus nerve, while the later lengthening is predominantly mediated by the sympathetic nervous system. The initial tachycardia is most likely a manifestation of the "exercise" or "muscle-heart" reflex [37,38]. Squatting The cardiovascular response to squatting has been measured in a group of controls and diabetic subjects [39,40]. In this test, subjects stand still for three minutes, squat down for one minute, and then stand up during inspiration. Squatting results in lengthening of the R-R interval that is abolished by atropine, suggesting a vagal-mediated response; the shortening of the R-R interval that occurred after standing from a squatting position is attenuated by propranolol, suggesting mediation by sympathetic activation. In one report, a vagal ratio based upon this test (the ratio between the R-R interval mean before squatting and the longest R-R interval after squatting) was calculated [39]. The result was outside the 99 percent confidence interval in 42 percent of diabetic patients versus 1.3 percent of the controls. The results showed an inverse correlation with age. Apneic facial immersion The diving reflex in mammals is provoked by facial cooling and consists of bradycardia, apnea, decreased cardiac output, and vasoconstriction [41]. As a clinical test, the diving reflex assesses trigeminal-vagal-cardiac and trigeminalsympathetic-vascular smooth muscle pathways and does not directly involve the baroreflex or its primary central connections [42]. The test can also be performed in uncooperative or unconscious patients [43]. However, some investigators suggest that this test does not add significantly to other measures of autonomic function [44]. LONG-TERM MEASURES OF HEART RATE VARIABILITY Large, irregular, and episodic changes in heart rate can occur in normal subjects. These changes were quantified using a threshold value of 50 milliseconds difference from the preceding R-R interval (NN50) [45]. The number of such steps or "R-R counts" in normal subjects shows an inverse relationship with age and increases during sleep [45,46]. (See "Heart rate variability: Technical aspects".) A reduced number of these steps was found in diabetic subjects with autonomic neuropathy, some diabetics without autonomic neuropathy, patients with cardiac transplants, and in some patients after a myocardial infarction [46]. (See "Heart rate variability: Uses other than after myocardial infarction" and "Heart rate variability: Use after myocardial infarction".) In particular, 24 percent of diabetic subjects with normal cardiovascular reflexes had 24-hour R-R counts that were below the lower 95 percent confidence limit for healthy controls related to age. Based upon these results, the authors suggested that this method of heart rate variability analysis was more sensitive than the conventional tests of cardiovascular reflexes. This measure and the related pNN50 (the proportion of differences in consecutive normal R-R intervals that are greater than 50 milliseconds) correlates with the rMSSD and power in the high frequency of the heart rate power spectrum (>0.15 Hz) [9,47,48]. Use of UpToDate is subject to the Subscription and License Agreement.

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