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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. a short interval followed by a long compensatory pause [11]. which may lead to false-negative test results in younger patients and false-positive results in older patients.16]. although it can be used to assess heart rate variability in the smaller segments more typically obtained during clinical testing. 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 . ie. for a specific tidal volume. 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]. the actual differences between adjacent R-R intervals. Unlike the standard deviation. This measure is more frequently used to assess heart rate variability over longer periods (five minutes to 24 hours). This test is the best noninvasive test to assess cardiac vagal innervation. The diagnostic discrimination of this test is reduced by the use of a single normal value for all ages. however. There are a number of factors that influence respiratory mediated heart rate variability. the magnitude of heart rate variability is dependent on the breathing frequency. The maximum heart rate variation in response to deep breathing is a sensitive and specific index of autonomic function. The mean square successive difference (MSSD) is the average of the square of the differences between successive beats [5]. These studies suggest a decline in heart rate variability of 3 to 5 beats per minute per decade in control subjects. The standard deviation of the R-R interval or instantaneous heart rate is the most widely used statistical measure of heart rate variability. the mean successive difference (MSD) [4] is the average of the differences between successive beats.15]. 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]. As examples of the age-related decline in the maximum minus minimum heart rate difference with deep respiration. The maximal heart rate response in subjects with an autonomic neuropathy occurs at lower respiratory rates [13. They are. Smaller changes in heart rate occur at lower and higher respiratory rates for a given tidal volume [14. the rMSSD is its square root [9]. that is. sensitive to ectopic beats such as ventricular premature beats. the magnitude of change in heart rate at a given respiratory rate is dependent on the tidal volume and.) Other commonly used statistical approaches are based upon the hypothesis that successive differences in the R-R intervals. would be more sensitive than the standard deviation to short-term fluctuations in heart rate. while the SDSD is the standard deviation of the successive differences [10]. ie. these measures are dependent upon the sequence of RR intervals. This relationship has been expressed in most studies as a linear decline in the heart rate response to deep breathing with increasing age [19]. There is a well established relationship between age and heart rate variability. (See "Heart rate variability: Technical aspects". Other potential confounders that may reduce respiratory mediated heart rate variability include hypocapnia (that may occur with hyperventilation) [17] and increased sympathetic outflow [18]. Respiratory sinus arrhythmia is dependent on the both the frequency and depth of respiration.

is the most commonly used measure derived from the maneuver.   Phases 1 and 3 most likely reflect mechanical factors. and baroreflex interactions [21-25]. Variables that influence the Valsalva ratio include age [28] and the duration and magnitude of expiratory effort [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. which may be more reproducible but more dependent on resting heart rate than the Valsalva ratio [22.27]. Age and gender-based norms should be used for the Valsalva ratio. vagal. When these variables are properly controlled. Phase 4 is characterized by an increase in blood pressure above the resting value (the "overshoot") and by bradycardia. lower levels do not provide an adequate stimulus. 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. and reproducible measure of autonomic function.23. specific. while higher levels result in poor reproducibility. while phases 2 and 4 are a consequence of sympathetic. when sympathetic outflow is deficient. sensitive. 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. the ratio of the shortest RR interval during the maneuver to the longest RR interval before the maneuver. This test should be repeated several times to ensure a reproducible response [20]. In addition.50 for females ages 30 to 39 . is characterized by a gradual fall in blood pressure followed by a recovery. Other statistical measures of the heart rate response to the maneuver include the tachycardia ratio.59 for males and 1. As an example. the fifth percentile Valsalva ratio cut-off point is as follows [19]:   1. An expiratory pressure of 40 mmHg appears to result in an optimal response. 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]. and baroreceptor function. The heart rate change in response to this maneuver is a widely used indirect. The mercury column of the manometer is maintained at 40 mmHg. vagal.26. during the expiratory phase of the maneuver. The Valsalva ratio. the heart rate response to the Valsalva maneuver is a sensitive and specific test of cardiac vagal innervation. There should be a small air leak in the system to prevent closing of the glottis. The maneuver is typically performed by blowing through a mouthpiece connected to a mercury manometer for 15 or 20 seconds.46 for females ages 10 to 29 1.52 for males and 1.  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.

It was suggested that the acceleration index provides a measure of baroreceptor-mediated vagal withdrawal. the bradycardia does not occur. buttocks. When cardiovagal function is deficient.12 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 .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. pelvis. This ratio provides a measure of cardiac vagal function [31]. others have suggested that R-R interval lengthening does not occur after passive tilting [31.29 for males and 1.14) suggesting different physiological mechanisms are involved [36]. Baroreflex activation due to transient hypotension causes the later increase in heart rate [31. 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 = 0.12 1. 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. while the more gradual increase is due to further vagal inhibition and sympathetic activation.10 1. Analysis of the heart rate response to the upright posture provides a measure of the sympathetic nervous system. the parasympathetic nervous system.10 1.   1.32]. 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). 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. This orthostatic stress evokes a sequence of compensatory cardiovascular responses to maintain homeostasis.34]. 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. However.44 for males and 1.51 for females ages 40 to 49 1. and splanchnic circulation.08 1. all divided by the baseline R-R interval).47 for females ages 50 to 59 1. 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. This results in a response that is proportional to the intensity of the physical activity or perceived requirement for the physical activity [30].08 to to to to 1. The initial increase in heart rate is mediated by sudden inhibition of vagal tone. and baroreceptor function. Typical normal values for the 30:15 are as follows [12]:     1.36 for males and 1.33]. The heart rate and blood pressure return to a new baseline after approximately 30 seconds. while the brake index assesses the vagal response to the sympathetic-mediated increase in peripheral resistance [35].15 1.

The result was outside the 99 percent confidence interval in 42 percent of diabetic patients versus 1.) A reduced number of these steps was found in diabetic subjects with autonomic neuropathy. suggesting mediation by sympathetic activation.3 percent of the controls. In this 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]. and then stand up during inspiration. squat down for one minute. which is followed by an increase in the R-R interval value (greater than the resting value) at approximately the 25th to 30th beat. 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.48]. irregular. These changes were quantified using a threshold value of 50 milliseconds difference from the preceding R-R interval (NN50) [45]. suggesting a vagal-mediated response. while the later lengthening is predominantly mediated by the sympathetic nervous system. As a clinical test. LONG-TERM MEASURES OF HEART RATE VARIABILITY — Large. the authors suggested that this method of heart rate variability analysis was more sensitive than the conventional tests of cardiovascular reflexes. Squatting — The cardiovascular response to squatting has been measured in a group of controls and diabetic subjects [39. The initial tachycardia is most likely a manifestation of the "exercise" or "muscle-heart" reflex [37. subjects stand still for three minutes. and vasoconstriction [41]. there is a decrease in the R-R interval that is maximal around the third or fourth beat.38]. and episodic changes in heart rate can occur in normal subjects. some investigators suggest that this test does not add significantly to other measures of autonomic function [44]. . 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. (See "Heart rate variability: Uses other than after myocardial infarction" and "Heart rate variability: Use after myocardial infarction". the shortening of the R-R interval that occurred after standing from a squatting position is attenuated by propranolol.Lying down — A related test measures the heart rate response to assuming the supine position. Apneic facial immersion — The diving reflex in mammals is provoked by facial cooling and consists of bradycardia.46]. and in some patients after a myocardial infarction [46]. Autonomic blockade studies with atropine and propranolol have suggested that the initial R-R interval shortening is mediated by the vagus nerve. some diabetics without autonomic neuropathy. Squatting results in lengthening of the R-R interval that is abolished by atropine.15 Hz) [9. The number of such steps or "R-R counts" in normal subjects shows an inverse relationship with age and increases during sleep [45. However. Based upon these results. (See "Heart rate variability: Technical aspects". In one report. The results showed an inverse correlation with age. Use of UpToDate is subject to the Subscription and License Agreement.) In particular. decreased cardiac output. apnea. After lying down. The test can also be performed in uncooperative or unconscious patients [43]. patients with cardiac transplants. 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].40].47.

Eckberg DL. Human sinus arrhythmia as an index of vagal cardiac outflow. Neubauer B. Pfeifer MA. An improved method for measuring heart-rate variability: assessment of cardiac autonomic function. Diabetes 1990. J Appl Physiol 1993. Low. 20.297. Comparison of time. 7. Maling TJ. Opfer-Gehrking TL. 9. Harry JD. The effect of intensive diabetes therapy on the development and progression of neuropathy. 18:74. 16:267. and standard tests of heart rate variation and blood pressure responses. . 75:2310. In: Clinical Autonomic Disorders. Biometrics 1984. Diedrich AM. Am J Physiol 1998. R. Clarke BF. 13:137. Muscle Nerve 1995. Determining heart-rate variability: comparing methodologies using computer simulations. Laux G. 2. Diabetes Metab Rev 1988. Gundersen HJ. Borsey DQ. Diagnostic value of the Valsalva ratio reduction in diabetic autonomic neuropathy: use of an age-related normal range. Am J Cardiol 1966. p. 19. Bellavere F. 9:166. Dannehl K. Respiratory sinus arrhythmia in diabetic neuropathy. Eckberg DL. L. 4:255. Myers CW.the time domain. Brown TE. Freeman R. 5. Genovely H. Pfeifer MA. Weinberg CR. 22. Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Watkins PJ. Ann Intern Med 1995. Controlled breathing protocols probe human autonomic cardiovascular rhythms. Am J Cardiol 1989. vector analysis. Diabetologia 1977. Lilja. Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans. 14. Diabet Med 1984. 280:H2804. Taylor JA. et al. Ziegler D. 21:18. Freeman. Diabetologia 1981. et al. G. Muscle Nerve 1993. A simple test of cardiac function based upon the heart rate changes induced by the Valsalva maneuver. 11. 6. Malpas SC. Use of the photoplethysmographic technique to analyze the Valsalva maneuver in normal man. 1:295. The Diabetes Control and Complications Trial Research Group. 18. Bigger JT Jr. Cohen RJ. 3. RR-variation: the autonomic test of choice in diabetes. et al. 54:961. J Appl Physiol 1983. 274:H709. Halliwill JR. 21. 4:584. Benarroch EE. 14:1165. Denq JC. Transfer function analysis of respiratory sinus arrhythmia: a measure of autonomic function in diabetic neuropathy. Ewing DJ. Smith SA. Wheeler T. 4. Beightol LA. Br Med J 1973. Heart rate variability . 64:536. Albrecht P. Koh J. Steinman RC. Little Brown. 10. A long-term diabetic autonomic nervous abnormality. Muscle Nerve 1991. Diabet Med 1992. Saul JP.REFERENCES 1. Cardiac autonomic neuropathy in diabetes: comparison of measures of R-R interval variation. Reduced variations in resting heart rate measured by a simple and sensitive method. Low PA. et al. Cox JF. Low PA. Cooke WH. 24:253. 1:924. Cardiac denervation in diabetes. 18:90. Boston 1997. Am J Physiol Heart Circ Physiol 2001. et al. 15. 12. 13. 39:1177. Br Med J 1979. Levin AB. 122:561. Freeman R. 8. 40:855.and frequency domainbased measures of cardiac parasympathetic activity in Holter recordings after myocardial infarction. Heart-rate variability and cardiac autonomic function in diabetes. B. 16. Diabetologia 1983. Sundkvist. Muscle Nerve 1997. PA (Ed). 17. Respiratory influence on heart rate in diabetes mellitus. 20:1561. Opfer-Gehrking TL. Almer. Important influence of respiration on human R-R interval power spectra is largely ignored. Mackay JD. Assessment of cardiovascular autonomic function: agerelated normal ranges and reproducibility of spectral analysis.

Wieling W. Reflex control of heart rate in normal subjects in relation to age: a data base for cardiac vagal neuropathy. 4:41. Reproducibility in normals. Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes. Ewing DJ. The sympathetic nervous system in alcoholic neuropathy. 52:396. Khurana RK. Initial blood pressure fall on stand up and exercise explained by changes in total peripheral resistance. J Appl Physiol 1991. J Appl Physiol 1979. 1:145. van Brederode JF. 2:1354. Wesseling KH. Am J Physiol 1982. van Lieshout JJ. 243:H676. . 76:523. Br Med J 1978. van Brederode JF. Sahinen F. Neurology 1991. Hampton JR. 44. Bellavere F. Mohanty SK. 43:607. Wesseling KH. Autonomic pathways responsible for bradycardia on facial immersion. Ewing DJ. Finley JP. et al. Clin Sci (Lond) 1989. Eckberg DL. Ferrer MT. a test of autonomic dysfunction. 22:163. Giugliano D. 42. Imholz AL. 30. The squatting test. 239:H581. Watabiki S. 41. A useful tool to assess both parasympathetic and sympathetic involvement of the cardiovascular autonomic neuropathy in diabetes. Lilja B. Ewing DJ. New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms. 33. 17:149. de Rijk LG. Huang CY. Mechanisms of initial heart rate response to postural change. Murray A.23. 10:192. Parasympathetic cardiovascular control in human disease: a critical review of methods and results. Campbell IW. Low PA. Salvatore T. 19:433. et al. et al. 38. Cardiovascular reflex responses to apnoeic face immersion and mental stress in diabetic subjects. Ewing DJ. Ewing DJ. Diabetes Care 1994. 29. J Appl Physiol 1980. J Appl Physiol 2003. Giugliano D. Neilson JM. 40. Campbell IW. 37. Solders G. 32. Standing to lying heart rate variation. et al. 36. et al. 31. Marfella R. R-R variations. Diabet Med 1987. 41:1462. Autonomic mechanisms in the initial heart rate response to standing. Marfella R. Br Heart J 1991. 7:144. 94:1726. Bellavere F. 25. et al. Karemaker JM. Raczkowska M. 34. Ewing DJ. Wieling W. Sundkvist G. Clin Sci (Lond) 1982. Neilson JM. Acta Neurol Scand 1983. 27. Hosking DJ. Heart rate response to Valsalva manoeuvre. Baroreflexes in patients with diabetes mellitus. 28. Borst C. McLeod JG. Williamson JW. Vascular reflexes in diabetic autonomic neuropathy. Ann Neurol 1980. sleep. Br Heart J 1984. 26. Almér LO. 62:57. Sprangers RL. Campbell IW. 47:1218. Cold face test in the assessment of trigeminalbrainstem-vagal function in humans. 347:75. Eckberg DL. J Physiol 1984. Trigeminal-baroreceptor reflex interactions modulate human cardiac vagal efferent activity. 98:357. Walsh JC. Bonet JF. di Maro G. Bennett T. 70:523. Cardone C. et al. Br Heart J 1977. 35. Travis P. 43. Abnormal diastolic blood pressure and heart rate reactions to tilting in diabetes mellitus. A new simple test in the diagnosis of diabetic autonomic neuropathy. Diabetologia 1980. et al. Cardiovasc Res 1976. Persson A. Wieling W. Evidence for central command activation of the human insular cortex during exercise. Baldwa VS. A clinical and pathological study. Mathews D. 49:809. Pitfalls in the assessment of cardiovascular reflexes in patients with sympathetic failure but intact vagal control. Kennedy WR. 39:641. Autonomic control of the immediate heart rate response to lying down. Twenty four hour heart rate variability: effects of posture. McColl R. 46. 24. Diabetologia 1982. et al. 45. Hebel JR. and time of day in healthy controls and comparison with bedside tests of autonomic function in diabetic patients. Lancet 1973. Am J Physiol 1980. 67:285. Waxman MB. 65:239. Ferri M. Shapiro CM. Brain 1975. et al. Hume L. and relation to variation in resting heart rate in diabetics. Clarke BF. Ewing DJ. Burt AA. Detection of early sympathetic cardiovascular neuropathy by squatting test in NIDDM. 39. Diabetes 1994.

Steinman RC. Am J Cardiol 1991. Kleiger RE. Bigger JT. 48. Bosner MS. et al. Bigger JT Jr. Am J Cardiol 1992. . Stability over time of variables measuring heart rate variability in normal subjects. et al. Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction.47. 68:626. Fleiss JL. 69:891.