Exercise Precautions and Recommendations for Patients With Autonomic Neuropathy

In BriefNearly everyone with diabetes can derive some benefit from an exercise program, although not all benefits will be realized by each person with diabetes. Autonomic neuropathy may affect several systems that are necessary for the body’s adjustment to exercise, and careful screening is extremely important. The risks and benefits of exercise must be carefully considered in those with chronic complications of diabetes, as should the deleterious effects of not participating in any physical activity.

 Physical activity has the potential to yield several health benefits for people with diabetes. These benefits can include improvements in glucose control,^1-3 insulin sensitivity,^4-6 lipid profile,^7,8 blood pressure,^9,10 coagulation properties,¹¹ body composition,^12,13 and psychological well-being.^14,15

Nearly everyone with diabetes can derive some benefit from an exercise program, although not all benefits will be realized by each person with diabetes. Both health care professionals and patients with diabetes need to remember this when determining the components of an exercise program. When chronic complications of diabetes develop, the benefits and risks of exercise must be carefully considered to maximize the benefits and assure safety.¹⁶ This is especially true when evaluating the use of exercise in diabetes complicated by autonomic neuropathy.

In considering the benefits and risks of exercise for those with chronic complications of diabetes, attention must also be given to the effects of not participating in some level of physical activity. Known as disuse syndrome, the deleterious effects of an imbalance between rest and physical activity include decreased physical work capacity, muscle atrophy, negative nitrogen and protein balance, cardiovascular deconditioning, pulmonary restrictions, and depression.¹⁷ The consequences of disuse combined with the complications of diabetes are likely to lead to more disability than the diabetes complications alone. Since physical activity can prevent or reverse disuse syndrome, serious consideration must be given to the use of exercise in all people with diabetes, including those with autonomic neuropathy.

Table 1. Effects of Diabetic Autonomic Neuropathy on Exercise Risk

Silent myocardial ischemia Resting tachycardia and decreased maximal responsiveness Decreased heart-rate variability Orthostasis/hypotension with exercise Exaggerated blood pressure responses with supine position and exercise. Loss of diuranal blood pressure variation Cardiovascular and cardiorespiratory instability Abnormal systolic ejection fractions at rest/exercise Poor exercise tolerance Failure of pupil adaptation to darkness Gastroparesis and diabetic diarrhea Hypoglycemia Decreased hypoglycemia awareness Hypoglycemia unresponsiveness Heat intolerance due to defective sympathetic thermoregualtion and sweating (prone to dehydration) Susceptibility to foot ulcers and limb loss due to disordered regulation of cutaneous blood flow Incontinence Reprinted with permission from the American Diabetes Association, Health Professional's Guide to Diabetes and Exercise, p. 190

Diabetic autonomic neuropathy can strike any system of the body (e.g., cardiovascular, respiratory, neuroendocrine, gastrointestinal, genitourinary, sudomotor, or ocular), since the autonomic nervous system regulates all involuntary functions in the body. Many of these systems are integral to the ability to perform exercise. The possible risks from autonomic neuropathy on the body’s response to exercise and resulting safety considerations are discussed below. Table 1 provides a summary of the effects of autonomic neuropathy on exercise risk.¹⁸
EFFECTS OF AUTONOMIC  NEUROPATHY ON EXERCISE RESPONSE Cardiovascular Autonomic NeuropathyHeart rate. The impact of autonomic neuropathy on the cardiovascular system is of utmost importance to exercise capacity and safety, since cardiovascular autonomic neuropathy (CAN) is manifested by abnormal heart rate, blood pressure, and redistribution of blood flow. The cardiovascular anomalies of autonomic neuropathy involve both the sympathetic and parasympathetic nervous systems.¹⁹ Resting heart-rate is primarily controlled by the parasympathetic system, whereas maximal heart-rate and blood pressure responses to standing, sustained hand grip, and other types of exercise are mainly functions of sympathetic activity (which controls blood vessel tone).
It is generally considered that parasympathetic dysfunction precedes sympathetic loss. However, more sensitive tests have revealed that there may be pervasive but uneven areas of sympathetic denervation of the heart, which otherwise appears normal, and these findings indicate significant risk for premature death.^20,21
Patients with CAN have higher resting heart rates and lower maximal heart rates during exercise than diabetic patients without autonomic neuropathy.²² The lower maximal heart rate achieved during exercise makes the use of heart rate to gauge exercise intensity inappropriate for many of these patients.
Unexplained sudden death not associated with myocardial infarction, in which the heart becomes unresponsive to nerve impulses (cardiac denervation syndrome), has been reported in diabetic patients with CAN.^23,24 A variety of potential mechanisms have been proposed to explain sudden death, but an exact understanding of this occurrence remains speculative.
Prolonged QT intervals corrected for heart rate (QTc) have been found in diabetic patients with autonomic neuropathy.^24,25 A prolonged QTc is an indicator of increased risk for sudden death. Lengthening of QT/QTc intervals over time is associated with deterioration of autonomic function.
Some investigators have suggested that the electrocardiographic evaluation of QT/QTc interval should be conducted to evaluate autonomic neuropathy in that this evaluation may provide some information about the risk of sudden death.¹⁸ It should be noted, however, that inter-observer variability with regard to the measurement of QT interval and QT dispersion is high.²⁶ Thus, although this noninvasive method for identifying patients who may be at an increased risk of life-threatening ventricular arrhythmias is promising, one should be aware of difficulties with regard to QT measurements.
Ventricular function. Abnormal left ventricular responses to exercise have been observed in patients with CAN.^27,28 Zola and associates found depressed left ventricular systolic function in the absence of ischemic heart disease in approximately one-third of patients with autonomic neuropathy.^22,29 Reduced mean ejection fractions at rest and with maximal exercise have also been reported.³⁰Abnormal diastolic function has been found in patients with more severe CAN.³¹This finding was correlated with a reduction in catecholamine levels and postural hypotension, indicating sympathetic involvement with cardiac diastolic dysfunction.³¹ These potential ventricular function abnormalities indicate the importance of prescribing exercise at low to moderate intensities in this patient population.
Blood pressure. Blood pressure response with posture change and during exercise is abnormal in those with CAN. Postural hypotension, often defined as a drop in systolic blood pressure of >20–30 mmHg or a drop in diastolic blood pressure of >10 mmHg upon standing, may be seen.
Postural hypotension is caused by the failure of reflex vasoconstriction in the splanchnic area and the subcutaneous tissues, and its extent is related to the severity of baroreflex dysfunction.³² As a result of this vasoconstrictive dysfunction, the blood pressure response to exercise does not increase to expected levels in these patients. A lower mean systolic blood pressure response at comparable relative exercise workloads in patients with autonomic neuropathy compared to diabetic subjects without this complication has been reported.^19,22 Zola and Vinik, however, also found that subjects occasionally have severely exaggerated increases in blood pressure.³
The symptoms of postural hypotension may occur with eating or within a few minutes of taking insulin. The effect of insulin may be the result of direct action on the peripheral blood vessels, causing vasodilation.³⁴ The insulin-induced hypotension is often worse in the morning and improves later in the day.¹⁸ This must be taken into consideration when determining the timing of exercise in relation to meals and insulin injections. Exercise may need to be deferred to later in the day, and insulin should not be injected just before exercise, regardless of the location of the injection.
Postural hypotension symptoms are similar to those of hypoglycemia and may be mistaken for a drop in blood glucose, even though they are due to a drop in blood pressure. Patients should be alerted to the potential confusion in these symptoms and instructed to check blood glucose before treating for hypoglycemia.
Ventilatory ReflexesPatients with autonomic neuropathy may have impaired ventilatory reflexes. However, it is not clear if this is the direct result of autonomic dysfunction.
Sobotka and associates reported that five of eight patients with diabetic autonomic neuropathy lost their ventilatory drive and ventilatory response to hypoxemic conditions at rest.³⁵ They concluded that the respiratory dysfunction in these patients resulted from the failure of initiation of respiratory drive under conditions of hypoxia and that the defect was either in the carotid body or in the parasympathetic afferents. No significant difference in the ventilatory response to transient hypoxia with exercise between diabetic subjects with and without autonomic neuropathy was found by Calverly and associates.³⁶
During exercise, additional input from other sources, such as catecholamines or local chemical changes in muscles, may compensate.³⁷ Tantucci and associates found that diabetic subjects with autonomic neuropathy had an excessively increased respiratory rate and alveolar ventilation with stressful exercise (>90% maximum predicted heart rate or symptom-limited).³⁸ A progressively higher inspiratory activity was proposed to be involved with the greater ventilatory response to exercise. The suggested mechanism was reduced neural inhibitory modulation from sympathetic afferents and/or increased CO2 chemosensitivity. This finding emphasizes the need to be cautious about exercise intensity.
Abnormal Neuroendocrine ResponseIn the normal response to exercise, catecholamines rise due to activation of the sympathetic nervous system. The increase in catecholamines is directly related to the intensity of the exercise. This catecholamine response causes blood glucose levels to increase through hepatic glycogenolysis and gluconeogenesis, as well as through lipolysis. In addition, glucagon, cortisol, and growth hormone are increased by adrenergic stimulation, adding to the increase in blood glucose.
A blunted response of catecholamines and other glucoregulatory hormones to exercise has been reported in those with autonomic neuropathy, but with no effect on blood glucose values.³⁹ The specific importance of this abnormal neuroendocrine response on exercise or post-exercise metabolism is unclear, but it may be a contributing factor to exercise intolerance.
GastroparesisGastroparesis may be present in some patients with autonomic neuropathy. The effect of gastroparesis on exercise capacity is related to timing of the arrival of nutrients to the bloodstream. It is important that patients be aware of their specific presentation of gastroparesis and timing of nutrient delivery. Use of medications and techniques to assist with normalizing gastric emptying should be attempted if not contraindicated.⁴⁰
Liquids are preferred over solids to prevent or treat hypoglycemia in patients with gastroparesis, since the rate of liquid emptying remains within the normal range for most of these patients.⁴⁰ Individuals using diabetes medications that can cause hypoglycemia should keep liquids containing carbohydrate available during and after exercise.
Hypoglycemia UnawarenessThe loss of early warning signs of hypoglycemia (hypoglycemia unawareness) can occur in diabetic patients with autonomic neuropathy. Normally, as blood glucose begins to fall, there is an asymptomatic slowing of the heart rate and mild hypotension produced by a parasympathetic response. This is followed by sympathetic release of norepinephrine that does produce symptoms of hypoglycemia, which are usually easily recognized.³¹ With diabetic autonomic neuropathy, the ability to recognize these symptoms may be reduced or absent.
It is vital for patients with hypoglycemia unawareness to frequently check their blood glucose to prevent episodes of unconsciousness. Frequent monitoring of blood glucose is especially important when participating in physical activity, since reductions in blood glucose can occur up to several hours after the conclusion of exercise.
Sweating and Cutaneous Blood Flow DisturbancesReduced or absent sweating in the lower body and hyperhydrosis of the upper half of the body may be present in autonomic neuropathy. The loss of sweating in the lower body can cause dry, brittle skin on the feet, which can contribute to ulcer formation. In addition, microvascular skin blood flow may be impaired in patients with autonomic neuropathy. This causes a poor response to vasoconstrictors (such as cold) and vasodilators (such as heat).⁴¹ Vinik identifies dryness of the skin with cracking fissures and cold toes with bounding pulses as sufficient indication of reduced small-vessel reactivity.¹⁸
Both sweating disturbances and compromised cutaneous blood flow in the lower limbs underscore the need to provide appropriate foot care information to these patients before they begin an exercise program. Patients must use properly fitting shoes and routinely examine their feet before and after exercise. It is also extremely important that patients stay adequately hydrated and do not exercise in extreme temperatures.
NECESSARY TESTING
Autonomic FunctionThe clinical features of autonomic neuropathy are often easily missed since they can be mild and nonspecific.⁴² Subclinical abnormalities may be present at diagnosis, even in teenagers.^43-46 This emphasizes the importance of careful screening and appropriate testing for the presence of autonomic neuropathy before embarking on an exercise program.
Tests that evaluate the cardiovascular reflexes are most often used because of their noninvasive nature and the importance of identifying the potentially serious cardiovascular problems resulting from autonomic neuropathy. The reader is referred to pages 224 and 227 for discussions of autonomic testing.
Exercise Capacity and Evaluation for the Presence of Coronary Artery DiseaseIn addition to evaluating the patient for the presence and severity of autonomic neuropathy, testing should be conducted to determine exercise capacity and whether coronary artery disease (CAD) is present. Exercise testing protocols for populations at risk for CAD are recommended for those who meet any of the following criteria: type 1 diabetes and >35 years of age, type 2 diabetes and >35 years of age, type 1 diabetes for >15 years, presence of any microvascular or neurological diabetes complications, presence of one or more additional coronary risk factors, or presence of suspected or known CAD.^47,48
The exercise test should begin at an intensity significantly below the expected peak or symptom-limited capacity. The test should gradually increase in 2- or 3-minute stages with a suggested duration of 10 ± 2 minutes.⁴⁹ Indications for terminating the test should be carefully observed. Test results should be the basis for determining duration and intensity of the exercise program.
CAD is a major concern in patients with diabetes, and it is important that those with autonomic neuropathy also be screened carefully for this. Symptoms of angina are not reliable indicators of CAD in those with autonomic neuropathy, since these patients have a higher frequency of silent myocardial ischemia and infarction. Exercise thallium scintigraphy is the preferred screening for CAD in those with diabetic autonomic neuropathy.^29,50
The need to carefully assess patients should not serve as a deterrent for recommending safe exercise for those with autonomic neuropathy, particularly if a patient expresses an interest in physical activity.
EXERCISE PRESCRIPTIONTo maximize the benefits of physical activity, it is imperative that exercise prescriptions be tailored to each person’s individual set of circumstances (e.g., extent of complication involvement, medications, interest level, and desired outcomes of the exercise program). Exercise prescriptions must be developed jointly by the health care team and the person with diabetes.¹⁶ The desired outcomes of an exercise program must be carefully considered, remembering that not all benefits of exercise (especially the cardiovascular-related ones) will be realized by each patient. The increased sense of well-being and positive outlook that can result from regular physical activity are extremely important benefits for this population.
Exercise recommendations for those with complications of diabetes are based primarily on test results from acute bouts of exercise and on clinical judgement, with primary attention given to safety—not on the results of specific training studies in these diabetic populations. Therefore, exercise guidelines are considered approximate, and modifications must be made for each patient. A conservative approach to exercise is recommended for those with autonomic neuropathy.
The exercise prescription must address recommendations on intensity, type, duration, frequency, and rate of progression of physical activity based on the findings of careful evaluation. In addition, patients must be given information on safety precautions and symptoms to be aware of if discernible ones do develop. It may be most appropriate for those with CAN to participate in exercise programs supervised by people trained in cardiac care who have an adequate understanding of diabetes.¹⁸

Table 2. Rating of Perceived Exertion

RPE Scale 0 Nothing at all 0.5 Very, very weak 1 Very weak 2 Weak 3 Moderate 4 Somewhat strong 5 6 Strong 7 8 9 Very strong 10 Very, very strong Maximal

IntensityIt is frequently recommended that heart rate be used to determine the intensity of exercise. In patients with CAN, heart rate is not an appropriate indicator of intensity, since maximal heart rate is depressed.
Instead, careful attention should be given to a patient’s subjective feelings of intensity using the Rating of Perceived Exertion (RPE) scale (Table 2). The exercise intensity is prescribed according to the numerical values associated with corresponding adjectives subjectively describing intensity. Vinik recommends that patients strive to reach a moderate-range RPE (~3) gradually over 2–4 weeks.18 It is important that health care professionals clearly explain the RPE scale and emphasize its reliance on patients’ subjective feelings. Exercise should be terminated if a patient is unable to continue talking or, if pedaling, to maintain a consistent pedaling frequency.⁵¹
TypeA patient’s interest level should be what primarily drives the type of activity selected. It is important, however, that the person with diabetes and the health care professional give careful consideration to the Ease of Access and Ease of Performance Indices when selecting the most appropriate types of activities (see below).
Activities that should be encouraged in this population are stationary cycling, semi-recumbent cycling, and water exercises.⁵¹ Water activities and semi-recumbent cycling are especially beneficial for those with orthostatic hypotension, since the pressure of water surrounding the body and the semi-recumbent posture, respectively, help maintain blood pressure. Sitting in a chair doing light resistance exercises (e.g., lifting light weights or using an elastic exercise band) may help maintain or increase muscle strength.
Activities that should be avoided are those that cause rapid changes in body position (e.g., certain calisthenics) or that cause rapid and significant changes in heart rate and blood pressure (e.g., high-intensity running or lifting heavy weights).
DurationPatients with clinically significant autonomic neuropathy have reduced exercise tolerance resulting, in large part, from reduced cardiac output and faulty redistribution of blood flow to the working muscles. Consequently, the duration of exercise in these patients must be determined by patient tolerance. The starting duration should be based on the results of the exercise screening that was conducted before initiation of the exercise program and may be just a few minutes. The intensity of the exercise should not be increased to compensate for shortened exercise sessions.¹⁸
FrequencyThe U.S. Surgeon General now recommends for all people that physical activity be performed on most, if not all, days of the week to obtain health-related benefits.⁵²For those with diabetes complications, this recommendation has added significance.
The intensity and duration of physical activity may be modest in many of these patients. If even a small amount of physical activity can be done each day, it will allow patients to derive some of the benefits of physical activity more safely. It is more likely the activity will become a habit if participation occurs on a daily basis. In addition, daily activity will lessen the difficulty of balancing insulin dosages and food intake with physical activity in those taking insulin. Daily physical activity should be attempted, but it is important to remind patients that when days are missed, they should begin again as soon as possible and not feel defeated.
Rate of ProgressionProgression of exercise in those with autonomic neuropathy must be done cautiously. Emphasis should be placed on increasing the frequency (if exercise is not yet being done daily) and duration of activity before increasing the intensity. The duration of physical activity should be gradually increased to accommodate the patient’s functional capacity and clinical status. Any increase in intensity should be small and approached cautiously to minimize the risk of any dangerous cardiovascular events, musculoskeletal injuries, and/or relapse. Since those with CAN have a higher incidence of abnormal ventricular response to exercise, it is especially important to advance the exercise program slowly and with more careful monitoring.¹⁸
PREVENTION OF HYPERGLYCEMIA AND HYPOGLYCEMIAThe importance of self-monitoring of blood glucose (SMBG) cannot be overemphasized for those with autonomic neuropathy, since the metabolic response to exercise is highly variable in these patients. In patients with type 1 diabetes, when the blood glucose is greater than ~240 mg/dL (13.3 mmol/L) and adequate insulin will not soon be available, there is decreased muscle uptake of glucose and ongoing hepatic glycogenolysis and gluconeogenesis. Under these circumstances, blood glucose may become severely elevated, and it is best to postpone exercise until metabolic control is regained.
A mismatch between insulin levels and blood glucose may be especially common in patients with gastroparesis. Exercise should be planned around gastric delivery of nutrients in order to try to maximize the acute glucose-lowering effects of exercise.
Because of the risk of hypoglycemia unawareness in patients with autonomic neuropathy, patients must receive careful instruction about the frequency and timing of SMBG, insulin action (peak and duration), and the importance of trying to avoid exercise at the peak of insulin action or before the stomach has delivered its contents (if gastroparesis is also present). Patients should be instructed on how to treat hypoglycemia, and significant others should be trained in the use of glucagon. A set time for participating in physical activity may be helpful in reducing the adjustments that need to be made to avoid hypo- and hyperglycemia.
MAINTENANCE OF THE EXERCISE PROGRAM In addition to developing a safe exercise prescription and considering exercise precautions for those with autonomic neuropathy, attention must be given to factors that will assist patients in maintaining a regular physical activity program. Marrero and Sizemore have developed the Ease of Access Index and Ease of Performance Index to help patients determine how realistic their activity selections are.⁵³
The Ease of Access Index asks the question, "How easily can I engage in my activity of choice where I live?" Many times, people select activities that they initially feel they can accomplish, but when examined in more depth, they find that they may have ignored, rationalized, or just not been aware of factors that may serve as barriers to long-term adherence to an exercise plan. To determine the ease of access for a given activity, patients should be asked to consider the following questions:

1. Does it require special facilities, and are these facilities available?
2. Does it require special equipment, and is this equipment available and affordable?
3. Does it require special training or instruction, and is this instruction readily available, scheduled at convenient times, easy to get to, and affordable?
4. Does it require others to do it, and will these people be available at the appropriate times?
5. Is it seasonal, and what will be done at other times of the year?

If the selected exercise activity is reasonably accessible, then an assessment of the ease of performance should be conducted. The Ease of Performance Index assesses of how suitable the activity is in terms of personal physical attributes and lifestyle. Patients should be asked to consider the following questions:

1. Does the activity suit your physical attributes?
2. Can you realistically integrate the chosen activity into your current lifestyle?
3. Can you afford any costs associated with it?
4. Do you have a good support network if you need one for the activity?

The use of these two indices will hopefully help patients and health care professionals to consider in advance issues that often undermine long-term participation in physical activity.
Other factors that may assist patients in maintaining a physical activity program include the following:⁵⁴

1. Taking measures to avoid injury. A warm-up and cool-down consisting of low-intensity activity and static stretches should be done to reduce the likelihood of injury.
2. Setting well-defined exercise goals. The goals should be precisely defined by exercise behavior (e.g., walk for 10 minutes daily at a 2 RPE rating) rather than by a hoped-for outcome (e.g., reduction in HbA_1c by 1%).
3. Setting an exercise schedule in advance. Having a schedule can help both in terms of forming a habit of physical activity and in making adjustments to the diabetes management plan easier.
4. Involving an exercise partner. An exercise partner can help with motivation and encouragement, as well as provide safety for a patient with chronic complications. As mentioned above, a monitored exercise program may be best for patients with CAN.
5. Identifying alternative activities. To reduce boredom, it may be helpful to assist patients in considering more than one type of activity. All possible activities should be evaluated for safety, as well as ease of access and ease of performance, as described above.

SUMMARYPhysical activity should be carefully considered for all patients with diabetes. When the chronic complications of diabetes develop, it is especially important to weigh the risks and benefits of an exercise program in formulating the exercise prescription. The deleterious effects of not participating in any physical activity must also be factored in when making decisions about the use of exercise in those with chronic complications.

Autonomic neuropathy may affect several systems that are necessary for the body’s adjustment to exercise, particularly the cardiovascular system. Careful testing to evaluate autonomic function and to determine exercise capacity and the presence of CAD are extremely important. The need for careful evaluation before starting an exercise program should not prevent participation in physical activity. Working with patients to develop an appropriate exercise plan will yield a program with the greatest capability of maximizing the benefits.