, Rohit Arora3, 4, Nicholas L. DePace5 and Aaron I. Vinik6
(1)
Autonomic Laboratory Department of Cardiology, Drexel University College of Medicine, Philadelphia, PA, USA
(2)
ANSAR Medical Technologies, Inc., Philadelphia, PA, USA
(3)
Department of Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, IL, USA
(4)
Department of Cardiology, The Chicago Medical School, North Chicago, IL, USA
(5)
Department of Cardiology, Hahnemann Hospital Drexel University College of Medicine, Philadelphia, PA, USA
(6)
Department of Medicine, Eastern Virginia Medical School Strelitz Diabetes Research Center, Norfolk, VA, USA
Overview
Dizziness or lightheadedness is one of the most debilitating symptoms of autonomic dysfunction, including DAN or CAN [1]. Dizziness may result from one of four general disorders: (1) vestibular dysfunction, (2) arrhythmia, (3) orthostatic dysfunction, or (4) syncope. Only the first of these does not include the P and S nervous systems. In fact, especially in geriatrics, P&S monitoring should always be considered together with vestibular studies to ensure that comorbid dizzy diagnoses are not overlooked [2]. P&S monitoring documents P or S components underlying arrhythmia and guides therapy to relieve the P or S abnormalities contributing to the arrhythmia [3]. P&S abnormalities are involved in orthostatic dysfunction [4].
Normal P&S responses to standing (Fig. 23.1, top, left graph) include, first, a parasympathetic decrease (blue vertical line from the resting state, “A”) followed by a sympathetic increase of between 10 and 500 % (The red horizontal line ending on the standing state, “F.”)
Fig. 23.1
Sample PC (stand) response plots demonstrating the normal and abnormal states
Any decrease in sympathetic activity is abnormal and indicates (preclinical) orthostatic dysfunction. Decreases in sympathetic response to standing are called sympathetic withdrawal (SW, Fig. 23.1, top, right and middle right graphs).
SW with a significant decrease in BP upon standing is associated with (preclinical) orthostatic hypotension (OH).
SW with an excessive increase in BP upon standing is associated with (preclinical) orthostatic hypertension.
SW with an excessive increase in HR upon standing is associated with (preclinical) postural orthostatic tachycardia syndrome (POTS).
By default, SW with a change in BP upon standing that is within normal limits is associated with (preclinical) orthostatic intolerance.
Any increase in parasympathetic activity is abnormal and is associated with parasympathetic excess (PE, Fig. 23.1, middle, two, and bottom, left graphs), which may mask SW (Fig. 23.1, middle, left graph).
An excessive sympathetic response to standing (SE, Fig. 23.1, bottom, two graphs) is associated with (preclinical) syncope.
Stand SE with a little or no HR response to standing is associated with neurogenic syncope (Fig. 23.1, bottom, right graph). Apparently, sympathetic signaling is not reaching the heart.
Stand SE with excessive parasympathetic activity somewhere during the test is associated with vasovagal syncope (Fig. 23.1, bottom, left graph).
Stand SE with a normal HR response to standing and no PE anywhere during the Autonomic Assessment is not neurogenic syncope. It may be associated with possible (preclinical) cardiogenic syncope (Fig. 23.1, bottom, right graph); however, additional testing may be required to fully diagnose.
Neurocardiogenic syncope, the most common form, is a combination of two of the above. P&S monitoring helps to differentiate the neurologic component.
With the additional information available from P&S monitoring, preclinical, including presymptomatic, conditions that lead to dizziness are elucidated and are available to guide therapy to prevent dizziness. This is especially important in geriatric patients, or sicker patients, who are at risk for falling and causing additional comorbidities. P&S monitoring may pre-identify these patients to prevent falls. From an autonomic dysfunction perspective, early identification of stand challenge abnormalities is coincident with early identification of the advanced stages of autonomic dysfunction. Autonomic PC dysfunction may contribute to hypertension [5] and can be a fall risk indicator in geriatric patients [2]. Restoring and maintaining normal autonomic responses to PC (stand) slows the onset of advanced autonomic dysfunction, including CAN, or reduces morbidity and mortality risk in the face of CAN [6]. The 5 min of rest (the initial baseline, section “A,” of the Autonomic Assessment) prior to these 5 min of standing (section “A,” of the Autonomic Assessment) are equivalent to a passive, head-up, tilt-table study [7].
With P&S monitoring additional information is available and earlier diagnoses and earlier intervention are facilitated [5]. For example, the clinical standard for OH is a 20 mmHg over 10 mmHg drop in BP upon standing. This highly significant change is required because there is no other information to help differentiate the disorder. From our database, stand abnormalities may also be associated with hypertensive patients that seem to not tolerate antihypertensive therapy due to dizziness. It seems to be that the hypertension is a protective mechanism against dizziness and possibly falling. Higher BP ensures that the drop in BP upon standing results in a BP above the minimum required for that patient to have sufficient brain perfusion. Treating the high BP as the primary disorder causes the minimum standing BP to be too low and results in dizziness and the patient reporting feeling worse on medication. Consider treating the stand abnormality (including the vascular or cardiac dysfunction) as the primary, while protecting from raising the BP too much higher. If the stand abnormality is relieved, often the high BP follows without further treatment and the patient may be weaned from the antihypertensive, history dependent. Abnormal sympathetic responses to standing also seem to be associated with the expression of symptoms in patients at risk for hypertrophic cardiomyopathy. To date, 90 of 90 (100 %) hypertrophic cardiomyopathy patients tested have persistent stand abnormalities, including approximately 25 % who report being tilt negative. A significant number of patients (perhaps as many as 40 %, depending on the practice) demonstrating abnormal sympathetic responses to standing are simply dehydrated.
Orthostatic Dysfunction
Sympathetic Withdrawal May Cause Orthostatic Dysfunction: Possible Physiology and Therapy Options
The next manuscript is a composite of manuscripts first published as abstracts and accepted at the American Heart Association’s Scientific Session in Chicago, IL, 17–20 November 2002 [8], in Dallas, TX, 13–16 November 2005 [9, 10], and in Orlando, FL, 4–7 November 2007 [11]; at the American Autonomic Society, 17th International Symposium, Kauai, HI, 29 October to 1 November 2008 [12]; and at the International Symposium on Diabetes Neuropathy, 7th Annual Congress, 29 November to 2 December 2007 [13]. Excerpts of these manuscripts are collected and integrated here.
Introduction
Normal P&SS activity upon standing includes a decrease in parasympathetic activity followed by an increase in sympathetic activity. The faster PSNS (a response possible within one to two heartbeats [4]) decreases first to facilitate and potentiate required vasoconstriction that enables the assumption of an upright posture. In normal subjects, this also reduces the amount of sympathetic activation required to affect PC. Then the slower SNS (a response possible within three to five heartbeats [4]) increases, perpetuating the vasoconstriction to help support the heart to continue to deliver blood to brain. Abnormalities in this process may lead to orthostatic syndromes that are associated with dizziness, lightheadedness, frequent headache or migraine, lower extremity edema, cardiac dysrhythmias, exercise intolerance, and injuries secondary to falling [14, 15].
In chronic diseases, autonomic neuropathy is often associated with defects in the P&S responses to PC, leading to orthostatic dysfunction symptoms [16]. Underlying autonomic pathophysiology may include SW and stand SE and PE. DAN is a risk factor for CAN, and both DAN and CAN are associated with heart and vascular control anomalies, including BP, and may lead to orthostatic dysfunction and its subforms [1, 17–21].
A standard test for postural difficulties is the tilt-table study [4]. Although this is technician and physician intensive, this test will often cause the symptoms associated with the different postural difficulties to present. The subsequent diagnosis is based on the symptoms. However, not all patients experience symptoms, which could lead to an incorrect diagnosis. In this respect, actively changing posture from seated to standing was found to more reliably elucidate autonomic changes [7]. Changes in BP from a supine to standing position also reveal postural difficulties [4], but do not sufficiently differentiate autonomic involvement. Goldstein et al. [22, 23] report that in chronic primary autonomic failure, supine hypertension accompanies OH. Decreased baroreflex–cardiovagal gain correlates with, and therefore might play, a pathophysiological role in both abnormalities of BP regulation (i.e., cardiovagal and vascular). Typically, autonomic labs combine tilt and other studies with HRV measures obtained during DB and Valsalva challenges [4, 20, 24–26]. HRV-alone measures in these cases tend to require highly trained and experienced physicians to assess the underlying autonomic dysfunction, differentiating waveforms and sub-waveforms and symptomatology, and still there may be confusion. The confusion is due to the mix of P&S information in the HRV-alone, btbBP, HR, and BP signals [27, 28].
SW is a physiologic characteristic of orthostatic dysfunction and may be an early marker. SW may result in orthostatic dysfunction and falls with serious consequences. Patients at risk may be quantitatively measured with autonomic profiling and P&S monitoring. If SW is detected and treated early as an orthostatic syndrome, the orthostatic dysfunction may be prevented and typically with lower-dose and shorter-term therapy [5]. SW confirms that the abnormal BP or HR may already be trending towards orthostatic dysfunction. SW defines the continuum of orthostatic dysfunction and corresponding abnormal BP or HR changes that occur upon assuming an upright posture. SW helps to differentiate orthostatic dysfunction from syncope, and BP and HR changes help to differentiate the subforms, including orthostatic hypotension (OH), orthostatic hypertension also known as postural orthostatic hypertension syndrome (POHS) or vasoconstrictor syndrome (SW is demonstrated with a abnormally, large increase in BP response to PC), postural orthostatic tachycardia syndrome (POTS) and postural orthostatic bradycardia syndrome (POBS), and by default orthostatic intolerance (OI).
OH may be relieved with pharmaceutical and non-pharmaceutical therapies, history dependent. POTS may be relieved with beta-adrenergic agonists, history dependent. POBS may be relieved with cholinergic antagonists or beta-adrenergic agonists. POHS may be relieved with adrenergic antagonists. PE may mask SW. OH is the more common and is considered to be the more severe condition and is the primary disorder discussed herein. OH is marked by an abnormal decrease in BP of 20/10 mmHg or more upon upright posture. OI is marked by a normal BP response to PC or an abnormal change in BP of less than a 10 % increase and a decrease of 20/10 mmHg upon upright posture [4].
Orthostatic dysfunction is not always a specific disease, but rather a manifestation of abnormal BP regulation due to various causes, including abnormal autonomic regulation due to chronic disease. Orthostatic dysfunction seems to be a component accompanying many clinical syndromes (e.g., Diabetes [29, 30], some cardiovascular diseases [31–35] (e.g., hypertension, CHF, and atrial fibrillation), and neurological diseases [29, 36–41] (e.g., Parkinson’s, multiple sclerosis, multiple system atrophy, and Shy–Drager syndrome). Furthermore, symptoms (e.g., BP and HR changes) may be masked or mimicked by components of the clinical syndrome or the therapy plan for the clinical syndrome without affecting the underlying autonomic issues.
Methods
The cohort includes 441 consecutive patients (255 females, mean age 62 ± 15.7 years) who presented to their primary care physician and followed for up to 24 months. The patients are from four ambulatory clinics along the eastern seaboard, including an internal medicine practice, two cardiology practices, and an endocrinology practice. Patients were followed as a matter of routine, based on their primary diagnosis (e.g., hypertension, diabetes, heart diseases, COPD, and Parkinson’s disease). Periodic, Autonomic Assessments were made, including a PC from a relaxed seated position (with proper back support) to head-up posture (standing). No patients had unexplained fainting, nor were any tilt positive.
Average and instantaneous changes in P&S activity, including SB, were recorded and analyzed clinically in conjunction with the patient’s own history. The results were compared with normal patient data ranges and expected changes [26].
All cases reporting dizziness, or demonstrating SW, were recommended proper daily hydration (six to eight glasses of water daily and reduce caffeinated, sugary, and alcoholic beverages), and their diuretics were titrated lower if their BP was well managed. Some patients found to have P&S abnormalities that included symptoms of orthostatic dysfunction were treated with a short course of the vasopressor midodrine (ProAmatine™), titrated from 2.5 mg BID QD, dinner, as needed [5]. The course of this therapy was up to 12 weeks. Other P&S abnormalities that resulted in cardiovascular disease, including hypertension, were treated with 3.125 mg bid carvedilol, titrated up to 12.5 bid, against normalizing the patient’s P&S response. P&S abnormalities that did not result in cardiovascular disease were treated with amitriptyline (25–50 mg daily) as needed. Other clinical conditions (e.g., diabetes) were treated as per usual. All patients prescribed with midodrine were first tested negative for supine hypertension. Also, no patient was prescribed with midodrine with a resting BP greater than 160/90. All midodrine dosing was considered low and maintained low (e.g., 2.5 mg QD or bid).
In a follow-up study, the patients treated with proper daily hydration only were then treated, in a randomized fashion, with fludrocortisone, or support hose, or when possible were requested to modify their diets to add salt and build fluid volume. Again, patients with dysautonomia or with symptoms of elevated BP when supine were omitted from the study.
Results: General Orthostatic Dysfunction
Patients’ primary indications include hypertension (46 %), type 2 diabetes mellitus (34 %), heart diseases (29 %), COPD (17 %), and Parkinson’s disease (13 %). Dizziness was reported in 39 % of the cases. Symptoms of orthostatic dysfunction were demonstrated in 34 % of the patients. Orthostatic dysfunction was diagnosed in 14 % of the cases. SW was demonstrated in 57 % of the cases. After recommending proper daily hydration to all cases reporting dizziness or demonstrating SW, 18 % continued to report dizziness and 25 % continued to demonstrate SW. This suggests that 38 % of the patients reporting dizziness and 43 % of the patients demonstrating SW were dehydrated.
Resting HR, resting BP, and HRV-alone parameters were uncorrelated (p > 0.050) with orthostatic dysfunction. SW was correlated (p = 0.008) with elevated or high BP, suggesting SW may contribute to increased BP. Decreases in BP in response to PC were 85 % correlated (p < 0.001) with a diagnosis of orthostatic dysfunction. Decreases in resting HR were 11 % correlated (p = 0.022) with a diagnosis of orthostatic dysfunction. Changes in the “sdNN” time-domain measure of HRV were 20 % correlated (p = 0.048) with a diagnosis of orthostatic dysfunction and were heterogeneous. Decreases in sdNN were 9 % correlated (p = 0.037) with a diagnosis of orthostatic dysfunction and 50 % correlated (p = 0.011) with SW. Other parameters, including LF and LF/HF ratio, are even less correlated (p > 0.050).
The P&S monitoring sympathetic measure, LFA, identified more patients with orthostatic dysfunction than SB (57 % vs. 32 %, p < 0.01). LFA identified more patients than physician diagnosis (57 % vs. 14 %, p < 0.01) and combination of diagnosis and symptoms (57 % vs. 44 %, p < 0.01). The ratio identified more patients than physician diagnosis (32 % vs. 14 %, p < 0.01), but less compared to combination of diagnosis and symptoms (32 % vs. 44 %, p < 0.01).
SW is correlated (p < 0.001) with 69 % of the cases that demonstrate a decrease in BP in response to PC. SW is correlated (p < 0.001) with 90 % of the cases that demonstrate a significant decrease in BP (>20/10 mmHg) in response to PC and 71 % of the cases (p < 0.001) diagnosed with orthostatic dysfunction. Of the cases that demonstrate a decrease in BP in response to PC, but do not demonstrate SW, 64 % demonstrate parasympathetic excess (PE). PE may mask SW. This is confirmed by patients reporting increased dizziness with PE therapy: either low-dose carvedilol in cases of PE with resting sympathetic excess (SE) or high BP or low-dose anticholinergic, antidepressant otherwise. Note, SW in response to PC is believed to be an alpha-adrenergic response and the resting or Valsalva SE is a beta-adrenergic response. Often (resting) SE is demonstrated concurrently with (PC) SW. The abnormal decrease in LFa from baseline to upright posture was reversed or reduced in all of the patients treated with the short course of midodrine, with or without the PE therapy. Patients who did not report symptoms, but demonstrated SW and were treated for SW, reported feeling better, and the physicians reported that the patients were more stable and that they were able to be aggressive with the treatment of the comorbidity itself.
Results: Orthostatic Dysfunction Subforms
To differentiate the continuum of definitions for orthostatic dysfunction based on its autonomic definition of SW, BP and HR differences are noted.
A BP decrease of any kind is considered as orthostatic hypotension (OH). Clinically, however, a BP decrease of more than 20 mmHg systolic and 10 mmHg diastolic with SW is considered OH. OH describes 6 % of the cohort.
A lesser decrease in BP with SW is considered preclinical OH. This accounts for 32 % of the cohort.
An increase in BP of more than 30 mmHg systolic with SW is considered orthostatic hypertension. Orthostatic hypertension describes 5 % of the cohort.
An increase of BP of between 11 and 30 mmHg with SW is considered preclinical orthostatic hypertension. This accounts for another 5 % of the cohort.
SW with an abnormal increase in HR, either an increase of more than 30 bpm or an HR in excess of 120 bpm on average upon standing, is considered postural orthostatic tachycardia syndrome (POTS) or postural tachycardia syndrome. POTS describes 6 % of the cohort.
By default, SW with a normal increase in BP upon standing is considered orthostatic intolerance (OI). OI describes 48 % of the cohort.
These clinics have shown that earlier detection of these disease states, especially in the preclinical phases, may lead to earlier interventions, prior to the onset of potential end-organ effects or other comorbidities. This in turn has led to therapy plans that are only about 6 months long in over 90 % of the preclinical cases, where the therapies were weaned based on the stability of the patients’ ANS, and the patient was able to remain ANS drug-free until some other clinical event occurred.
Results: Orthostatic Dysfunction Therapy
The entire cohort was recommended proper daily hydration. Of this cohort, 210 patients were treated with 2.5 mg midodrine QD, dinner, and followed for 18 months. The remaining patients were not administered any additional medication. The remaining patients included those with dysautonomia or supine hypertension. Of the experimental group, 89 % demonstrated relief of SW within 6 months and were weaned from midodrine. The remaining experimental group patients were relieved but required maintenance dosing. In the control group, only 38 % of the patients demonstrated relief of SW.
In the follow-up study, 46 % of the patients on fludrocortisone, 4 % of the support hose patients, and 12 % of the diet modification patients corrected SW within the 2-year period.
Discussion
Treatment of Orthostatic Dysfunction
Perhaps the greatest fear in treating SW is the possibility of inducing cerebrovascular or cardiovascular events due to conditions including elevated or high BPs, especially supine hypertension.
A family of therapies is available [29]:
1.
Proper daily hydration which involves increasing water intake (six to eight glasses per day, reducing caffeinated, sugary, and alcoholic drinks), modifying dietary salt intake, and (if prescribed) considering diuretic dosing.
2.
Mechanical intervention, including compression stockings, is also a mild intervention and may be helpful if the patient is compliant. Of course, these work by applying pressure to the lower extremities to help force blood to the level of the abdomen to help the heart pump blood to the brain.
3.
The next strongest interventions (from a SNS perspective) are the volume builders, e.g., fludrocortisone (Florinef). Fludrocortisone is a mineralocorticoid, which has an indirect effect on the SNS. Therefore, the systemic issues of elevated sympathetic activation in high risk or supine hypertension patients are ameliorated.
4.
Midodrine, in low dose and typically over short time periods, is recommended [5]. Midodrine is an alpha-1 adrenergic agonist. It directly stimulates the peripheral vasculature to constrict. In this way, it supports the SNS in increasing peripheral resistance to keep blood in the abdomen to help the heart pump it to the brain.
5.
Recently, Dr. Phillip A. Low, a neurologist from the Mayo Clinic, resurrected the drug pyridostigmine (Mestinon) [44] as effective for orthostatic patients. Pyridostigmine is an acetylcholinesterase inhibitor. As such, it helps to maintain choline levels longer and thereby indirectly reduce sympathetic levels. In this way, it treats severe OH in patients with intractable hypertension, such as in patients with advanced Parkinson’s, primary autonomic failure, myasthenia gravis, advanced diabetes, etc. Pyridostigmine is typically only administered by properly trained subspecialists.
There is a concern regarding midodrine. Since it is a vasopressor, there is a caution when prescribing patients with supine or frank hypertension. However, it seems as if the perception outweighs reality. Since most physicians do not perform supine to standing blood pressure tests, they do not have the data to specify the presence of supine hypertension. So, instead of possibly prescribing a vasopressor to an unknown supine hypertensive, midodrine is not being prescribed at all. Of course, supine and frank hypertension are concerns when prescribing midodrine. However, midodrine is most effective (in low dose and over a short time; typically 2.5 mg once a day around dinner over 6 months) in correcting SW [5], including before the diagnosis of hypertension. A recommended course to circumvent the hypertension complications is to first prescribe stockings or low-dose Florinef. When the BP is lower, then switch to low-dose, short-term midodrine to correct the patient’s ANS imbalance.
Treatment of SW may correct orthostatic dysfunction and prevent early onset of orthostatic dysfunction. These treatments may also include nonpharmacologic therapies. Nonpharmacologic therapies include adequate fluid and salt intake [45], lifestyle modifications, and compression stockings [46]. The currently published logic tree to detect, diagnose, and treat orthostatic dysfunction is presented in Fig. 23.2 (adapted from [47]). A proposed logic tree to detect, diagnose, and treat SW as preclinical orthostatic dysfunction or clinical orthostatic dysfunction is presented in Fig. 23.3.
Fig. 23.3
A logic flow diagram for testing, detecting, and diagnosing SW as preclinical orthostatic dysfunction or as clinical orthostatic dysfunction and its subforms
Conclusion
Outpatient profiling of LFa from seated to standing identified orthostatic dysfunction more readily than SB and physician diagnosis. Given the known variability in identifying orthostatic dysfunction, LFa could become a requisite component of its definition. Limitations of BP and HR as indicators of orthostatic dysfunction are thought to be a result of the secondary or tertiary nature of those measures. For example, BP is controlled by baroreceptor reflex which is controlled by sympathetic activity. Changes in the sympathetic measure, LFa, are more reliably correlated with orthostatic dysfunction. Orthostatic dysfunction is revealed as a P and S disorder and is measured as a withdrawal of sympathetic tone (SW) from baseline to upright posture, which may be affected (masked) by an excessive parasympathetic (PE) response to PC. Orthostatic dysfunction (SW with or without PE) is a dynamic imbalance within the ANS and is also an indicator of the lack of coordination between the P and S branches. This lack of coordination is associated with complications of orthostatic dysfunction, including chronic fatigue, high BP, unexplained arrhythmia, restless leg syndrome, and sleep disturbances. Restoring this dynamic balance between the P and S branches relieves both the orthostatic dysfunction and the secondary symptoms. From the initial study, low-dose, short-term vasopressor (midodrine, an alpha-1 adrenergic agonist) relieved the majority of SW and orthostatic dysfunction cases within 6 months. From the follow-up study, vasopressor (midodrine) was found more effective than dietary or mechanical intervention or volume builders. Also, correcting SW may lower resting BP.
In another study, presented to the International Symposium on Diabetes Neuropathy [13], 354 adult patients diagnosed with type 2 diabetes (ave. 63.2 years; range 25–96 years, 161 females) were assessed with P&S monitoring. Resting (baseline) measurements were obtained from all patients and were compared with measurements after an upright PC maneuver. Low, normal, borderline, and high ranges were determined based on published results [48, 49] and physiologic changes for the various possible combinations of sympathetic and parasympathetic tone, mean arterial pressure (MAP), and HR. The expected normal responses to PC are as follows:
The PSNS is expected to decrease by 5 %.
The SNS is expected to increase by 120–500 %.
HR is expected to increase of 10 % or more, but no more than 30 bpm.
Systolic BP is expected to increase by 10–30 mmHg.
Results
From the population as a whole, 50.8 % are positive for SW or PE. Clinically, 58.6 % are positive for symptoms of orthostatic dysfunction (7.5 % with POTS, 44.9 % with OH,1.6 % with POBS, and 4.7 % with POHS; see Table 23.1). SW or PE is present in 95.8 % of the patients diagnosed with POTS. SW or PE was present in 66.7 % of the patients diagnosed with OH. SW or PE was present in 80.0 % of the patients diagnosed with POBS. SW or PE was present in 73.3 % of the patients diagnosed with POHS (see Table 23.1). SW or PE is not found in the 13.3 % of the population with orthostatic symptoms. SW or PE is found in 12.0 % of the population without orthostatic symptoms. There is no significant difference between females (POTS = 6.2 %, OH = 43.5 %) and males (POTS = 8.8 %, OH = 46.3 %). The numbers of patients with POBS and POHS are too small for statistical comparison across gender.
Table 23.1
Patient population with autonomic and clinical symptoms of orthostatic dysfunction
POTS | OH | POBS | POHS | |
|---|---|---|---|---|
% Pts with orthostatic symptoms | 7.5 | 44.9 | 1.6 | 4.7 |
% Pts symptomatic with SW or PE | 95.8 | 66.7 | 80.0 | 73.3 |
Conclusions
Orthostatic symptoms and presymptomatic conditions are documented by P&S monitoring. SE and a large increase in HR indicates POTS. SW with a large decrease in BP indicates OH. SW with a large decrease in HR indicates POBS. SE with a large increase in BP indicates POHS. The results of P&S monitoring appropriately depict the autonomic PC responses associated with HR and BP. This noninvasive methodology may be used to correctly diagnose the cause of orthostatic symptoms and provide a guide for therapies to improve autonomic dysfunction and relieve symptoms of these disorders.
Autonomic Mechanisms and Therapeutic Implications of Postural Diabetic Cardiovascular Abnormalities
These are excerpts from a published peer reviewed article entitled “Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities” [5]. The introduction and background sections were presented in the “Secondary Orthostatic dysfunction” subsection under “Interpreting P and S Results.” Also, in part, the first five figures of this article compare P&S monitoring and HRV-alone results, with HR and BP responses. These results are presented in “Introduction” under “The Fix.” The objective of this article is to offer a method for documenting, differentiating, and diagnosing orthostatic abnormalities, including preclinical orthostatic indications, as a potential early marker for CAN.
Methods
Autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients, with type 2 diabetes mellitus, serially recruited from ambulatory clinics was performed by P&S monitoring. Either patients had a history of alpha-1 agonist prior to P&S monitoring or an alpha-1 agonist was introduced immediately following P&S monitoring. The patient cohort (see Table 23.2) included 86 (46.7 %, 64 female) patients whom an alpha-1 agonist was the only therapy introduced from one test to the next; 37 (20.1 %, 33 female) patients for whom the alpha-1 agonist was the only therapy discontinued; and 61 (33.2 %, 45 female) patients who had a history of an alpha-1 agonist, and for whom no therapy changes were made. Forty-five (24.5 %) of the 184 patients in the cohort demonstrated a change in BP, from sitting to standing, that qualified as clinical OH (a decrease of 20/10 mmHg or more). The clinical diagnosis of OH based on abnormal BP was made from the autonomic assessment for 19 (42.2 %) of the cohort. The remaining 26 (57.8 %) patients were diagnosed prior to the study. All patients reported symptoms of OH prior to dosing.
Table 23.2
Patient demographics
Patients (#) | Females (#) | HTN (#) | CVD (#) | Weight (#) | Height (in) | Age (years) | |
|---|---|---|---|---|---|---|---|
Totals | 184 | 142 | 99 | 47 | 150.6 | 63.6 | 57.5 |
Midodrine (− +) | 86 | 64 | 52 | 19 | 153.1 | 63.8 | 60.7 |
Midodrine (+ −) | 37 | 33 | 15 | 10 | 145.1 | 63.1 | 52.4 |
Midodrine (+ +) | 61 | 45 | 32 | 18 | 153.4 | 63.9 | 59/3 |
Serial P&S assessments were separated by an average of 3.1 ± 1.4 months. Midodrine (ProAmatine) was the alpha-1 agonist prescribed. All patients were diagnosed with type 2 diabetes. Of the cohort, 99 (53.8 %) patients also had hypertension and 47 (25.5 %) also had cardiovascular disease. Patients with supine hypertension were excluded from this study. See “The Autonomic (P and S) Assessment” section of this compendium for a complete methodology describing Autonomic Assessment. The Autonomic Assessment section includes a figure depicting a model of the P&S method.
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