DAN is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated.
Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function and hypoglycemic autonomic failure.
DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). DAN is among the least recognized and understood complications of diabetes despite its significant negative impact on survival and quality of life in people with diabetes. A subtype of the peripheral polyneuropatheies, DAN can involve the entire autonomic nervous system (ANS). Many organs are dually innervated, receiving fibers from the parasympathetic and sympathetic divisions of the ANS.
DAN typically occurs as a system - wide disorder affecting all the parts of the ANS. Clinical symptoms of autonomic neuropathy generally do not occur until long after the onset of diabetes. Sub clinical autonomic dysfunction can, however, occur within a year of diagnosis in type 2 diabetes patients within two years in type 1 diabetes patients. Because of its association with a variety of adverse outcomes including cardiovascular deaths, cardiovascular autonomic neuropathy (CAN) is the most clinically important and well-studied form of DAN. Simple, noninvasive tests of cardiovascular autonomic function have supported extensive clinical and epidemiological investigation of CAN.
CARDIAC AUTONOMIC NEUROPATHY (CAN):
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 result 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 the individuals without cardiovascular autonomic involvement.
CLINICAL TESTING OF AUTONOMIC FUNCTION
Assessing cardiovascular autonomic function:
Quantitative tests of autonomic function have historically lagged behind measures of motor nerve function and sensory nerve function deficits. In the early 1970s, Ewing et al., proposed five simple noninvasive cardiovascular reflex tests( i.e., Valsalva maneuver, heart rate response to deep breathing, heart rate response to standing up, blood pressure response to standing up and blood pressure response to sustained hand grip) that have been applied successfully by many.
The tests are valid as specific markers of autonomic neuropathy if end-organ failure has been carefully ruled out and other potential factors such as concomitant illness, drug use, lifestyle issues, and age are taken into account.
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 that act of standing involves low-level exercise and parasympathetic tone is withdrawn to produce a sudden tachycardia response. 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.
Heart rate response to standing:
This test evaluates the cardiovascular response elicited by a change from a horizontal to a vertical position. 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.
Valsalva Maneuver:
In healthy subjects the reflex response for the Valsalva maneuver includes tachycardia and peripheral vasoconstriction during strain, followed by an overshoot in blood pressure and bradycardia after release of strain. In the standard Valsalva maneuver test, the patient in supine position, connected to the ECG machine, forcibly exhales for 15 seconds against a fixed resistance (40mmHg) with an open glottis. 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 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 because of residual vasoconstriction and restored normal venous return and cardiac output.
The Valsalva ratio is determined by calculating the ratio of the longest R - R interval after the maneuver to the shortest R - R interval during or shortly after the maneuver.
Systolic Blood Pressure response to standing:
Blood pressure normally changes only slightly on standing from supine position. The response to standing is mediated by sympathetic nerve fibers. In normal individuals the systolic BP falls by <10 mmHg in 30 seconds. In diabetic patients with autonomic neuropathy, the systolic BP falls by 30 mmHg within 2 min after standing. American Academy of Neurology (AAN) and the American Autonomic Society defined orthostatic hypertension as a fall in systolic blood pressure of >_20 mmHg or diastolic blood pressure of >_10 mmHg accompanied by symptoms.
Diastolic Blood Pressure response to sustained handgrip:
In this test, sustained muscle contraction as measured by a handgrip dynamometer causes a rise in systolic and diastolic BP and heart rate. The dynamometer is first squeezed to isometric maximum, and then held at 30% of maximum for 5 min. The normal response is a rise of diastolic blood pressure >16 mmHg, whereas a response of <10 mmHg is considered abnormal.
Diabetic with autonomic neuropathy are prone for sudden death from painless myocardial infarction and cardio-respiratory arrest.
