World Journal of Diabetes. American Diabetes Association. Autonomic neuropathies. Loscalzo J, et al. Diabetes mellitus: Complications. In: Harrison's Principles of Internal Medicine. McGraw Hill; Accessed June 16, Jankovic J, et al. Disorders of the autonomic nervous system.

In: Bradley and Daroff's Neurology in Clinical Practice. Elsevier; Effectiveness checker. Natural Medicines. Accessed June 17, Transcutaneous electrical nerve stimulation. Accessed June 7, Treatment for erectile dysfunction. Coon EA expert opinion. Mayo Clinic.

June 20, Associated Procedures. Tilt table test. Show the heart some love! Give Today. Help us advance cardiovascular medicine. Find a doctor.

Explore careers. Sign up for free e-newsletters. About Mayo Clinic. About this Site. Contact Us. Health Information Policy. Media Requests. News Network. Price Transparency. Medical Professionals. Clinical Trials. Mayo Clinic Alumni Association. Refer a Patient. Executive Health Program. Why UpToDate?

Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large.

Diabetic autonomic neuropathy of the gastrointestinal tract. Formulary drug information for this topic. No drug references linked in this topic.

Find in topic Formulary Print Share. View in. Language Chinese English. Author: Thomas Frieling, MD Section Editors: Nicholas J Talley, MD, PhD David M Nathan, MD Deputy Editor: Shilpa Grover, MD, MPH, AGAF Literature review current through: Jan This topic last updated: Aug 10, Abnormalities of GI function in diabetics are thought to be related, at least in part, to autonomic neuropathy of the enteric nervous system [ 1,2 ].

If more strict criteria were used i. Another study group observed nearly an identical prevalence rate Additional studies suggest that the prevalence of DAN may be even more common than these studies report.

For example, using a variety of simple, validated, and noninvasive tests e. These results, however, recapitulate that prevalence rates will vary depending on 1 different patient cohorts studied, 2 varied testing modalities utilized, and 3 different criteria used to define autonomic dysfunction.

The metabolic disorders of diabetes lead to diffuse and widespread damage of peripheral nerves and small vessels. Clinical manifestations of autonomic dysfunction and other microvascular complications frequently occur concurrently but in inconsistent patterns The ubiquitous distribution of the ANS renders virtually all organs susceptible to autonomic dysfunction.

Therefore, a patient diagnosed with diabetes should be suspected of having at least subclinical disturbances of the ANS. Overt signs and symptoms of autonomic disease fall into one or more of the following categories. Medications, with anticholinergic or sympatholytic effects insulin, vasodilators, sympathetic blockers.

DAN is typically assessed by focusing on symptoms or dysfunction attributable to a specific organ system. CAN is the most prominent focus because of the life-threatening consequences of this complication and the availability of direct tests of cardiovascular autonomic function.

However, neuropathies involving other organ systems should also be considered in the optimal care of patients with diabetes. Perhaps one of the most overlooked of all serious complications of diabetes is CAN CAN results from damage to the autonomic nerve fibers that innervate the heart and blood vessels and results in abnormalities in heart rate control and vascular dynamics Reduced heart rate variation is the earliest indicator of CAN In a review of several epidemiological studies among individuals diagnosed with diabetes, it was shown that the 5-year mortality rate from this serious complication is five times higher for individuals with CAN than for individuals without cardiovascular autonomic involvement 4.

In this report, the clinical manifestations e. It will also be shown that autonomic dysfunction can affect daily activities of individuals with diabetes and may invoke potentially life-threatening outcomes. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of autonomic function.

Autonomic dysfunction can impair exercise tolerance In a study of individuals with and without CAN, Kahn et al. Roy et al. The severity of CAN has also been shown to correlate inversely with an increase in heart rate at any time during exercise and with the maximal increase in heart rate.

It should also be noted that decreased ejection fraction, systolic dysfunction, and diastolic filling limit exercise tolerance 1. Given the potential for impaired exercise tolerance, it has been suggested that diabetic patients who are likely to have CAN have cardiac stress testing before undertaking an exercise program Hemodynamic changes occur during surgery for individuals with and without diabetes.

Burgos et al. The normal autonomic response of vasoconstriction and tachycardia did not completely compensate for the vasodilating effects of anesthesia. Kitamura et al. Complications arising from intraoperative hypothermia include decreased drug metabolism and impaired wound healing.

Sobotka et al. These data suggest that preoperative cardiovascular autonomic screening may provide useful information for anesthesiologists planning the anesthetic management of diabetic patients and identify those at greater risk for intraoperative complications.

Orthostatic hypotension is defined as a fall in blood pressure i. In patients with diabetes, orthostatic hypotension is usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature In addition, there is a decrease in cutaneous, splanchnic, and total vascular resistance that occurs in the pathogenesis of this disorder.

Normally, in response to postural change there is an increase in plasma norepinephrine. For individuals with orthostatic hypotension, there may be a reduction in this response relative to the fall in blood pressure Diminished cardiac acceleration and cardiac output, particularly in association with exercise, may also be important in the presentation of this disorder 53 , Less frequently, there is a rise in norepinephrine that may be due to low blood volume or reduced red cell mass 55 , Frequently, there are fluctuations in the degree of orthostatic hypotension.

This may reflect postprandial blood pooling, the hypotensive role of insulin, and changing patterns of fluid retention due to renal failure or congestive heart failure 57 — Patients with orthostatic hypotension typically present with lightheadedness and presyncopal symptoms.

Symptoms such as dizziness, weakness, fatigue, visual blurring, and neck pain also may be due to orthostatic hypotension. Many patients, however, remain asymptomatic despite significant falls in blood pressure If the cause of orthostatic hypotension is CAN, treatment goals should not only consist of therapies to increase the standing blood pressure, balanced against preventing hypertension in the supine position 61 , but should also provide education to patients so that they avoid situations e.

Such symptoms can result in injuries from falling. Cardiovascular autonomic function testing may help differentiate CAN from other causes of weakness, lightheadedness, dizziness, or fatigue and promote appropriate therapeutic intervention The cause of silent myocardial ischemia in diabetic patients is controversial.

It is clear, however, that a reduced appreciation for ischemic pain can impair timely recognition of myocardial ischemia or infarction and thereby delay appropriate therapy.

Table 2 and Fig. Of the 12 studies, 5 showed a statistically significant increased frequency of silent myocardial ischemia in individuals with CAN compared with individuals without CAN.

The point estimates for the prevalence rate ratios in these 12 studies ranged from 0. Via meta-analysis, the Mantel-Haenszel estimate for the pooled prevalence rate risk for silent myocardial ischemia was 1. These data demonstrate a consistent association between CAN and the presence of silent myocardial ischemia.

There are several additional published studies that have examined the relationship between autonomic dysfunction and silent myocardial ischemia in diabetic individuals but that are not included in the meta-analysis because the raw numbers of case and control subjects among individuals with and without cardiovascular autonomic dysfunction were not presented 75 — However, virtually all of these studies also provide evidence for an association.

For example, Ambepityia et al. The perception of angina was severely impaired in the diabetic patients, allowing these individuals to exercise longer after the onset of myocardial ischemia.

The delay in perception of angina was associated with the presence of cardiovascular autonomic dysfunction. A study by Marchant et al. All 52 individuals manifested ischemia during exercise. A total of 16 individuals did not experience angina, and 10 of these had diabetes.

In subgroup analysis, the impaired autonomic function was found to be confined to just the diabetic individuals and not seen in the nondiabetic individuals with silent myocardial ischemia, thus indicating that subclinical autonomic neuropathy is associated with silent ischemia in individuals with diabetes Hikita et al.

Some investigators, however, have questioned whether the association between CAN and silent myocardial ischemia is a causal one 79 , suggesting instead that underlying coronary artery disease might be a cause of both autonomic dysfunction and silent myocardial ischemia The presence of CAN does not exclude painful myocardial infarction MI among individuals with diabetes Chest pain in any location in a patient with diabetes should be considered to be of myocardial origin until proven otherwise; but, of equal importance, unexplained fatigue, confusion, tiredness, edema, hemoptysis, nausea and vomiting, diaphoresis, arrhythmias, cough, or dyspnea should alert the clinician to the possibility of silent MI 1.

Table 3 summarizes investigations that have examined the association of autonomic dysfunction and mortality. These studies have consistently provided evidence for an increased mortality risk among diabetic individuals with CAN compared with individuals without CAN Table 3.

Ewing et al. This study also revealed that symptoms of autonomic neuropathy, especially postural hypotension, and gastric symptoms in the presence of abnormal autonomic function tests carried a particularly poor prognosis.

Among individuals who died, there was no difference in duration of diabetes between those with and without autonomic neuropathy. As was true for the study performed by Ewing et al.

Rathmann et al. Autonomic dysfunction was found to be an independent risk factor with poor prognosis. Some autonomic neuropathic symptoms orthostatic hypotension, gastroparesis, gustatory sweating, and erectile impotence were found more frequently among subjects who died Two separate population-based studies have also examined the association of CAN and mortality.

Orchard et al. Individuals for this study were identified through a hospital-based registry system and were considered to be representative of all type 1 diabetic patients residing in Allegheny County, Pennsylvania.

Initial analyses based on a 2-year follow-up of subjects revealed a fourfold higher mortality rate in individuals with CAN at baseline compared with individuals without. However, after adjusting for baseline differences between individuals with and without CAN for markers related to renal and cardiovascular disease, the relative risk decreased from 4.

Another population-based study the Hoorn study examined individuals with type 2 diabetes 85 had newly diagnosed diabetes who were followed for an average of nearly 8 years.

All-cause as well as cardiovascular mortality were found to be associated with impaired autonomic function in this study. In addition, the investigators suggested that cardiovascular autonomic dysfunction in individuals already at high risk e.

As noted above, the relationship of CAN and mortality in diabetic individuals has been evaluated in a number of studies on an individual basis. Analysis of each of these studies as a single entity, however, only includes a limited number of subjects.

Thus, in this section, results were pooled from a number of studies into a meta-analysis for the purpose of obtaining more precise estimates. Studies were included in this meta-analysis if they were based on diabetic individuals, included a baseline assessment of HRV, and included a mortality follow-up 94a.

Table 3 and Fig. The follow-up intervals in these studies ranged from 1 to 16 years. In all 15 studies, the baseline assessment for cardiovascular autonomic function was made on the basis of one or more of the tests described by Ewing et al. Total mortality rates were higher in subjects with CAN at baseline than in subjects whose baseline assessment was normal, with statistically significant differences in 11 of the studies.

The study-specific relative risks ranged from 0. The pooled estimate of the relative risk, based on 2, total subjects, was 2. The relationship between CAN and major cardiovascular events has been assessed in two prospective studies. Specifically, the relationship between baseline CAN and the subsequent incidence of a fatal or nonfatal cardiovascular event, defined as an MI, heart failure, resuscitation from ventricular tachycardia or fibrillation, angina, or the need for coronary revascularization, was examined 64 , The relative risks associated with CAN in these studies were 2.

It would appear, therefore, that there is an association between CAN and major cardiovascular events, but given the small number of events that occurred in each of these studies, more follow-up studies are required.

Despite the increased association with mortality, the causative relationship between CAN and the increased risk of mortality has not been conclusively established. Several mechanisms have been suggested including a relationship with autonomic control of respiratory function.

Page and Watkins 96 reported 12 cardiorespiratory arrests in eight diabetic individuals with severe autonomic neuropathy and suggested that diabetic individuals with CAN have impaired respiratory responses to conditions of hypoxia and may be particularly susceptible to medications that depress the respiration system.

An impaired ability to recognize hypoglycemia and impaired recovery from hypoglycemic episodes due to defective endocrine counterregulatory mechanisms are also potential reasons for death Other investigators have noted explanations for the high mortality rate as an interaction with other concomitant disorders that also carry high risks of mortality.

Clarke et al. The presence of autonomic neuropathy may accelerate the rate of progression of diabetic glomerulopathy by mechanisms not completely understood A consequential increase in cardiovascular risk experienced by individuals with nephropathy has also been noted.

In one study of type 1 diabetic individuals, hypertension along with LDL and HDL cholesterol concentrations were found to be independent correlates of CAN These results suggested that a disturbed cardiovascular risk profile seen in individuals with nephropathy might lead to both cardiovascular disease and CAN.

Other investigators have also shown independent associations of autonomic dysfunction with markers of cardiovascular risk e. Long-term follow-up studies are needed to distinguish the exact roles of cardiovascular risk factors, nephropathy, and CAN in the etiology of cardiovascular disease.

Nonetheless, CAN cosegregates with indexes of macrovascular risk, which may contribute to the marked increase in cardiovascular mortality. Diabetic patients with CAN are predisposed to a lack of the normal nighttime decrease in blood pressure because of an increased prevalence of sympathetic activity A disturbed circadian pattern of sympathovagal activity with prevalent nocturnal sympathetic activity combined with higher blood pressure values during the night and increased left ventricular hypertrophy could represent another important link between CAN and an increased risk of mortality.

A number of researchers have reported sudden unexpected deaths among subjects identified with autonomic neuropathy 31 , 82 , One potential cause of sudden death may be explained by severe but asymptomatic ischemia, eventually inducing lethal arrhythmias An autonomic imbalance resulting in QT prolongation may also predispose individuals to life-threatening cardiac arrhythmias and sudden death Results from the EURODIAB IDDM Complications Study showed that male patients with impaired HRV had a higher corrected QT prolongation than males without this complication Imaging of myocardial sympathetic innervation with various radiotracers e.

The significance of CAN as an independent cause of sudden death has, however, been recently questioned In the Rochester Diabetic Neuropathy Study, the investigators found that all case subjects individuals with and without diabetes with sudden death had severe coronary artery disease or left ventricular dysfunction.

Therefore, they suggested that although CAN could be a contributing factor, it was not a significant independent cause of sudden death. Heart failure is, however, common in individuals with diabetes, identified by the presence of neuropathy, even in individuals without evidence of coronary artery disease or left ventricular dysfunction The association of cardiovascular autonomic dysfunction in the absence of coronary disease and cardiomyopathy requires further study.

Mortality rates after an MI are also higher for diabetic patients than for nondiabetic patients This may be due to autonomic insufficiency, increasing the tendency for development of ventricular arrhythmia and cardiovascular events after infarction.

Fava et al. In another study, Katz et al. These investigators also suggested that cardiovascular autonomic function testing provided a predictive value that could be used to identify a subgroup of patients after an MI who are a high risk for cardiovascular death Dysfunction of the ANS is associated with increased risk of mortality in individuals with diabetes.

It is true, however, that at least some of the association between CAN and mortality appears to be due to an increased prevalence of other complications in individuals with CAN.

Though the exact pathogenic mechanism is unclear, it is realized that some deaths may be avoidable through early identification of these higher-risk patients and by slowing, with therapy, the progression of autonomic dysfunction and its associated conditions.

In addition, it would appear that autonomic function testing is a valuable tool in identifying a subgroup of post-MI patients who are at high risk for death. The frequency of ischemic cerebrovascular events is increased in individuals with type 2 diabetes. The impact of autonomic dysfunction on the risk of the development of strokes was examined by Toyry et al.

During the study period, 19 individuals had one or more strokes. Abnormalities of parasympathetic and sympathetic autonomic function were found to be independent predictors of stroke in this cohort Results of the cardiovascular autonomic function tests that are mediated mainly by the parasympathetic nervous system e.

Although one might speculate then that parasympathetic damage occurs before sympathetic damage, this may not always be true. The increased frequency of abnormalities detected via tests of the parasympathetic system may merely be a reflection of the test e.

Thus, it may be better to describe the natural history of autonomic dysfunction as developing from early to more severe involvement rather than to anticipate a sequence of parasympathetic to sympathetic damage Although much remains to be learned about the natural history of CAN, previous reports can be coalesced into a few observations that provide some insight with regard to progression of autonomic dysfunction:.

It can be detected at the time of diagnosis 24 , 44 , Neither age nor type of diabetes are limiting factors in its emergence, being found in young individuals with newly diagnosed type 1 diabetes and older individuals newly diagnosed with type 2 diabetes 5 , 24 , 40 , 44 , , Poor glycemic control plays a central role in development and progression 44 , — Intensive therapy can slow the progression and delay the appearance of abnormal autonomic function tests Subclinical autonomic neuropathy can be detected early using autonomic function tests 26 , 41 , Autonomic features that are associated with sympathetic nervous system dysfunction e.

There is an association between CAN and diabetic nephropathy that contributes to high mortality rates 31 , 44 , Some individuals with symptoms associated with autonomic neuropathy die suddenly and unexpectedly 31 , 44 , Clinical signs and symptoms of autonomic dysfunction do not always progress.

This underscores the need for performance of quantitative autonomic function tests to identify individuals at risk for premature death The relationship between autonomic damage and duration of diabetes is not clear although numerous studies support an association Prevalence and mortality rates may be higher among individuals with type 2 diabetes, potentially due in part to longer duration of glycemic abnormalities before diagnosis.

GI symptoms are relatively common among patients with diabetes and often reflect diabetic GI autonomic neuropathy 7 , It should be noted, however, that although GI symptoms are common, symptoms may be more likely due to other factors than to autonomic dysfunction.

GI manifestations of DAN are diverse, and symptoms and pathogenic mechanisms have been categorized according to which section of the GI tract is affected:.

Diarrhea impaired motility of the small bowel [bacterial overgrowth syndrome], increased motility and secretory activity [pseudocholeretic diarrhea]. Constipation dysfunction of intrinsic and extrinsic intestinal neurons, decreased or absent gastrocolic reflex. Fecal incontinence abnormal internal anal sphincter tone, impaired rectal sensation, abnormal external sphincter.

Esophageal dysfunction results at least in part from vagal neuropathy ; symptoms include heartburn and dysphagia for solids. Gastric emptying largely depends on vagus nerve function, which can be severely disrupted in diabetes.

Gastroparesis in diabetes is usually clinically silent, although severe diabetic gastroparesis is one of the most debilitating of all diabetic GI complications.

Major clinical features of this disorder are early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating.

Episodes of nausea or vomiting may last days to months or occur in cycles Diarrhea is typically intermittent, but bowel movements may occur 20 or more times per day with urgency, and the stools are often watery.

Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics e.

Individuals with constipation may have less than three bowel movements per week, and these may alternate with diarrhea. Treatment of diarrhea with or without constipation should always involve the use of a prokinetic agent rather than constipating agents that create vicious cycles of constipation and diarrhea 1.

Fecal incontinence due to poor sphincter tone is common for individuals with diabetes and may be associated with severe paroxysmal diarrhea or constitute an independent disorder of anorectal dysfunction. The neurogenic bladder, also called cystopathy, may be due to DAN An examination of the neuroanatomy of the genitourinary system provides an insight into the extent to which autonomic fibers are involved with its proper control.

Serving as a receptacle for the storage and appropriate evacuation of urine, the urinary bladder comprises three layers of interdigitating smooth muscle i. This muscle forms an internal sphincter at the junction of the bladder neck and urethra, and although it is not anatomically discrete, there is localized autonomic innervation so that it functions as a physiological sphincter.

Afferent nerve impulses of bladder sensation and reflex bladder contraction are carried by sympathetic, parasympathetic, and somatic nerves to the spinal cord The earliest bladder autonomic dysfunctions are sensory abnormalities that result in impaired bladder sensation, an elevated threshold for initiating the micturition reflex and an asymptomatic increase in bladder capacity and retention.

The parasympathetic nerves that originate in the intermediolateral column of sacral segments S2—S4 provide the major excitatory input to the urinary bladder. Activation of the muscarinic, cholinergic, and postganglionic pelvic nerve fibers result in contraction of the urinary bladder.

When there is damage to the efferent parasympathetic fibers to the urinary bladder, symptoms such as hesitancy in micturition, weak stream, and dribbling ensue, with a reduction in detrusor activity i. This leads to incomplete bladder emptying, an increased postvoid residual, decreased peak urinary flow rate, bladder overdistention, and urine retention.

Finally, overflow incontinence occurs because of denervation of the external and internal sphincter , The somatic pudendal nerve innervates the external sphincter, whereas the sympathetic hypogastric nerves innervate the internal sphincter.

Individuals with bladder dysfunction are predisposed to the development of urinary tract infections, including pyelonephritis, which may accelerate or exacerbate renal failure , Urinary frequency is another commonly associated symptom of autonomic dysfunction of the genitourinary system.

ED is defined as the consistent inability to attain and maintain an erection adequate for sexual intercourse, usually qualified by being present for several months and occurring at least half the time. An estimated 20—30 million men in the U. have ED In a large cohort study of men 53—90 years old, a significant association between diabetes and duration of diabetes and ED was found when comparing diabetic men with nondiabetic men of similar age ED is a marker for the development of generalized vascular disease and for premature demise from a myocardial infarct, and penile failure may be a portent of upcoming, and possible preventable, cardiovascular events ED etiology in diabetes is multifactorial, including neuropathy, vascular disease, metabolic control, nutrition, endocrine disorders, psychogenic factors, and anti-diabetes drugs.

Retrograde ejaculation into the bladder also occurs in diabetic males. ED should alert physicians to perform cardiovascular evaluations for these patients. Females with diabetes may have decreased sexual desire and increased pain during intercourse and are at risk of decreased sexual arousal and inadequate lubrication It has been shown that type 1 diabetic individuals with early nephropathy and symptomatic autonomic neuropathy have inappropriately low levels of erythropoietin for the severity of their anemia These individuals can, however, mount an appropriate erythropoietin response to moderate hypoxia.

The mechanism that underlies the erythropoietin-deficient anemia is unclear. Reduced sympathetic stimulation of erythropoietin production has been previously hypothesized as the cause of ineffective erythropoiesis resulting in anemia DAN plausibly could cause or contribute to hypoglycemia unawareness, but this relationship is complex.

Two groups concluded that unawareness of hypoglycemia and inadequate counterregulation occur independently of autonomic neuropathy. Ryder et al. They also observed no history of unawareness of hypoglycemia in seven patients with clear evidence of autonomic neuropathy, and in six of the seven, there was adequate hypoglycemic counterregulation.

Based on these findings, they suggested that there was no causal relation between DAN and unawareness of hypoglycemia or inadequate hypoglycemic counterregulation Hepburn et al.

Based on these data, they suggested that loss of hypoglycemia awareness is not invariably associated with abnormal cardiovascular autonomic function tests. Careful examination of these studies suggests, however, that the relationship between autonomic neuropathy and hypoglycemic unawareness may be more complex than these reports suggest.

observed that patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response 3. Furthermore, 10 of 17 individuals with hypoglycemia unawareness reported by Hepburn et al.

had evidence of autonomic dysfunction Taken together, even these data suggest that there is some overlap between the features of autonomic neuropathy and hypoglycemic unawareness. More recent data suggest that the presence of autonomic neuropathy further attenuates the epinephrine response to hypoglycemia in diabetic individuals after recent hypoglycemic exposure — Hypoglycemia-induced autonomic failure leads to a vicious cycle of hypoglycemia unawareness that induces a further decrease in counterregulatory hormone responses to hypoglycemia.

This vicious cycle occurs commonly in individuals with diabetes who are in strict glycemic control. The reduced epinephrine response to antecedent hypoglycemia occurs in the absence of DAN as measured by standard tests of autonomic function , , The presence of autonomic neuropathy, however, further attenuates the epinephrine response to hypoglycemia in diabetic subjects after recent hypoglycemic exposure — in most, but not all, studies Furthermore, individuals with abnormal autonomic function have a greater risk for severe hypoglycemia Microvascular skin flow is under the control of the ANS and is regulated by both the central and peripheral components.

In diabetes, the rhythmic contraction of arterioles and small arteries is disordered. Microvascular insufficiency may be a cause of diabetic neuropathy Microvascular blood flow can be accurately measured noninvasively using laser Doppler flowmetry.

Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, handgrip, and heating. The defect is associated with a reduction in the amplitude of vasomotion and resembles premature aging There are differences in the glabrous and hairy skin circulations.

In hairy skin, a functional defect is found before the development of neuropathy The clinical counterpart is dry skin, loss of sweating, and the development of fissures and cracks that are portals of entry for microorganisms leading to infectious ulcers and ultimately gangrene.

A prospective study by Boyko et al. Autonomic neuropathy may also lead to increased osteoclastic activity resulting in reduced bone density. Thus, Young et al. Quantitative tests of autonomic function have historically lagged behind measures of motor nerve function and sensory nerve function deficits.

The lack of interest in the development of such measures was partly due to the erroneous but commonly held view that autonomic neuropathy was only a small and relatively obscure contributor to the peripheral neuropathies affecting individuals with diabetes , , In the early s, Ewing et al.

The clinical literature has consistently identified these five tests as they have been widely used in a variety of studies. A large body of evidence indicates that these factors can, to various degrees, affect the cardiovascular ANS and potentially other autonomic organ systems Heart rate response to deep breathing is for the most part a function of parasympathetic activity, although the sympathetic nervous system may affect this measure Similarly, it is parasympathetic activity that plays the greatest role in the heart rate regulation for short-term standing, where the act of standing involves low-level exercise and parasympathetic tone is withdrawn to produce a sudden tachycardic response In response to subsequent underlying blood pressure changes while standing, a baroreceptor-mediated reflex involves the sympathetic nerves for further heart rate control Heart rate response to the Valsalva maneuver is influenced by both parasympathetic and sympathetic activity.

Measurements of blood pressure response to standing and blood pressure response to sustained handgrip are used to assess sympathetic activity. Beat-to-beat variation in heart rate with respiration depends on parasympathetic innervation.

Pharmacological blockade of the vagus nerve with atropine all but abolishes respiratory sinus arrhythmia, whereas sympathetic blockade with the use or pretreatment of propranolol has only a slight effect on it Several different techniques have been described in clinical literature, but measurement during paced deep breathing is considered the most reliable.

The patient lies quietly and breathes deeply at a rate of six breaths per minute a rate that produces maximum variation in heart rate while a heart monitor records the difference between the maximum and minimum heart rates.

Over a number of years, there have been several different measures of R-R variation. The following six measures have most consistently been reported standard deviation, coefficient of variation, mean circular resultant, maximum minus minimum, expiration-to-inspiration [E:I] ratio, and spectral analysis There are advantages, disadvantages, and considerations that need to be recognized for all of the measures of R-R variation.

This test evaluates the cardiovascular response elicited by a change from a horizontal to a vertical position. The typical heart rate response to standing is largely attenuated by a parasympathetic blockade achieved with atropine In healthy subjects, there is a characteristic and rapid increase in heart rate in response to standing that is maximal at approximately the 15th beat after standing.

This is followed by a relative bradycardia that is maximal at approximately the 30th beat after standing. In patients with diabetes and autonomic neuropathy, there is only a gradual increase in heart rate. The patient is connected to an electrocardiogram ECG monitor while lying down and then stands to a full upright position.

ECG tracings are used to determine the ratio, calculated as the ratio of the longest R-R interval found at about beat 30 to the shortest R-R interval found at about beat Because the maximum and minimum R-R intervals may not always occur at exactly the 15th or 30th beats after standing, Ziegler et al.

In healthy subjects, the reflex response to the Valsalva maneuver includes tachycardia and peripheral vasoconstriction during strain, followed by an overshoot in blood pressure and bradycardia after release of strain. The response is mediated through alternating activation of parasympathetic and sympathetic nerve fibers.

In patients with autonomic damage from diabetes, the reflex pathways are damaged. This is seen as a blunted heart rate response and sometimes as a lower-than-normal decline in blood pressure during strain, followed by a slow recovery after release.

In the standard Valsalva maneuver, the supine patient, connected to an ECG monitor, forcibly exhales for 15 s against a fixed resistance 40 mmHg with an open glottis.

A sudden transient increase in intrathoracic and intra-abdominal pressures, with a consequent hemodynamic response, results. With performance of the Valsalva maneuver, there is a transient increase in intraocular and intracranial pressure, creating a small theoretical risk of intraocular hemorrhage and lens dislocation In practical terms, however, the risk is minimal because comparable pressures occur in the performance of daily activities.

The response to performance of the Valsalva maneuver has four phases and in healthy individuals can be observed as follows:. Phase I: Transient rise in blood pressure and a fall in heart rate due to compression of the aorta and propulsion of blood into the peripheral circulation. Hemodynamic changes are mostly secondary to mechanical factors.

Phase II: Early fall in blood pressure with a subsequent recovery of blood pressure later in the phase. The blood pressure changes are accompanied by an increase in heart rate. There is a fall in cardiac output due to impaired venous return causing compensatory cardiac acceleration, increased muscle sympathetic activity, and peripheral resistance.

Phase III: Blood pressure falls and heart rate increases with cessation of expiration. Phase IV: Blood pressure increases above the baseline value overshoot because of residual vasoconstriction and restored normal venous return and cardiac output.

The Valsalva ratio is determined from the ECG tracings by calculating the ratio of the longest R-R interval after the maneuver reflecting the bradycardic response to blood pressure overshoot to the shortest R-R interval during or shortly after the maneuver reflecting tachycardia as a result of strain.

With regard to the progression of autonomic dysfunction in diabetes, the Valsalva maneuver may be the best method to monitor this longitudinally Quantitative analysis of nerve function e. In a study by Levitt et al. All of the tests described above for the assessment of cardiovascular autonomic function can be performed by a general practitioner.

Those patients with cardiovascular autonomic dysfunction who have system-specific symptoms will need to be referred to a specialist for refined testing.

Analysis of HRV can also be assessed by spectral analysis of a series of successive R-R intervals frequency domain analyses.

This can be performed on short R-R sequences e. The main advantage of power spectral analysis PSA is that HRV can be measured across a range of frequencies and that less patient participation is necessary The heart rate power spectrum is typically divided into two frequency bands: low 0.

The high-frequency region is generally considered a marker of vagal activity, whereas the low-frequency component is influenced by both sympathetic and vagal activity A study providing a direct comparison of PSA and some time-domain techniques for quantifying HRV was completed by Freeman et al.

The time-domain values were found to correlate very strongly with high-frequency spectral indexes, especially the Valsalva and ratios linear regression gave R 2 values of 0. Another study by Howorka et al. A band from 0.

Spectral indexes were power and density and were compared with standard Ewing tests of HRV I:E difference, Valsalva ratio, and ratio.

Ziegler et al. PSA testing with subjects at rest was performed with low frequency being defined as 0.