The Autonomic (P and S) Assessment study is comprised of six phases with four clinical challenges: (1) a 5 min resting baseline challenge, (2) a 1 min deep breathing (DB) challenge at six breaths per minute, (3) a 1 min baseline, (4) a Valsalva challenge (1:35 min) consisting of five short Valsalva maneuvers, (5) a 2 min baseline, and (6) a quick head-up PC (e.g., standing) followed by 5 min of quiet standing. The DB, Valsalva, and head-up PC challenges are known as Ewing challenges [1–3].

The intent and purpose of the autonomic (P and S) study challenges have been published for decades [4–6]. More recently, the ADA recommended a set of nine tests for cardiovascular autonomic neuropathy (CAN) [7 (Table 5)]. Since CAN is the risk indicator for sudden cardiac death, regardless of disease or history, this has been adopted as the test criteria for detecting the onset of asymptomatic autonomic dysfunction (AD) prior to autonomic neuropathy (AN). The nine tests [8] include:

To qualify the testing, the ADA recommends testing “at least annually” [7, 9, p. S37, 10]. In the following discussion regarding the ADA’s stipulations for the nine tests, the impact of P&S monitoring will also be discussed.

For resting HR, a result of >100 bpm is abnormal. For beat-to-beat HRV (HRV alone), the patient is to be at rest in a supine position (having had no coffee nor a hypoglycemic episode the night before). The HR is monitored by EKG or autonomic instrument while the patient breathes in and out at six breaths per minute, paced by a metronome or similar device. A difference in HR of >15 bpm is normal and <10 bpm is abnormal. The supine requirement is difficult to implement in many physician practices due to patient volume and space limitations. An equivalence between relaxed seated posture with firm back support and supine posture is accepted [5, 11]. The office physical takes as its basis the resting BP in a relaxed, seated posture. Therefore, the supine stipulation from the ADA is met by equivalency. The second test in the list also refers to what is called the DB challenge. While the difference in HR is still measured, like other measures, HR (including mHR) is a function of both P&S activity. Normal responses for parasympathetic activity in response to DB challenge are published [12, p. 194–5] and have been corroborated with healthy normal subjects testing by the P&S monitoring technique [13]. The result is a direct measure of parasympathetic activity in response to paced or DB.

The E/I ratio is computed from the DB challenge as a ratio of the HBI at peak exhalation to that at peak inhalation. This parameter is thresholded, with no published upper bound and lack clinical trending. The measure of parasympathetic activity as computed from P&S monitoring in response to DB is represented in the “Deep Breathing (RFA)” response plot as seen in Fig. 5.1. The gray area represents age-adjusted normal responses [12]. “B” indicates the DB challenge; “x” indicates a resting, baseline adjustment to the age-related response. “Ref” indicates the expected normal range from age-matched normal subjects [12]. P&S monitoring has superseded the E/I ratio as a more sensitive and specific measure of vagal outflow (parasympathetic or cardiovagal activity) [13]. If the spectral analysis employed is the FFT, a much longer (e.g., 5 min) recording period would be required. Typically, a 1 min DB recording results in an E/I ratio. The short (1 min) recording period for spectral analysis and determination of P&S activity during DB is enabled by the CWT [13]. It is assumed that the SNS response to DB is expected to decrease with respect to rest. A clinical correlation with abnormal sympathetic responses to DB has not been elucidated.

P&S monitoring offers additional information. As a measure of vagal outflow, abnormally high DB responses are associated with (early) pulmonary disease or upper respiratory disorders, prior to typical symptoms. Abnormally low DB responses are associated with early autonomic dysfunction (see Chap. 1). According to Dr. Low (ed) [4], abnormally low DB responses are found to be the earliest signs of autonomic dysfunction, even when all other measures are normal. Abnormally high DB results are often treated (or corrected) by treating the underlying disease or disorder (typically a pulmonary or upper respiratory disorder), history dependent. Low DB results are often treated with alpha-lipoic acid (ALA, an antioxidant selective for nerves) which is recommended to slow the progression of autonomic dysfunction and may lower resting BP [11, 14–18].

The third test in the ADA’s list of recommended tests is HR response to standing (upright PC). The ADA stipulates that the 30:15 ratio is computed from a continuous EKG record. The 30:15 ratio is the ratio of the HBI measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia; therefore, the 30:15 ratio is always greater than 1.0. The ADA published that a normal 30:15 ratio is >1.03. The PC challenge may be executed from a supine position to standing. However, this causes significant artifact that masks the patient’s gravitational response to PC. If the patient is unable to stand, the PC challenge may be executed from a supine position to a proper seated position. Typically, the absolute values of the P&S response are different. However, the relative changes in P&S responses are the more important issue, especially in wheelchair-bound patients; more so than the issues of orthostasis or syncope. The importance in these patients is the coordination between the PSNS and the SNS, since a lack of coordination indicates morbidity risk. The similarity in physiologic response between active standing from a well-supported seated position and passive head-up tilt or active standing from a supine position is nearly perfect (96.3 %) [19].

Like the E/I ratio, the 30:15 ratio is also a mixed measure, thresholded, and lacking in clinical trending. The P&S monitoring measures have superseded the 30:15 ratio. The P&S measures provide more specific and sensitive results regarding both the parasympathetic response to standing (which is expected to decrease) and the sympathetic response (which is expected to increase). These expectations form the basis for normal responses (see Fig. 5.2). The gray area represents normal PC responses, “A” represents the resting (seated or supine) response, and “F” represents the upright posture (head-up posture) response. The PSNS response to standing with respect to resting is unbounded, as long as it decreases. Any increase in PSNS activity with respect to rest is denoted as parasympathetic excess (PE). The SNS response to standing with respect to resting is considered normal if it increases, but not by more than fivefold (500 %). A decrease in SNS activity with respect to rest is abnormal and denoted sympathetic withdrawal (SW). Any increase in sympathetic activity with respect to rest greater than 500 % is denoted sympathetic excess (SE).

P&S monitoring offers additional information. As with the DB challenge, the short time recording and ability to monitor P&S activity during transitions is facilitated by the CWT. A 5 min recording is the minimum possible given the autonomic physiology of standing. After the initial orthostatic response (aka, the gravitational reflex), there is the exercise reflex that concludes after 2–3 min, depending on age and history. The last 2 min is included to measure the P&S response following the exercise reflex, especially in the presence of pathology. The ability to measure and observe all of these transitions and the dynamics of the PSNS and SNS during and after standing is due to the CWT technique. It is not possible with any other common HRV-alone method with or without FFT spectral analysis.

p7: The combination of spectral analysis of HRV with spectral analysis of respiratory activity enables real-time, quantitative, non-invasive, independent, simultaneous measures of parasympathetic and sympathetic activity, both at rest and in response to various challenges. This technique enables early detection and quantification of CAND and CAN in terms that are clinically trendable and reflective of disease progression, therapeutic intervention, and outcomes. Commercially available computer programs (e.g. NeuroDiag II, ANSAR) are usually employed to assess autonomic nerve function. [1]

In adults, abnormal P&S responses to standing are often associated with increase morbidity and degraded quality of life, including GI upset, sleep disturbances, urogenital dysfunction, hypertension secondary to autonomic dysfunction, as well as dizziness or lightheadedness upon standing. This fact is confirmed in an academic review article, citing the creators of P&S monitoring by name [1, p. 7]. Vinik et al. state that frequent autonomic testing reduces morbidity. This increase in morbidity is common in many chronic diseases and disorders, suggesting that it is associated with autonomic dysfunction (autonomic imbalance) rather than the disease itself. Correcting abnormal stand responses (history dependent), including recommending proper daily hydration, reduces morbidity.

P&S monitoring results in response to PC challenge which is sensitive enough to provide early (preclinical) indication of orthostasis or syncope and is a fall risk indicator in geriatric patients. In effect, the stand test, when compared with the resting baseline, is a tilt study [19]. It is known that the expected, normal, sympathetic (alpha-adrenergic) response to PC is an increase, causing the necessary vasoconstriction to support the heart in perfusing the brain upon standing. Therefore, SW upon standing is abnormal. It is also known that BP is expected to increase upon standing as a result of the sympathetic increase. Therefore, any decrease in BP upon standing is also abnormal. In fact, the clinical definition of orthostatic hypotension is a 20 mmHg drop in systolic BP with a 10 mmHg drop in diastolic BP. SW from P&S monitoring is additional information that, when coupled with a smaller drop in BP upon standing, indicates and documents preclinical orthostasis. SW, when documented and treated early, enables short-term, low-dose therapy [8]. Similarly, SE upon standing provides additional information, helping to indicate and document possible preclinical syncope.

p8: Given that there are therapies that can reorient the functional abnormalities of the ANS toward improved function, the importance of determining the presence of CAN and CAND early cannot be overemphasized. [1]

Note, while the stand challenge is specific and sensitive for assessing risk of orthostasis and risk of syncope, this is not its sole function. The stand challenge should also be administered to patients who cannot stand (e.g., wheelchair-bound patients) because its true function is to assess the coordination between the P and S branches (see Chap. 4) [20]. Vinik et al. summarize the effect of autonomic neuropathy on morbidity: “Structural damage to the ANS, found in approximately one-quarter of type 1, and one-third of type 2, diabetic patients, is associated with a number of serious complications, including an increased risk of mortality. Various assessment modalities are available to determine the presence of CAND [CAN-Dysfunction] and CAN. Once determination of the presence of autonomic dysfunction has occurred, a number of different therapeutic agents are available for the correction of functional defects in the ANS [1, p. 8]..”