1. health and fitness
2. disease
3. diabetes

Diabetic Cardiac Autonomic Neuropathy
and Anesthetic Management: Review of
the Literature
Ingrid Oakley, CRNA, DVM
Lyne Emond, CRNA, MNA
Cardiac autonomic neuropathy is a serious complication among diabetic patients. It occurs in both type
1 and type 2 diabetes, and its progression results in
poor prognosis and increased mortality. During its
course, parasympathetic and sympathetic nerve fibers
of the cardiovascular system are damaged, resulting
in potentially serious cardiac complications and even
death. Poor glycemic control is believed to play a pivotal role in the pathogenesis of cardiac autonomic neuropathy. Its underlying etiology is not well understood;
however, several potential pathologic mechanisms
have been identified.
Several clinical manifestations of cardiac autonomic neuropathy have been reported, including
resting tachycardia, exercise intolerance, loss of heart
rate variability, orthostatic hypotension, prolonged QT
interval, silent ischemia, and sudden death. Diabetic
D
iabetic autonomic neuropathy is a complication of type 1 and type 2 diabetes. It affects
multiple organ systems throughout the body,
causing impairment of the gastrointestinal,
genitourinary, and cardiovascular systems.
Cardiac autonomic neuropathy (CAN) is the most serious
and clinically significant form of diabetic autonomic neuropathy.1 It has been extensively studied over the years
but remains the least understood complication of diabetes
mellitus. The prevalence of CAN in diabetic patients varies greatly, from as low as 7.7% in people with recently
diagnosed type 1 diabetes to as high as 90% in diabetic
patients waiting for pancreas transplants.1 It can present
itself early in its progression; however, many patients
remain asymptomatic during the initial course, making a
diagnosis extremely difficult.1,2
Synthesis of the literature reveals that both poor glycemic control and duration of diabetes play substantial
roles in the development and progression of CAN.1,2
Patients in whom diabetes has not been well controlled
for many years are more likely to have progressive
cardiac abnormalities.3 Moreover, CAN has also been
reported to coexist in patients with diabetic retinopathy, peripheral neuropathies, diabetic nephropathy, and
other diabetic complications.4,5 The prognosis is said to
www.aana.com/aanajournalonline.aspx
patients exhibiting these signs and symptoms are at
greater risk of anesthesia-related complications. A
series of noninvasive autonomic tests were developed
for the diagnosis of cardiac autonomic neuropathy,
improving the management of diabetic patients requiring general anesthesia.
These patients often experience cardiovascular
events that may increase perioperative morbidity and
mortality. The presence of cardiac autonomic neuropathy alters the hemodynamic response to induction and
tracheal intubation during general anesthesia, resulting in intraoperative hypotension. A thorough preoperative assessment and vigilant monitoring perioperatively ensure successful anesthesia management.
Keywords: Anesthesia, cardiac autonomic neuropathy,
diabetic autonomic neuropathy, diabetes mellitus.
be poor and mortality risk greatly increased once CAN
develops; however, new research reveals that improved
glycemic control can potentially slow the progression of
CAN in patients with type 1 and type 2 diabetes.6,7
Cardiac autonomic neuropathy has been of particular
interest to anesthesia professionals over the years because
of its direct effect on the development of potential cardiovascular complications during general anesthesia.1 A
thorough understanding of the pathophysiology process
and its clinical manifestations are of clinical importance
for optimal anesthetic management of diabetic patients
with CAN. In this article we review the literature pertaining to this topic.
Pathophysiology
Despite intensive research, the precise etiology and
pathologic mechanisms of diabetic autonomic neuropathy remain unclear. It is, however, well established in the
literature that both the parasympathetic and sympathetic
divisions of the autonomic nervous system suffer progressive nerve fiber loss during the course of this disease.
The insult to the sensory and motor nerve fibers that
innervate the major organs in the human body results in
considerable widespread autonomic dysfunction. Cardiac
autonomic neuropathy is said to be the most serious and
AANA Journal

December 2011

Vol. 79, No. 6
473
1. Increase polyol pathway influx
Activation of the polyol pathway→ leads to the accumulation of sorbitol in the nerves→ ↑ reactive oxygen species (free radicals), ↑
activity of protein kinase C and ↓ activity of Na-K-ATPase activity→ causing direct nerve damage and a ↓ neuronal blood flow.
2. Oxidative stress
Induced oxidative stress leads to ↑ accumulation of oxygen free radicals causing vascular endothelial damage and dysfunction of
Schwann cells, as well as ↓ nitric oxide (a potent vasodilator).
3. Activation of protein kinase C
Hyperglycemia → ↑ second messenger diacylglycerol → activates protein kinase C → leading to a series of pathologic consequences such as ↓ nitric oxide→ vasoconstriction and ↓ nerve blood flow → vascular damage.
4. Accumulation of advanced glycation end product formation
Intracellular hyperglycemia appears to be the initiating factor in the formation of advanced glycation end product→ causing ↑ angiotensin II (vasoconstrictor) and free fatty acid synthesis→ activation of protein kinase C→ endothelial damage.
5. Endoneuronal ischemia and hypoxia
Endoneuronal hypoxia appears to be caused by ↑ resistance in vascular system and ↓ nerve blood flow. Hypoxia leads to further
damage to capillaries and eventually causes axonal transport dysfunction.
6. Destruction of nerve growth factors and axonal transport
Nerve growth factors are found in target organs innervated by sympathetic nervous system. Regulation of cardiac sensory nerves
appear to be dependent on nerve growth factors. Hyperglycemia ↓ production of nerve growth factors for endothelial and neuronal
cells→ leading to degeneration of nerves.
7. Disorder of fatty acid metabolism
Deficiency in essential fatty acids: accumulation of linoleic acid and ↓ linolenic acid changes the cell membrane → ↓ neuronal blood
flow.
8. Immunologic mechanism
Progressive changes in immune system may also be implicated. Autoimmune damage has been noted in earlier research.
Table 1. Proposed Pathologic Mechanisms of Diabetic Autonomic Neuropathy
Abbreviations: →, leads to; ↑, increased; ↓, decreased or decreases; Na-K-ATPase, sodium-potassium-adenosine triphosphatase.
fatal complication of diabetic autonomic dysfunction.8
The parasympathetic and sympathetic nerve fibers are
vital to the innervation of the cardiovascular system
such as control of heart rate, blood pressure, and cardiac
contractility, as they provide the body’s homeostasis.9,10
Therefore, disturbances in the integrity of the cardiovascular system results in potentially serious cardiac complications in diabetic patients with CAN.1
Recent research studies have proposed several mechanisms that may be implicated in the pathology of diabetic
autonomic neuropathy (Table 1). Poor glycemic control
appears to play a central role in several of these pathologic processes, but the degree of involvement and interrelationship among them all is not well understood1,6,11,12
These proposed mechanisms are somewhat complex,
and a comprehensive review is beyond the scope of this
research article.
Clinical Manifestations
Synthesis of the literature reveals that loss of parasympathetic and sympathetic cardiac innervation may lead
to several cardiac manifestations in diabetic patients.
Many patients remain asymptomatic during the progression of CAN, whereas others are severely affected.13 It is
still not well known whether patients with type 1 and
type 2 diabetes experience the same degree of autonomic
impairment, as there is a lack of evidence in the current
literature. A brief discussion of cardiovascular manifestations follows.
474
AANA Journal

December 2011

Vol. 79, No. 6
• Resting Tachycardia. Resting tachycardia is commonly observed in diabetic patients with autonomic
nervous system dysfunction.14,15 A resting heart rate of
90/min to 130/min is a known manifestation of CAN.2,16
In a recent study, resting heart rate was evaluated in type
1 diabetic patients with CAN. The results of this study
revealed that diabetic patients with CAN experienced a
significantly higher resting heart rate, 94/min, compared
with diabetic patients without CAN, who exhibited a
resting heart rate of only 79/min.16 This suggests that
an increase in sympathetic activity may occur because
of damage to parasympathetic nerve fibers. It is believed
to occur before sympathetic impairment observed in
CAN.16 According to the literature, dysfunction of the
parasympathetic nerve system normally precedes sympathetic dysfunction in the progression of CAN.2,10 Resting
tachycardia is usually seen as a late sign of parasympathetic nerve damage.2
• Exercise Intolerance. Recent studies have shown
that cardiac autonomic dysfunction can greatly impair
the cardiovascular compensatory response to moderate exercise. As CAN progresses, both parasympathetic
and sympathetic nervous systems are impaired, and as a
result, heart rate, blood pressure, and cardiac output are
simply unable to increase in response to exercise.2,6,17,18
A patient’s capacity to tolerate moderate exercise or stress
is therefore limited, and the patient may experience
symptoms of weakness, fatigue, and syncope.2
• Loss of Heart Rate Variability With Deep Breathing.
www.aana.com/aanajournalonline.aspx
Normally heart rate should increase by more than
15/min in response to deep breathing. In diabetic patients
with CAN, however, the heart rate is mainly fixed and
will usually increase less than 10/min.19 Heart rate variability, as seen on the electrocardiogram (ECG) as the R-R
interval, is controlled by the autonomic nervous system
and is dependent on parasympathetic activity.1 With the
onset of cardiac autonomic nerve dysfunction, lack of
heart rate variability with deep breathing is often seen.
It is often one of the first and most commonly occurring
symptoms in diabetic patients with CAN.1 A recent metaanalysis demonstrated a significant relationship between
lack of heart rate variability and increased risk of silent
myocardial ischemia and mortality in these patients.1 It
has also been associated with intraoperative hypotension
in diabetic patients with CAN during general anesthesia.20
• Orthostatic Hypotension. The literature defines orthostatic hypotension as a decrease in systolic blood
pressure of greater than 30 mm Hg or a decrease in
diastolic blood pressure of greater than 10 mm Hg.2
Normally blood pressure decreases slightly with postural change, from supine to standing. This response is
primarily regulated by the efferent sympathetic nerve
fibers.6 Autonomic nerve dysfunction impairs the body’s
ability to control blood pressure, causing substantial orthostatic hypotension in diabetic patients with CAN.6,21
Patients can experience symptoms such as weakness,
fainting, dizziness, visual impairment, and syncope.2 The
underlying disturbance is the lack of vasoconstriction
as a result of sympathetic dysfunction and a decrease in
norepinephrine release when changing from a supine to
standing position.6,21
A study, as recent as 2009, demonstrated that type
1 and type 2 diabetic patients experienced a significant
decrease in orthostatic systolic blood pressure (88.9%)
with advanced progression of CAN.22 Results were similar
for both types of diabetes.22 Orthostatic hypotension is
usually seen as a late complication and is usually indicative of a poor prognosis in diabetic patients with CAN.2
Many of these patients, however, appear to remain asymptomatic, even with a significant fall in blood pressure.6
• Silent Myocardial Ischemia or Infarct. A meta-analysis
of 12 cross-sectional studies showed a statistically significant relationship between CAN and painless ischemia in
diabetic patients with CAN.1 The presence of afferent autonomic nerve dysfunction appears to decrease the sensitivity to myocardial ischemia by altering pain transmission, thus preventing prompt recognition of myocardial
ischemia or infarct.1,2,19 Marchant and colleagues23 evaluated 22 diabetic patients and 30 nondiabetic patients
during a treadmill stress test. All study subjects experienced ischemia during the test. Sixteen of them did not
experience angina, and 10 of them were diabetic patients.
It was later revealed that diabetic patients with silent
ischemia had evidence of significant autonomic nerve
www.aana.com/aanajournalonline.aspx
dysfunction compared with symptomatic patients. This
important finding suggests that CAN may cause silent
ischemia in patients with diabetes.23 The underlying
mechanisms of silent myocardial ischemia are complex
and still not well understood by many researchers.2
• QT Abnormalities. The QT interval on ECG indicates
the duration of ventricular myocardial depolarization and
repolarization.24 A QTc value greater than 440 ms is considered prolonged, according to the literature.10 Several
research studies have found a direct relationship between
CAN and prolonged QT interval in patients with diabetes
mellitus who have autonomic dysfunction.10,15,16,25 As a
result, these patients are predisposed to potential fatal
ventricular arrhythmias such as torsades de pointes and
sudden death.2 The underlying mechanism responsible
for prolonged QT in these patients remains poorly understood. Some studies suggest that alterations in cardiac
sympathetic innervation may possibly cause prolongation of the QT interval.2,19,26
• Intraoperative Cardiovascular Instability. Diabetic
patients with evidence of CAN are at higher risk of intraoperative cardiovascular instability and sudden cardiac
death.6,14 Vasoconstriction and tachycardia are primary
autonomic responses to vasodilating effects of general
anesthesia. In patients with CAN, however, those compensatory mechanisms are altered, predisposing these
patients to bradycardia, hypotension, and cardiac arrest
during the perioperative period.6,14 Intraoperative cardiovascular instability experienced by these patients will
be discussed further in the “Anesthetic Considerations”
section of this article.
• Hypertension. Hypertension was also noted in the literature as a possible symptom of CAN. Boulton and colleagues19 explain that an increase in sympathetic activity
may result as a consequence of parasympathetic nerve
dysfunction, causing an increase in blood pressure. A
recent study, however, was unable to prove a significant
relationship between CAN and hypertension.27 There
seems to be a lack of evidence in recent literature to
substantiate a correlation. Further studies are needed to
establish hypertension as a manifestation of CAN.
• Sudden Death Syndrome. There is a high risk of
sudden death in diabetic patients with CAN, according
to recent research. Silent ischemia and prolonged QT
interval are possible explanations for sudden deaths in
these diabetic patients.2,19,26
All of these cardiac manifestations may be seen during
the development and progression of CAN. They collectively contribute to a poor prognosis and a greater
mortality risk among these patients.8
Cardiac Autonomic Neuropathy Testing
There has been much research over the years on autonomic neuropathy testing in diabetic patients, but much
debate remains as to which current method or methods
AANA Journal

December 2011

Vol. 79, No. 6
475
are best suited for the diagnosis of autonomic neuropathy. Detection of CAN in type 1 and type 2 diabetic patients is of great interest to anesthesia providers because
of its potential clinical impact during general anesthesia.
Given that CAN may be life-threatening and increase the
risk of mortality of diabetic patients during surgery, its
detection provides valuable information to the clinical
assessment of these patients.1
The literature reports that clinical observation and
physical examination alone are not effective in helping
detect cardiac autonomic dysfunction in its early stages;
therefore, standard autonomic testing should be used
for the diagnosis of CAN.1,28 A series of cardiovascular
reflex tests known as Ewing’s battery of tests has been
extensively used in scientific research for the diagnosis
of CAN over the last 3 decades.10,29 These noninvasive
tests have been described as simple bedside tests that
are effectively reliable with a sensitivity and specificity
greater than 90%.10,13 Ewing’s autonomic tests will now
be discussed briefly.
• Heart Rate Response to Deep Breathing. Heart rate
variation with breathing is dependent on parasympathetic
nerve activity. Patients in a supine position breathe deeply
at a rate of 6/min, which produces a maximum heart
rate variation. Electrocardiography is used to evaluate
the heart rate. A difference in heart rate of greater than
15/min is considered normal, whereas less than 10/min is
abnormal and indicative of cardiac parasympathetic dysfunction13,19,29 This testing method is considered by many
researchers as the most reliable test of CAN.1,13
• Heart Rate Response to Valsalva Maneuver. The
Valsalva maneuver is dependent on sympathetic and
parasympathetic cardiac nerve fibers.30 In this particular
test, the patient is seated and blows into a mouthpiece at
a pressure of 40 mm Hg for approximately 15 seconds.13
In most cases, reflex response to the Valsalva maneuver
produces tachycardia and peripheral vasoconstriction
during strain, with a subsequent increase in blood pressure and bradycardia after its release. In patients with
CAN, the heart rate response is altered, and an abnormal decrease in blood pressure is seen with strain, with
a slower recovery phase. These findings are indicative
of parasympathetic and sympathetic nerve dysfunction.1,13,19,29
• Heart Rate Response to Standing. Normally the heart
rate increases rapidly upon standing, reaching a maximal
heart rate at the 15th beat after standing followed by
reflex bradycardia at the 30th beat. The ratio between
R-R interval at the 15th beat and R-R interval at the 30th
beat as seen on ECG is referred to as the 30:15 ratio. This
ratio is considered to be a measurement of cardiac parasympathetic function.30 In diabetic patients with CAN
the 30:15 ratio is decreased. Only a gradual increase in
heart rate is seen.1,13
• Blood Pressure Response to Standing. Orthostatic
476
AANA Journal

December 2011

Vol. 79, No. 6
hypotension results from sympathetic nerve damage.
Therefore, blood pressure response to standing is often
used to assess sympathetic dysfunction.30 There is usually
a small decrease in blood pressure when someone stands
up from a supine position. In diabetic patients with
CAN, however, sympathetic peripheral vasoconstriction
is altered, causing an abnormal decrease in blood pressure. A diastolic blood pressure decrease greater than 10
mm Hg or systolic blood pressure decrease greater than
30 mm Hg within 2 minutes of standing is considered
abnormal.1,13,19
• Blood Pressure Response to Sustained Handgrip. This
test involves a handgrip to be maintained at the patient’s
30% maximal voluntary contraction using a handgrip
dynamometer for 5 minutes.13 Efferent sympathetic
nerve fibers involved in sustained muscle contraction
normally produce an increase in blood pressure, heart
rate, and cardiac output as a result of increased peripheral resistance. The response is considered normal if
diastolic blood pressure is increased greater than 16 mm
Hg and is abnormal if the increase is less than 10 mm
Hg. Patients with CAN usually experience only a slight
increase in diastolic blood pressure.1,13,19
Two abnormal tests are required to establish the
clinical diagnosis of CAN.16,29 Activity of both parasympathetic and sympathetic nerves is involved in all
5 autonomic tests just described. Changes in heart rate
appear to be affected by cardiac parasympathetic dysfunction, whereas abnormal blood pressure changes are
usually seen with more extensive sympathetic dysfunction.13 According to recent literature, heart rate response
to deep breathing, Valsalva maneuver, and standing up
(30:15 ratio) show the highest sensitivity in detecting
CAN in diabetic patients.2 In a meta-analysis, several
studies provided strong scientific evidence that these diagnostic tools are effective and useful in monitoring the
progression of CAN in symptomatic and asymptomatic
diabetic patients.1 Despite their extensive use in scientific
research, the current literature fails to elaborate on the
routine use and effectiveness of these tests in the nonresearch setting. Are these diagnostic tools really practical?
Recent research studies, however, argue that Ewing’s
series of tests are impractical in the clinical setting, as
they require patient cooperation and compliance that is
not always feasible with pediatric and elderly patients.31
Other methods have been developed for the testing of
CAN and appear to be gaining popularity in the assessment of autonomic nerve dysfunction. The noninvasive
evaluation can be done with spectral analysis of heart rate
variability. This modern technology utilizes a mathematical computerized approach (fast Fourier transform) to
indirectly assess cardiac autonomic dysfunction. It assesses heart rate variability of diabetic patients with CAN
by power spectral analysis using a series of consecutive
R-R intervals.1,16,32 Heart rate amplitudes are presented
www.aana.com/aanajournalonline.aspx
as different oscillation frequencies and then analyzed.2
The heart rate power spectrum is classified into low frequency of 0.04 to 0.15 Hz and high frequency of 0.15 to
0.4 Hz. High frequency analyzes parasympathetic activity
while low frequency is a measurement of parasympathetic
and sympathetic innervation.1 Diabetic patients with
CAN who present primarily parasympathetic dysfunction exhibit decreased or no high-frequency amplitudes,
whereas patients with sympathetic dysfunction have decreased low-frequency amplitudes. In patients with severe
CAN, there is an absence of all frequency amplitudes.1,28
Spectral analysis method for assessing the cardiovascular nervous system appears to be a more sensitive
tool in the detection of early stages of CAN by some researchers.16,32 In addition, it does not require active participation from the patient, as it is performed at rest and
demonstrates a high sensitivity of 99% and specificity of
100% in the early diagnosis of CAN.16,31,32 Early identification of autonomic nerve dysfunction is crucial as
progression causes irreversible autonomic nerve injury.32
Despite all of the autonomic testing performed in scientific research, the current literature fails to elaborate
on its usefulness and effectiveness in the nonresearch
setting. Future research studies are needed to demonstrate their reliability and accuracy in routine clinical
practice. Lastly, monitoring and evaluation of prolonged
QT interval could potentially provide useful information
for the diagnosis of CAN, according to Krahulec et al.16
The reliability of a prolonged QT interval on ECG as a
diagnostic tool has yet to be established in the current
research literature, however.
Anesthetic Considerations
• Preoperative Assessment. Diabetic patients with evidence of CAN may present a major challenge to the anesthetist. Research studies have shown that CAN increases
the risk of intraoperative cardiac events.1,14 Therefore, a
comprehensive preoperative assessment is essential for
optimal anesthetic management of these patients. The
preoperative medical history and physical assessment
may provide useful information and reveal symptoms indicative of autonomic cardiac dysfunction such as loss of
heart variability, exercise intolerance, orthostatic hypotension, and QT interval prolongation on ECG. The presence of these symptoms should caution the anesthetist
of possible intraoperative hemodynamic instability.14,33
A review of the preoperative ECG is important and may
provide insightful information. As previously discussed,
prolonged QT interval and loss of heart rate variability,
as seen on ECG as R-R variation, have demonstrated
an increase in the risk of cardiovascular complications
during surgery as well as increased mortality in diabetic
patients with CAN.1,14 Furthermore, exercise tolerance
can provide valuable information in regard to their
cardiopulmonary function. Exercise intolerance could
www.aana.com/aanajournalonline.aspx
1.Review preoperative electrocardiogram.
2.Evaluate preoperative exercise tolerance.
3.Review medical history.
4.Review physical assessment.
5.Review home medications.
6.Review past surgical history.
7.Perform preoperative cardiac autonomic neuropathy testing.
Table 2. Perioperative Evaluations for Diabetic
Cardiac Autonomic Neuropathy
indicate possible dysfunction of the cardiac autonomic
nervous system requiring further evaluation.6 Some
studies advocate preoperative CAN testing because of its
sensitivity and effectiveness in detecting and diagnosing
CAN in diabetic patients.1,33 Screening of CAN preoperatively may be helpful to improve the management of
diabetic surgical patients requiring general anestheisa.2
Vinik and colleagues1 reported in their meta-analysis
that the preoperative presence of 2 or more abnormal
autonomic function tests in diabetic patients with CAN
was associated with greater intraoperative hemodynamic
changes and a higher incidence of sudden death in these
patients. Despite this research evidence, it appears that
screening for cardiac autonomic dysfunction in diabetic
patients is not frequently performed in clinical practice.1
Also noteworthy is the fact that cardiac manifestations
exhibited by diabetic patients with CAN during general
anesthesia could also potentially be influenced by home
medications such angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, and insulin.34
The incidence of postinduction hypotension and bradycardia may be increased with the concomitant use of
these medications (Table 2).34
• Induction and Maintenance of General Anesthesia.
Type 1 and type 2 diabetic patients with CAN are at
higher risk of cardiac complications and mortality during
surgery than are nondiabetic patients.2 Knowing these
potential complications, the anesthetist needs to be
cognizant of and prepared to effectively manage sudden
intraoperative situations that may arise during general
anesthesia. Vigilant monitoring of potential cardiovascular abnormalities is essential for optimal intraoperative
anesthetic management of diabetic patients with CAN.14
Diabetic patients with CAN experience a higher risk
of intraoperative cardiovascular instability.1,14 In a study
involving ophthalmologic surgery, researchers demonstrated that diabetic patients with CAN experienced a
more profound decrease in heart rate and arterial blood
pressure during induction of anesthesia compared with
nondiabetic individuals. The mean arterial blood pressure (MAP) decreased an average of 30 mm Hg during
induction. The drop in MAP was significantly greater
than in the nondiabetic group. The diabetic subjects also
reported less tachycardia and hypertension after tracheal
AANA Journal

December 2011

Vol. 79, No. 6
477
intubation and extubation compared with nondiabetic
subjects. Their data showed only a slight increase in MAP
of 7 mm Hg during tracheal intubation, which was significantly less than the control group.14,18 In addition, 35%
of diabetic patients with CAN required vasopressors such
as phenylephrine to treat hypotension, whereas only 5%
of the control group required treatment.14 The findings
suggest that alterations to the cardiac autonomic fibers
prevent compensatory mechanisms such as vasoconstriction and increased heart rate to respond to the vasodilating effects of general anesthesia. In this particular study,
hypotension occurred most frequently after tracheal
intubation and before surgical stimulation.14 There has
been strong evidence in several studies that intraoperative vasopressor support is needed more often in diabetic
patients with CAN than those without CAN.1,14,20
Cardiac autonomic dysfunction can be greatly affected
by anesthetic drugs used during general anesthesia. The
literature suggests that induction or maintenance of anesthesia with an induction agent such as etomidate and
opioids may produce less hemodynamic instability in
diabetic patients with CAN.18,34 There is a significantly
higher risk of hypotension with induction drugs such as
thiopental and propofol; however, no specific anesthesia
drug or volatile gas has been shown to be more advantageous in patients with diabetic CAN.14,34
There have been published reports of unexpected occurrences of intraoperative bradycardia and hypotension
during general anesthesia not responsive to intravenous
(IV) administration of atropine and ephedrine in diabetic
patients with CAN. Intravenous epinephrine proved to be
the most effective treatment in the successful resuscitation of these patients. The lack of heart rate response to
atropine suggests the presence of sympathetic nervous
system dysfunction.14,35-38 Sudden deaths have also been
reported during general anesthesia in diabetic patients
with CAN.39 In one case report bradycardia suddenly
developed in an elderly patient with diabetic CAN following muscle relaxant therapy with IV glycopyrrolate and
neostigmine. The patient was, however, responsive to IV
epinephrine and cardiac compressions.5
Additionally, diabetic patients with CAN are at significantly increased risk of silent ischemia or infarct as
previously discussed. Vigilant monitoring of ECG, heart
rate, and blood pressure, as well as prompt treatment of
hypotension, during general anesthesia are of utmost importance during the perioperative management of these
patients.1,14 Invasive hemodynamic monitoring may be
necessary depending on the severity of CAN or the nature
of the surgical procedure.
• Postoperative Care. The postoperative phase of anesthesia can be a period of great hemodynamic instability
for diabetic patients. The coexistence of CAN, however,
can greatly increase their risk of severe cardiac complications. Postoperative cardiopulmonary arrest and even
478
AANA Journal

December 2011

Vol. 79, No. 6
deaths have been documented in diabetic patients with
CAN. In a small prospective study, Charlson and colleagues40 showed that 7% of diabetic patients with 2 or
more abnormal autonomic function tests experienced
postoperative cardiopulmonary arrest or death. This
finding suggests that all patients with evidence of CAN
should be closely monitored for potential postoperative
cardiac events.
Summary
Many diabetic patients will inevitably undergo some
type of surgical procedure during their lifetime. Diabetic
patients with coexisting CAN will be a great challenge to
the anesthetist. Patients with either type of diabetes mellitus who have coexisting cardiac autonomic dysfunction
are at greater risk of intraoperative hemodynamic instability, as well as other serious or fatal cardiac complications during general anesthesia. A good understanding
of the pathophysiology process, clinical manifestations,
autonomic testing, and potential intraoperative complications is necessary for effective anesthesia management of
these patients. A comprehensive preoperative assessment
and vigilant monitoring are of great importance for a successful outcome. The anesthetist must be fully prepared
to react promptly and appropriately to prevent potential
morbidity and mortality in diabetic patients with CAN.
Great progress has been made over the years in the research of autonomic nerve dysfunction. However, much
still remains unknown about this serious complication of
diabetes mellitus. Future research will hopefully provide
the evidence needed to prevent the progression and fatal
events experienced by the many diabetic patients who
have CAN.
REFERENCES
1. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic
neuropathy. Diabetes Care. 2003;26(5):1553-1579.
2. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy.
Circulation. 2007;115(3):387-397.
3. Harati Y. Diabetic neuropathies: unanswered questions. Neurol Clin.
2007;25(1):303-317.
4. Bilal N, Erdogan M, Ozbek M, et al. Increasing severity of cardiac
autonomic neuropathy is associated with increasing prevalence of
nephropathy, retinopathy, and peripheral neuropathy in Turkish type
2 diabetics. J Diabetes Complications. 2008;22(3):181-185.
5. Triantafillou AN, Tsueda K, Berg J, Wieman TJ. Refractory bradycardia after reversal of muscle relaxant in a diabetic with vagal neuropathy. Anesth Analg. 1986;65(11):1237-1241.
6. Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due
to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005;90(10):5896-5903.
7. Valensi P, Pariès J, Attali JR; French Group for Research and Study
of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic
patients: influence of diabetes duration, obesity, and microangiopathic complications—the French multicenter study. Metabolism.
2003;52(7):815-820.
8. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between
cardiovascular autonomic neuropathy and mortality in individuals
with diabetes: a meta-analysis. Diabetes Care. 2003;26(6):1895-1901.
9. Neukirchen M, Kienbaum P. Sympathetic nervous system: evalua-
www.aana.com/aanajournalonline.aspx
tion and importance for clinical general anesthesia. Anesthesiology.
2008;109(6):1113-1131.
10.Jermendy G. Clinical consequences of cardiovascular autonomic
neuropathy in diabetic patients. Acta Diabetol. 2003;40(suppl 2):
S370-S374.
11.Schonauer M, Thomas A, Morbach S, Niebauer J, Schonauer U,
Thiele H. Cardiac autonomic diabetic neuropathy. Diab Vasc Dis Res.
2008;5(4):336-344.
12.Brownlee M. Biochemistry and molecular cell biology of diabetic
complications. Nature. 2001;414(6865):813-820.
13. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes.
Diabetes Care. 1985;8(5):491-498.
14.Burgos LG, Ebert TJ, Asiddao C, et al. Increased intraoperative
cardiovascular morbidity in diabetics with autonomic neuropathy.
Anesthesiology. 1989;70(4):591-597.
15. Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden
cardiac death in diabetic autonomic neuropathy. J Clin Endocrinol
Metab. 1987;64(4):751-754.
16. Krahulec B, Mikes Z, Balazovjech I. The effect of cardiovascular autonomic neuropathy on resting ECG in type 1 diabetic patients. Bratisl
Lek Listy. 2002;103(2):54-58.
17. Vinik AI, Erbas T. Recognizing and treating diabetic autonomic neuropathy. Cleve Clin J Med. 2001;68(11):928-930, 932, 934-944.
18. Amour J, Kersten JR. Diabetic cardiomyopathy and anesthesia: bench
to bedside. Anesthesiology. 2008;108(3):524-530.
19. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28
(4):956-962.
20. Huang CJ, Kuok CH, Kuo TB, Hsu YW, Tsai PS. Pre-operative measurement of heart rate variability predicts hypotension during general
anesthesia. Acta Anaesthesiol Scand. 2006;50(5):542-548.
21. Vinik AI, Mehrabyan A. Diabetic neuropathies. Med Clin North Am.
2004;88(4):947-999, xi.
22. Spallone V, Morganti R, Fedele T, D’Amato C, Maiello MR. Reappraisal of the diagnostic role of orthostatic hypotension in diabetes.
Clin Auton Res. 2009;19(1):58-64.
23. Marchant B, Umachandran V, Stevenson R, Kopelman PG, Timmis
AD. Silent myocardial ischemia: role of subclinical neuropathy in
patients with and without diabetes. J Am Coll Cardiol. 1993;22(5):
1433-1437.
24. Giunti S, Bruno G, Lillaz E, et al; EURODIAB IDDM Complications
Study Group. Incidence and risk factors of prolonged QTc interval
in type 1 diabetes: the EURODIAB Prospective Complications Study.
Diabetes Care. 2007;30(8):2057-2063.
25.Pourmoghaddas A, Hekmatnia A. The relationship between QTc
interval and cardiac autonomic neuropathy in diabetes mellitus. Mol
Cell Biochem. 2003;249(1-2):125-128.
26. Pappachan JM, Sebastian J, Bino BC, et al. Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of
www.aana.com/aanajournalonline.aspx
corrected QT interval in the ECG for its diagnosis. Postgrad Med J.
2008;84(990):205-210.
27. Istenes I, Keresztes K, Hermányi Z, et al. Relationship between autonomic neuropathy and hypertension—are we underestimating the
problem? Diabet Med. 2008;25(7):863-866.
28. Rolim LC, Sa JR, Chacra AR, Dib SA. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis.
Arq Bras Cardiol. 2008;90(4):e24-e31.
29. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic
autonomic neuropathy. Q J Med. Winter 1980;49(193):95-108.
30. Hilsted J. Pathophysiology in diabetic autonomic neuropathy: cardiovascular, hormonal, and metabolic studies. Diabetes. 1982;31(8 pt
1):730-737.
31.Khandoker AH, Jelinek HF, Palaniswami M. Identifying diabetic
patients with cardiac autonomic neuropathy by heart rate complexity
analysis. Biomed Eng Online. 2009;8:3.
32.Gulli G, Fattor B, Marchesi M. Cross-spectral analysis of cardiovascular variables in supine diabetic patients. Clin Auton Res.
2005;15(2):92-98.
33. Robertshaw HJ, Hall GM. Diabetes mellitus: anaesthetic management.
Anaesthesia. 2006;61(12):1187-1190.
34. Keyl C, Lemberger P, Palitzsch KD, Hochmuth K, Liebold A, Hobbhahn
J. Cardiovascular autonomic dysfunction and hemodynamic response
to anesthetic induction in patients with coronary artery disease and
diabetes mellitus. Anesth Analg. 1999;88(5):985-991.
35. Ciccarelli LL, Ford CM, Tsueda K. Autonomic neuropathy in a diabetic patient with renal failure. Anesthesiology. 1986;64(2):283-287.
36. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet. 1978;1(8054):14-16.
37. Sampson MJ, Wilson S, Karagiannis P, Edmonds M, Watkins PJ. Progression of diabetic autonomic neuropathy over a decade in insulindependent diabetics. Q J Med. 1990;75(278):635-646.
38. Tsueda K, Huang KC, Dumont SW, Wieman TJ, Thomas MH, Heine
MF. Cardiac sympathetic tone in anaesthetized diabetics. Can J
Anaesth. 1991;38(1):20-23.
39. Thomas AN, Pollard BJ. Renal transplantation and diabetic autonomic
neuropathy. Can J Anaesth. 1989;36(5):590-592.
40. Charlson ME, MacKenzie CR, Gold JP. Preoperative autonomic function abnormalities in patients with diabetes mellitus and patients with
hypertension. J Am Coll Surg. 1994;179(1):1-10.
AUTHORS
Ingrid Oakley, CRNA, DVM, was an assistant professor and the director of
admissions at the University of Alabama at Birmingham School of Nurse
Anesthesia, Birmingham, Alabama. Dr Oakley passed away in December
2010.
Lyne Emond, CRNA, MNA, is a graduate of the University of Alabama
at Birmingham School of Nurse Anesthesia. She is currently employed by
Capital Anesthesiology Association, Austin, Texas. Email: lemond70@
gmail.com.
AANA Journal

December 2011

Vol. 79, No. 6
479