Acta Anaesthesiol Scand 2011; 55: 797811

Printed in Singapore. All rights reserved

r 2011 The Authors

Acta Anaesthesiologica Scandinavica
r 2011 The Acta Anaesthesiologica Scandinavica Foundation
ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/j.1399-6576.2011.02466.x

Review Article

Heart rate variability: a diagnostic and prognostic tool in

anesthesia and intensive care
A. T. MAZZEO1, E. LA MONACA1, R. DI LEO2,3, G. VITA2 and L. B. SANTAMARIA1

Anaesthesia and NeuroIntensive Care Unit, 2Unit of Neurology and Neuromuscular Diseases, Department of Neurosciences, Psychiatry and
Anaesthesiology, University of Messina, Messina, Italy and 3Department of Neurorehabilitation, IRCCS San Camillo, Venice, Italy

The autonomic nervous system (ANS) plays an important

role in the human response to various internal and external
stimuli, which can modify homeostasis, and exerts a tight
control on essential functions such as circulation, respiration, thermoregulation and hormonal secretion. ANS dysfunction may complicate the perioperative course in the
surgical patient undergoing anesthesia, increasing morbidity and mortality, and, therefore, it should be considered as an additional risk factor during pre-operative
evaluation. Furthermore, ANS dysfunction may complicate the clinical course of critically ill patients admitted to
intensive care units, in the case of trauma, sepsis, neurologic disorders and cardiovascular diseases, and its occurrence adversely affects the outcome. In the care of these
patients, the assessment of autonomic function may provide useful information concerning pathophysiology, risk
stratification, early prognosis prediction and treatment
strategies. Given the role of ANS in the maintenance of
systemic homeostasis, anesthesiologists and intensivists
should recognize as critical the evaluation of ANS func-

autonomic nervous system (ANS) plays an

important role in the human organism. This
system, throughout its multiple connections with
vessel and visceral smooth muscles and with
endocrine and exocrine glands, regulates the response to various stimuli that modify homeostasis
and exerts a tight control on essential functions
such as circulation, respiration, thermoregulation
and hormonal secretion that are also influenced by
anesthesia.1,2
ANS function can also be affected by a critical
illness requiring intensive care unit (ICU) admission.35 The incidence of ANS dysfunction in the
surgical population and in the critically ill patients
is not exactly known, but it is clear that its occurrence adversely affects the outcome.4,68
Given the role of ANS in the maintenance of
systemic homeostasis, anesthesiologists and intensivists should recognize as critical in their clinical
HE

tion. Measurement of heart rate variability (HRV) is an

easily accessible window into autonomic activity. It is a
low-cost, non-invasive and simple to perform method
reflecting the balance of the ANS regulation of the heart
rate and offers the opportunity to detect the presence of
autonomic neuropathy complicating several illnesses. The
present review provides anesthesiologists and intensivists
with a comprehensive summary of the possible clinical
implications of HRV measurements, suggesting that autonomic dysfunction testing could potentially represent a
diagnostic and prognostic tool in the care of patients both
in the perioperative setting as well as in the critical care
arena.
Accepted for publication 27 April 2011

r 2011 The Authors

Acta Anaesthesiologica Scandinavica
r 2011 The Acta Anaesthesiologica Scandinavica Foundation

practice the evaluation of ANS function. Nevertheless, nowadays, the presence of ANS impairment is still rarely assessed, and its potential
implication for anesthesiological perioperative outcome is poorly considered in daily practice. This is
probably related to the limited availability of tests
exploring ANS in the anesthesiological routine and
to the lack of confidence with instruments generally considered in the domain of neurologists or
cardiologists.
The measurement of heart rate variability (HRV)
is a bedside, non-invasive, low-cost and simple to
perform method, requiring standard hospital
equipment and a dedicated software, which, by
reflecting the balance of the ANS regulation of
heart rate (HR), detects the presence of ANS dysfunction complicating several illnesses.912
The aim of this review is to define the possible
role of HRV measurement in the perioperative

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A. T. Mazzeo et al.

period and in the ICU setting. The potential use of

HRV testing to identify patients with ANS dysfunction, to stratify risk for cardiovascular complications in these patients and to guide appropriate
perioperative management will be discussed.

Cardiovascular tests investigating

autonomic function
The variation of HR with respiration, often known
as sinus arrhythmia, is generated by autonomic
reflexes and central autonomic influences. Inspiration increases HR and expiration decreases it. The
variation is primarily mediated by the vagus innervation of the heart. Pulmonary stretch receptors
as well as cardiac mechanoreceptors and possibly
baroreceptors contribute towards regulating the
HR variation.13 Central factors like the interactions
between cardiovascular centers and respiratory
centers at medullar levels also contribute to HR
modifications. In conclusion, respiratory sinus arrhythmia is a reflection of parasympathetic effects
on the sinus node, and the high-frequency (HF)
component of HRV coincides with the respiratory
frequency.
HRV measurements require ECG recordings
with equipment satisfying current industrial standards with high-quality ECG electrodes and minimizing artifacts and a dedicated software for
calculating HRV parameters. Some electromyography equipment might also be used for HRV. The
HRV recording equipment may also be part of a
multi-channel polygraphic device for the contemporaneous acquisition of cerebral electrical activity,
hemodynamic parameters such as beat-to-beat
blood pressure (BP), derived cardiac output and
baroreflex, breathing and plethysmography. However, the limits to the use of these devices are
adjunctive costs and dedicated trained staff.
Optimal autonomic evaluation conditions include a quiet environment, a temperature-controlled room, adequate skin preparation, resting
for almost 15 min, fasting and refraining from
smoking and consuming alcohol, caffeine or other
excitatory drugs.
Different factors can modify HR: hypoxia, exercise, temperature and ANS. HRV represents the
beat-to-beat oscillation of HR and can be measured
using different time domain and frequency domain methodologies. Standard measurements suggested by the Task Force of the European Society of
Cardiology and The North American Society of

798

Pacing Electrophysiology have been widely accepted.12 Measures of HRV in time domain are
resulting from sinus node depolarizations. The
standard deviation of normal RR intervals
(SDNN) is the root square of the variance mathematically equal to the total power of spectral
analysis; however, the total variance depends on
the length of recording: usually, 5-min recording
and 24-h recording appear to be equally appropriate.14 Other parameters recorded under the resting
condition in the time domain are the standard
deviation of the mean values for normal-to-normal
intervals over 5 min (SDANN), the square root of
the mean square differences of successive RR
intervals (RMSSD), the number of interval differences of successive NN intervals 450 ms (NN50)
and the proportion derived by dividing NN50 by
the total number of NN intervals (pNN50).12 Other
HRV parameters can be obtained under different
stimuli such as deep breathing, Valsalva maneuver,
hyperventilation and postural change.15
Frequency domain techniques using the fast
Fourier transform method applied to 5-min recording determine a spectrum with two major bands of
frequency: low frequency (LF) is the expression of
baroreceptor-mediated regulation and due to the
contribution of parasympathetic and mainly sympathetic discharge, and HF reflects the modulation
of vagus nerve discharge caused by respiration
(Fig. 1). They can be measured as milliseconds
per second squared (ms2) or normalized units.
Finally, the LF/HF ratio reflects sympathovagal
balance.16 Long-term recording allows to recognize
very low and ultra low frequencies too.
Recently, Nunan et al.,17 from over 3100 citations
for spectral analysis of HR obtained in normally
healthy individuals, found 44 papers only in agreement with Task Force recommendations. HRV
measures showed a wide variability between
healthy controls in the same study and, except for
a few studies, papers lacked specifying information
about the general state such as the diet and the
physical and mental condition of the subjects
considered as healthy controls. Citations were excluded because of long-term or non-traditional
measures considered, an exiguous sample size (i.e.
o30) or unhealthy subjects. In fact, it is widely
accepted that each laboratory must calculate their
own age-adjusted normal values.18 This also holds
true for other HRV parameters that can be obtained
under different stimuli such as deep breathing,
Valsalva maneuver, hyperventilation and postural
change.15

Heart rate variability and anesthesiologist

Fig. 1. (A) Heart rate, tachogram and blood
pressure recordings
by Light6 system
s
(SPARKBIO , Bologna, Italy) in a normal
individual (above) and in a patient with
autonomic dysfunction (below) during quiet
breathing. Note heart rate and blood
pressure variability present in healthy
subject and absent in the patient. (B) Power
spectral analysis of a sequence of 500 RR
intervals estimated using the autoregressive
modeling technique, providing a
low-frequency (LF) band in the range
0.030.15 Hz and a high-frequency (HF)
band in the range 0.150.33 Hz in a normal
individual (above) and in a patient with
autonomic dysfunction (below) during quiet
breathing. Note the absence of the LF band
in the patient.

B
A

BP regulation involves peripheral receptors and

afferences, nervous system centers, autonomic cardiovascular nerve fibers, end-organ behavior and
humoral factors. BP responses to various stimuli
such as standing, sustained handgrip, mental stress
and cold pressure allow to evaluate the integrity of
the neural arc to the cardiovascular system.15 As
for HR, BP variability can be studied in time and in
the frequency domain.19

ANS, HRV and anesthesia

One-third of all post-operative complications and
more than half of the deaths are due to cardiac
complications,6 which represent a major perioperative threat even in an apparently minor surgery. A
strong correlation exists between ANS dysfunction
and life-threatening perioperative complications,
including sudden cardiac death; thus, ANS dysfunction representing a serious source of anesthesiologic risk affects the final outcome of patients
undergoing surgery.2,6,9,10,2025 Several cardiovascular variables, such as HR, BP and stroke volume,
all undergo beat-to-beat fluctuations that can be
measured, analyzed and related to clinical events.
The literature reports that HRV measurement
is a promising method to pre-operatively investigate the integrity of ANS and that it can independently predict post-operative short- and long-term
morbidity and mortality mainly for cardiac
events, allowing for pre-operative risk stratification.6,21,24,2630
The main objective of ANS is the maintenance of
cardiovascular, respiratory, metabolic and thermal
homeostasis, representing the primary defense

0.1

0.2
0.3
Frequency (Hz)

0.4

0.5

0.1

0.2
0.3
Frequency (Hz)

0.4

0.5

against any internal or external factor jeopardizing

systemic homeostasis.1 Autonomic denervation impairs the physiologic cardiocirculatory and respiratory responses to surgical stress (i.e. HR, BP and
cardiac output increase, bronchodilation) and predisposes to adverse events.
Cardiovascular events are the most commonly
observed and consist of hypotension not responding to vasopressors, severe hypertensive response
to endotracheal intubation, bradycardia, arrythmias, prolonged myocardial ischemia, increased
incidence of myocardial infarction (MI) and sudden death, cardiac arrest, altered response to atropine and ephedrine administration.24,2936
It has been demonstrated that diabetic patients
with autonomic neuropathy had an increased risk
of hemodynamic instability and cardiovascular
collapse in the perioperative period.31 More recently, it was observed that even when controlling
for age, history of diabetes mellitus, American
Society of Anesthesiologists physical status class and
other indices of autonomic function, the total HRV
power independently predicted the incidence of
hypotension during general anesthesia: it was also
demonstrated that LF, HF and total HRV were
significantly lower in patients who required intraoperative vasopressors compared with those who
did not.24
The possibility to predict hypotension in patients
with ANS dysfunction has also been investigated
during spinal anesthesia.23,37,22 It was demonstrated that the LF/HF ratio correlated strongly
with BP decrease, and that an LF/HF ratio of 2.5
could be a cut-off value for the prediction of
hypotension.37 This information, obtained pre-operatively, can guide the pre-emptive treatment of

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hypotension secondary to spinal anesthesia, especially during elective cesarean delivery.37

Recently, it was demonstrated that patients
with an increased HF component of HRV before
spinal anesthesia developed severe bradycardia
following sympathetic blockade, suggesting that
pre-operative determination of the balance between sympathetic and parasympathetic tone
might provide a useful tool to detect patients at
risk for severe hemodynamic impairment during
spinal anesthesia.30
ANS dysfunction also plays a significant role in
the pathophysiology of perioperative ischemia, by
altering the relationship between myocardial oxygen demand and supply, throughout an increase of
adrenergic activity and plasma catecholamine levels typical of the post-operative period. Impaired
HRV is a strong predictor for prolonged postoperative myocardial ischemia, as shown in elderly
patients undergoing hip surgery.35 Among various
HRV measures, the short-term fractal scaling exponent a1 is especially important in risk stratification. Pre-operative a1 was significantly lower
during the nighttime compared with the daytime
in patients with post-operative prolonged myocardial ischemia and the nightday difference of a1
was significantly associated with post-operative
ischemia.35 As the above-described alterations in
HRV can occur several hours before adverse cardiac events, this allows for the early identification
of potentially harmful events at the time where
patients can receive early treatment.6
Furthermore, in a prospective study in cardiacrisk patients undergoing major non-cardiac surgery, a reduced LF/HF ratio before the induction
of anesthesia and elevated cardiac Troponin I
post-operatively were identified as independent
and powerful predictors of 1-year mortality. In
particular, an LF/HF ratio o2 in the baseline
measurement was strongly associated with death
after 1 year.21
Apart from cardiovascular events, other system
functions also need to be considered in patients
with ANS dysfunction. Respiratory complications
in patients with dysautonomia can be the effect
of a reduction of airways vagal tone, a decreased
bronchodilator effect of anticolinergic drugs38 and
a diminished ventilatory response to hypoxia
and hypercapnia probably caused by dysfunction
of aortic and carotid sinus mechanoceptors
transmission.32
Bronchoaspiration and the risk of aspiration
pneumonia are also frequent, as well as an altera-

800

tion of the thermoregulatory response during the

perioperative period, with an increased risk of
accidental hypothermia.39
Cerebral blood flow autoregulation may also be
affected because of an ineffective neurogenic control on cerebral vessels.40

Perioperative anesthesiological considerations in

patients with ANS dysfunction
Pre-operative period. Clinical symptoms of autonomic neuropathy, as illustrated in Table 1, should
be investigated and ANS dysfunction with an
altered sympathovagal balance should be noticed
as any other organs insufficiency. Nevertheless,
the diagnosis of autonomic dysfunction cannot
only rely on clinical symptoms, which are often
aspecific, and have to be confirmed by specific
tests, among whom cardiovascular reflex tests are
used the most.41
Diabetes mellitus, hypertension and aging are
the clinical conditions most frequently affecting a
surgical population and, moreover, are recognized
risk factors for autonomic neuropathy. Furthermore, ANS function can be altered in several other
conditions or diseases, as illustrated in Table 2.
Diabetic autonomic neuropathy (DAN) is the
most common form of autonomic neuropathy,
occurring in 2040% of patients and increasing
morbidity and mortality risk.42 DAN is responsible
for abnormalities in HR control and vascular dynamics, potentially ranging from silent myocardial
ischemia to MI, heart failure or sudden death.
Vasopressor support is needed more often in diabetic individuals with cardiac autonomic neuropathy than in those without autonomic neuropathy.
The normal autonomic response of vasoconstriction and tachycardia does not completely compensate for the vasodilating effects of anesthesia and
an impaired hypoxic-induced ventilatory drive has
also been reported.43
Table 1
Clinical symptoms of autonomic neuropathy to be investigated
during pre-operative anesthesiological evaluation.
Cardiovascular: tachycardia at rest, intolerance to exercise,
orthostatic hypotension, sustained supine hypertension, silent
myocardial ischemia
Gastrointestinal: esophageal dismotility, constipation, diarrhea,
fecal incontinence, gastroparesis
Genito-urinary: neurologic bladder, erectile dysfunction,
retrograd ejaculation
Others: anhidrosis, heat intolerance, dry skin, gustatory
sweating

Heart rate variability and anesthesiologist

Table 2
Principal causes of autonomic nervous system dysfunction.
Degenerative disorders
Pure autonomic failure (PAF)
Multiple system atrophy (MSA)
Parkinsons disease
Acute and subacute diseases
Immune autonomic neuropathies (parasympathetic,
sympathetic, mixed)
Heart failure, myocardial infarction
Severe brain injury
Spinal cord injuries and myelopathies
GuillainBarre syndrome
Paraneoplastic neuropathies
Botulism
Drug-induced neuropathies
Toxic neuropathies (heavy metals, organic solvents, acrylamide,
organo-phosphorics, etc.)
Porphyria
Chronic diseases
Diabetes mellitus
Hypertension
Idiopathic orthostatic hypotension
Intracranial tumors with increased intracranial pressure
Hereditary neuropathies [RileyDay syndrome; Hereditary
Sensory Autonomic Neuropathy (HSAN) type I, II, III; CharcotMarie-Tooth]
Dopamine beta-hydroxylase deficiency
Uremia
Chronic alcoholism
Liver disease
Chronic pulmonary diseases
Amyloidosis
Infective neuropathies (i.e. leprosy, human immunodeficiency
virus, Chagas disease, diphtheria)
Chronic immune demyelinating polyneuropathies
Connective tissue diseases (reumathoid arthritis, systemic
Lupus erythematosus, Sjogren syndrome)
Others
Use of drugs acting on the autonomic nervous system
Cardiac transplant

Essential and secondary hypertension is another

common medical condition associated with altered
cardiovascular autonomic function. It has been
hypothesized that in essential hypertension, an
increased sympathetic and reduced vagal cardiac
drive are coupled with an enhancement of vasomotor sympathetic modulation. The severity of
essential hypertension is usually related to the
severity of impairment of cardiac autonomic control as measured by HRV.44
The effects of age on HRV should also be considered. Advanced age is responsible for increased
incidence of cardiovascular disorders and is primarily associated with an impairment of norepinephrine reuptake, a reduced baroreceptor
responsiveness, reduced HRV at rest and after
deep breathing. HRV declines linearly with age45
47,18
and orthostatic hypotension is a frequent

clinical manifestation in aging as well as reduced

HR response to changes in BP.2
A better understanding of the resting pre-operative ANS condition and performance capabilities
could help anesthesiologists predict undesirable
circulatory events29 and, furthermore, it could
help identify patients with the need for further
pre-operative cardiac testing.21
Finally, HRV measurement is a complement
allowing clinicians to guide premedication. The
potential use of b-adrenergic blockade, for its
recognized protective effects on the heart, by increasing HRV and vagal tone, thus decreasing the
incidence of post-operative myocardial ischemia
and death, should be considered in patients at a
high risk for myocardial ischemia.48 As an example, in diabetic patients with cardiac autonomic
neuropathy showing a decreased HRV on a preoperative measurement, the need to add new
medications, such as b-blockers, could be considered, and the treatment should be individualized
and titrated according to other comorbidities.49
Intraoperative period. During the intraoperative period, careful attention should be paid to prevent
possible cardiovascular events in patients with
ANS dysfunction, occurring more commonly during the induction of general anesthesia due to the
lack of a compensatory response to the hemodynamic effect of anesthetics or during the intraoperative phase due to events such as liquid loss,
surgical stimulation or changes in patient position.36,26 Respiratory issues, prevention of gastrointestinal reflux and careful attention to prevent
temperature loss should also be addressed.
The analysis of HRV can complement the reasoning for invasive monitoring and may hopefully
guide preventive strategies for risk reduction.50,51,26 In particular, autonomic monitoring
could provide a supplementary objective assessment to evaluate the impact of intervention on
autonomic tone.27 It could help in guiding intravascular volume loading and to tailor appropriate
pressure response and inotropic support.27
The knowledge of ANS dysfunction may provide an opportunity to guide prophylactic therapy
with either volume pre-hydration or a vasopressor
infusion and may significantly decrease the risk
of spinal hypotension.37 As in pregnant women,
HRV-derived variables are able to predict hypotension after spinal anesthesia,23,52 pre-operative
determination of the ANS regulation may provide
an opportunity to avoid, intraoperatively, the

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deleterious effects of hypotension, guiding adequate measures of prevention.37 A role for HRV
in assessing the sympathoexcitatory response to
changes in volemic status, which are common
intraoperative events,53 has also been demonstrated. In healthy blood donors, non-hypotensive
blood donation led to a significant increase in
plasma norepinephrine levels and a significant
decline of the vagally modulated HF HRV, indicating an overall shift of the autonomic balance
toward decreased parasympathetic and increased
sympathetic control.53
HRV analysis has also been positively evaluated,
as a means to better quantify patients intraoperative stress response during procedures in which
collaboration of the patient is required, as during
asleepawake craniotomy,54 and in which the increase in sympathetic tone over the parasympathetic component (increase in LF/HF ratio) may
jeopardize cardiovascular homeostasis.
Conversely, investigation of HRV as a method of
monitoring the depth of anesthesia, assessing the
response to painful stimuli, did not yield uniform
results5557 and needs more extensive investigations.
Post-operative period. The post-operative period is a
period of increased cardiovascular and respiratory
risk, and appropriate care is needed for all patients
in particular with ANS dysfunction.58 As prolonged
ischemia is a predictor of post-operative death and
MI in surgical patients, the pre-operative study of
HRV, helping to recognize high-risk patients, could
allow for a more careful clinical and instrumental
monitoring during the post-operative period.
Decreased HRV is recognized to be a more
powerful predictor for cardiovascular mortality
than established clinical predictors, such as left
ventricular ejection fraction (LVEF) and ventricular
premature complexes.6 Therefore, for patients admitted to ICU, the assessment of ANS function
could be continued, also allowing for a better guide
of cardiovascular management.27
In a large study evaluating the value of prognostic factors in the prediction of the risk of perioperative cardiac events after vascular surgery, on
multivariate analysis, increased age, previous MI,
aortic surgery, impaired HRV and a positive thallium scan were independent predictors of cardiac
death or non-fatal MI within 30 days of surgery.59
Decreased HRV was also an independent predictor
of prolonged hospitalization in patients undergoing
abdominal aortic surgery and could predict postsurgical resource utilization.60,61

802

Interference of anesthetic drugs on ANS function

It is important to consider that anesthetics can
affect, per se, ANS function and HRV measurements during both general and spinal anesthesia.
During general anesthesia, both LF and HF
oscillations are suppressed and different behaviors
have been recorded depending on the agents or the
combination of agents used and on the depth of
anesthesia.56,6264
In general, HR increases and is associated with a
decrease in HRV during inhalational anesthesia. A
corresponding decrease in SDNN, HF and LF
power has also been demonstrated.65 HRV is substantially reduced, by about 80%, with the loss of
consciousness, and further decreased at a  2
minimum alveolar concentration.65 The indices of
cardiac vagal activity (HRV and HF power) decrease with the depth of anesthesia, and agentspecific differences in the strength of the vagolytic
action have been observed.65
The induction of anesthesia with propofol was
associated with a significant decrease in BP and HF
proportional to the depth of anesthesia, with no
effects on HR or LF, indicating that the cardiac
parasympathetic nerve was inhibited to a higher
degree than sympathetic nerve. Conversely, inhalation of sevoflurane was associated with a
decrease in BP or LF, independent of anesthesia
depth, with little or no effect on the cardiac parasympathetic tone.56
Other studies demonstrated that thiopental reduced HF power, and increased LF power and the
LF/HF ratio, suggesting that the vagolytic effect is
associated with an increase in sympathetic activity.64 Midazolam reduces HRV in a dose-dependent
manner, according to the Ramsay score of sedation.66 Furthermore, a significant reduction in HF
power with midazolam or diazepam compared
with non-premedicated patients has been described, with midazolam showing a larger effect
than lorazepam and diazepam.67
Opioids predominantly reduce LF power, reflecting an increased parasympathetic tone.68,69 Remifentanil induces RR interval lengthening and an
increase of HF, not prevented by atropine administration.70 In healthy volunteers, it was recently
observed that low-dose fentanyl administration led
to sympathetic withdrawal, with a trend toward
vagal activation and ANS modulation decrease, so
that patients undergoing general anesthesia with
fentanyl could be exposed to vagal stimuli during
surgery and to hypotension without the possibility
of a sympathetic cardiac modulation response.71

Heart rate variability and anesthesiologist

The study of effect of spinal anesthesia on ANS

function demonstrated a significant decrease of the
LF/HF ratio.22
Cervical epidural anesthesia produces a significant decrease in HF and LF power without significantly altering the LF/HF ratio, whereas
lumbar epidural resulted in a minimal cardiac
autonomic effect, with a slight but significant
increase in the LF/HF ratio and HR, suggesting
sympathetic predominance.72
Larger and more focused clinical investigations
are needed to better elucidate the real impact of
anesthetic techniques on the perioperative course of
patients with ANS dysfunction, allowing to tailor
the anesthesiological approach based on a specific
population of patients and kind of procedures.

Interference of pre-operative cardiovascular

medications on ANS function
Important information that should be obtained
before HRV measurement relates to the use of
medications, which can affect ANS activity. Antihypertensives, diuretics, adrenergic blockers, Ca21
channel blockers, angiotensin-converting enzyme
inhibitors, phenothiazines, tricyclics and nitrates
are among the pharmacological agents that can
interfere with cardiovascular tests of autonomic
functions, amplifying or reducing responses.49,7375
Although the interference of a drug in cardiovascular tests is not easily predictable in any given patient,
diuretics, sympatholytic agents and tricyclic antidepressants should be considered the most interfering
drugs, in that they may yield false-positive responses
mainly in the orthostatic tests.49 It is possible that the
effects of spironolactone may be disease specific.
Acute administration of spironolactone has been
shown to improve HRV and baroreflex sensitivity
in healthy subjects and in patients with congestive
heart failure, but not in diabetics.49,73 Among calcium-channel blockers, verapamil increases HRV
due to a suppressive effect on the sympathetic outflow of catecholamines, but may not have a beneficial effect on HRV in diabetic subjects.49,73

How to set up a pre-operative HRV

study in the anesthesiological
workplace
In an ideal setting, a pre-operative HRV measurement should be performed to evaluate perioperative risk in patients with known ANS dysfunction

or in patients with suspected dysautonomia undergoing high-risk procedures. As an example, in

diabetic patients with a history of poor glycemic
control, high cardiovascular risk and microangiopathic complications, especially when planning
major surgical procedures, tests for ANS are highly
advised.49
We suggest to perform a thorough pre-operative
anesthesiological evaluation at least 2 weeks before
elective surgery. High-risk patients should be referred to a formal neurologist or cardiologist consultation (depending on the individual hospital
organization), with the aim to confirm the diagnosis and evaluate the severity of ANS impairment.
The adequacy of drug treatment should be evaluated and appropriate adjustment, if needed, should
be proposed. Competent perioperative monitoring
and the need for post-operative intensive care in
the most severely compromised patients should be
discussed and planned between the anesthesiologist, the neurologist and the cardiologist. A patient
information sheet with detailed instructions on the
tests and relevant risks associated with ANS dysfunction should be provided.49 In patients with
presumable HR or BP circadian alterations, HR
and/or BP 24-h monitoring might be needed.
Although HRV measurements can appear complex to the anesthesiologist, and require specific
expertise, the availability of computer-assisted systems has allowed a wider diffusion of these tests
into the clinical evaluation of patients. Adequate
knowledge of the physiopathological background
and the physiological and pathophysiological
confounding factors of cardiovascular tests is mandatory. Interestingly, recent evidence shows comparable reproducibility for autonomic function
assessments performed under standardized and
non-standardized conditions, suggesting that autonomic function tests may be viably performed in
settings such as the pre-operative assessment clinic,
where standardized conditions are difficult to reproduce, and suggesting that the implementation
of these tests during a pre-operative assessment
may be feasible.76

ANS, HRV and intensive care

An autonomic dysfunction is frequently seen in
disorders requiring ICU admission.35 In the care
of these patients, the assessment of the autonomic
function may provide information concerning
pathophysiology, disease severity, response to treat-

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A. T. Mazzeo et al.

ment and prognosis. In particular, the hypothesis

that depressed HRV may occur over a broad range
of critical illnesses and injuries and may be inversely correlated with disease severity and outcome
has been investigated more in depth, indicating that
power spectral analysis of HR signals may be used
as a complementary prognostic tool for outcome
prediction in the ICU.7779,4 In fact, the loss of HRV
in critical illness reflects decomplexification of the
human physiology because connections among
cells, organs and tissues are uncoupled and this is
proportional to the severity of critical illness; the
recovery of HRV can be transiently associated with
clinical improvement and survival.8 Evidences supporting potential indications for HRV measurement
in the care of a specific population of critically ill
patients are summarized herein.

Neurologic disorders
Severe brain injury and neurosurgical critically ill patients.

ANS control of HR is disrupted proportional to the

degree of neurologic insult after acute brain injury,
both in children and in adults.80,81
Low HRV has been demonstrated to be associated with episodes of increased intracranial pressure (ICP) and decreased cerebral perfusion
pressure (CPP), and with increased mortality and
disability.82 In particular, an ICP430 mmHg or a
CPPo40 mmHg may be associated with marked
autonomic dysfunction and poor outcome.82
Changes in HRV may precede changes in ICP,
and both increases in ICP and cardiac uncoupling
(low HRV) predict mortality.83 Therefore, HRV
monitoring could allow for an early detection and
treatment of the negative evolution of intracranial
diseases.
The LF/HF ratio may also allow identifying
patients who will progress to brain death and
could be used as a confirmatory test in this diagnosis as it immediately identifies the loss in the
spectral power of HR occurring during the transition to brain death.84
Autonomic dysfunction in neurosurgical patients with extradural, subdural or intracerebral
hematoma and especially subarachnoid hemorrhage is a recognized factor responsible for
neurogenic cardiomyopathy and can affect the
perioperative and ICU course.8588 In neurosurgical
critically ill patients, it has also been reported that a
reduction in the total power variability of RR
interval and a lowered LF/HF ratio of the RR

804

interval are associated with a poor-quality recovery

or death.89
Spinal cord injuries (SCI). Complete cord transection
is recognized among diseases leading to the most
severe alterations in ANS function. Various degrees
of autonomic dysfunction occur depending on the
site, extent and timing of the lesion,90 with profound alterations in cardiovascular, gastrointestinal, thermoregulatory and urinary systems, and
HRV is a reproducible measure to evaluate cardiovascular autonomic function in these patients.91 A
decreased LF HRV has been observed in cervical
SCI subjects at rest, reflecting reduced cardiac
sympathetic control. Combined with the reduced
LF/HF ratio, this suggests parasympathetic predominance after cervical SCI and is compatible with
the slower HRs.90 Conversely, in dorsal spine cord
lesions, a decrease in HF power and an increase of
sympathetic drive, determining high HR on standing, were found.90
Patients with SCI are prone to orthostatic intolerance and have an increased risk of cardiovascular
diseases. They may fail to respond to hypovolemia
with an increased HR and may, conversely, present
bradycardia.92
Guillain-Barre syndrome (GBS) and multiple sclerosis
(MS). Autonomic dysfunction is a frequent and

severe complication of GBS; in the affected patients, the sympathovagal balance is shifted to
sympathetic predominance at the height of the
disease.93,94 ANS dysfunction is often responsible
for cardiovascular abnormalities such as sinus
tachycardia, arrhythmias, even cardiac arrest, BP
instability, sustained hypertension or hypotension.95,96 Sweating abnormalities, gastrointestinal
or urogenital symptoms, neurogenic stunned
myocardium and intrapulmonary shunts have
also been reported.96 The 24-h HR power spectrum
may yield sensitive and specific markers for
assessing the risk of impending and potentially
life-threatening arrhythmias.93 The slope of the
power-law regression line was the best discriminator for vagal overreactivity and might indicate fatal
arrhythmias in GBS patients. The slope of the
regression line ranged from 0.66 to 2.18, and
was significantly steeper in patients with tachycardia than in those with vagal overreactivity who are
suspected to be at risk for fatal arrhythmias.93
In patients affected by MS, cardiovascular autonomic dysfunction is usually less common than in
GBS; it may be present in half of the cases and

Heart rate variability and anesthesiologist

could be easily detected by routine measurements

of HR and BP during rest and during standing.97 It
seems that interactions between the sympathetic
nervous system and the immune system exist,
giving rise to the hypothesis that autonomic dysfunction in MS may be a consequence of the disease
and affects its course.98 It has been observed that
patients with relapsingremitting MS (RRMS) had
significantly lower HRV variables, except the LF/
HF ratio, than healthy controls. RRMS patients
with lesser duration of disease had higher HRV
parameters, except the LF/HF ratio, compared
with RRMS patients with more than 5 years from
the diagnosis of MS. Furthermore, it seems that the
LF/HF ratio correctly presents sympathovagal balance in healthy subjects, whereas the LF/HF ratio
is useless in patients with seriously decreased
overall HRV and sympathetic overactivity.99
The literature supports the
use of HRV measurement in the care of patients
with acute stroke, for the possibility of transient
dysfunction of ANS in the acute phase of the
disease.100 Abnormal HR dynamics have been
identified as a prognostic marker for post-stroke
mortality.101103 All the measured components of
HRV (total power, VLF power, LF power, HF
power) were significantly lower than those of the
control subjects in both the acute phase after
infarction and at 1 and 6 months. Furthermore,
the low level correlated with the severity of the
neurological deficits and disability.101
In particular, it was demonstrated that the involvement of the insular cortex, the occurrence of a
pathologic night-time BP increase and an initially
increased serum norepinephrine concentration are
independent predictors of poor long-term outcome
after acute thromboembolic stroke.104
Acute ischemic stroke.

Therapeutic hypothermia in comatose survivors of cardiac

arrest. HRV is reduced in patients resuscitated

from a sudden cardiac arrest, with reduced lowand high-frequency spectral power.105
In a study evaluating the effect of mild 24-h
therapeutic hypothermia in comatose survivors of
cardiac arrest, it was observed that hypothermia
resulted in higher measures of HRV in the 024-h
recording, suggesting preserved autonomic modulation of the heart and a favorable effect of
hypothermia on outcome.106 The increased HRV
during hypothermia may be a physiologic phenomenon related to bradycardia, a true temperature-induced change in ANS activity, or it might

reflect a beneficial effect on myocardial function

during hypothermia or, lastly, it might be related to
neuroprotection induced by hypothermia. Whether
the mechanism of action behind preserved HRV is
the neuroprotective effect of hypothermia, the direct effect on HR or both is uncertain and should be
confirmed in larger studies.106107

Cardiovascular disorders
MI, malignant cardiac arrhythmias and sudden coronary
death. After acute MI, several abnormalities of the

autonomic control to the heart have been described

and HRV has been used to explore the neural
control to the heart. A general consensus of a
practical use of HRV in acute MI has been reached
since a long time, and depressed HRV indicates an
increased risk of malignant arrhythmias and
death.108110,12 A low HRV measured 713 days
after acute MI is significantly associated with
poor outcome and may be due to reduced vagal
and/or increased sympathetic outflow to the
heart.111
For the prediction of overall mortality, the value
of HRV is similar to that of LVEF; however, HRV is
superior to LVEF in predicting arrhythmic events
like ventricular tachycardia and sudden cardiac
arrest.112
There is a general consensus that HRV should be
measured approximately 12 days after the onset of
pain.113 Although HRV assessed from short-term
recordings provides prognostic information and
can be used for the initial screening of survivors
of acute MI,114 HRV measured in 24-h recordings is
the stronger risk predictor.115

Sepsis, multiple organ dysfunction and

septic shock
An autonomic dysfunction has been reported in
patients with sepsis, and its severity related to morbidity and mortality and has been recognized as a
contributive factor facilitating the development of
multiple organ dysfunction syndrome (MODS).116,117
Sepsis is associated with loss of variability in all
measures of HRV and the altered measurement can
be useful for early detection of the syndrome.118,119
A recent study investigating the possible association between different HRV indices and biomarkers
of inflammation in septic patients demonstrated
that a decrease in HRV and sympathovagal balance
during septic shock is associated with increa-

805

A. T. Mazzeo et al.

sed hyperinflammatory and anti-inflammatory

responses.120,121
Considering the interference of the mediators
and toxins with the cardiac cellular signal transduction, blunted or dysfunctional cellular responses may contribute to an increased or a
decreased reflex response of the target organ or
the central nervous system, leading to an impairment of the autonomic balance.3
HRV measurement can be considered, therefore,
a valid method to characterize autonomic function
and cardiorespiratory interactions in MODS patients3,118 and it may also have prognostic value;119
it has been shown that a reduction of the LF/HF
ratio inversely correlates with the sepsis-related
organ failure assessment score and predicts a clinical deterioration of septic patients.122,117 Also, the
APACHE II score correlates negatively with LF.123
Altered sympathetic modulation of cardiac activity may be an early marker for impending septic
shock also in the emergency department.122,124 The
suppression of HRV observed before the onset of
septic shock suggests that a collapse of homeostasis
is closely associated with a poor outcome.118,119,125

Severe trauma
In severely injured patients, a role for HRV has
been proposed, for remote non-invasive triage of
casualties when the Glasgow Coma Scale or other
score systems are unattainable because of factors
affecting their reliability.126 A reduced HRV in the
first 24 h of ICU admission can be an early predictor of morbidity and mortality, and it may also
reveal patterns of injury and heralds complications.127 In a large study on 2088 trauma patients,
it was demonstrated that the risk of mortality
increases with the increase in cardiac uncoupling,
which in turn increases in response to inflammation, infection and multiple organ failure and,
thereby, it is an independent cause of death, with
a predictive window of 24 days.128

Clostridial infections
Tetanus. Tetanus is recognized as a disease commonly associated with ANS disturbances, which
are responsible for life-threatening complications.
ANS dysfunction is manifested by a wide variation
in BP, ranging from hypotension to severe hypertensive crisis, cardiac dysrhythmias, tachycardia,
diaphoresis and hyperpyrexia. Spectral analysis of
HRV is able to reveal decreased activity of both

806

sympathetic and parasympathetic modulation of

cardiac rhythm.129131
Botulism. In small case series, dysautonomia, measured by recording HRV, has been detected during
infantile botulism, and persisted for many weeks
beyond the observable physical recovery of the
disease. The authors underlined the importance of
close cardiopulmonary monitoring following apparent functional recovery from the botulism neurotoxin, to avoid possible complications related to
autonomic dysfunction, such as syncope, arising
from ventricular arrhythmia, or sudden death.132133

Limiting factors for optimal HRV

measurement in perioperative and ICU
settings
In the perioperative period, several factors may
affect HRV measurement such as body and environment temperature, body position, volemic status, respiratory rate and tidal volume, depth of
anesthesia and maneuvers stressing the ANS such
as orotracheal intubation.134136,62 The known interactions between different anesthetic drugs and
HRV measurement need to be adequately considered during the intraoperative phase, as well as the
influence of anesthetic premedication69 and the
pre-operative use of drugs acting directly or indirectly on cardiac cronotropism and inotropism, or
on vessel tone.
In the ICU setting, besides concomitant diseases
affecting ANS, various factors interfering with
ANS should be considered: nursing maneuvers,
ambient noise, sedationanalgesia protocols, environments temperature, ventilatory settings, respiratory patterns, invasive monitoring and critical
illness per se.134138,66,49 Furthermore, the multidrug therapy of ICU patients can interfere with
ANS function, and consequently with autonomic
function tests.49
Cardiovascular autonomic reflex tests are well
standardized and reproducible tests performed in
the time domain, suitable for diagnosis, grading
and follow-up of cardiovascular autonomic dysfunction. There is no best method, but all methods
are complementary and a battery of three to six
tests is suggested, such as active standing, deep
breathing, Valsalva maneuver, sustained handgrip,
etc.139 Although these tests are very helpful in
routine clinical practice, they have been criticized
as being dependent on the patients cooperation

Heart rate variability and anesthesiologist

and of little use in the investigation of the sympathetic pathway. Several studies have then provided
evidence that specific HR power spectral analysis
components, revealed in a frequency domain investigation, may better reflect autonomic cardiovascular influences.140 Short-term recordings (2
5 min) yield VLF, LF and HF, whereas long-term
recordings allow the detection of ultralow frequencies that have not been well defined to date. On the
other hand, the influence of circadian rhythm and
uncontrolled recording settings may adversely
affect long-term recordings. Recently, Pinna
et al.141 tested the reliability of some HRV measures. They found that HRV parameters presented
large random variations within subjects showing
low absolute reliability and at the same time good
relative reliability. The high variability might be
due to an intrinsic liability of HRV parameters
related to some mood or breathing modifications
hardly verifiable. An expertise in performing and
interpreting the results is required.141

Conclusions
In the pre-operative period, the measurement of
HRV can be used as a helpful, non-invasive, bedside, low-cost monitoring tool to evaluate the
perioperative risk in patients with suspected autonomic dysfunction, to select individuals who need
further cardiac testing and to optimize pre-operative status.
The literature supports a role for HRV monitoring for early prognosis prediction and risk stratification in the critically ill patient, the reduction in
HRV generally being associated with the severity
of the illness and the restoration of HRV being
associated with recovery. HRV analysis may provide additional diagnostic and prognostic information within the context of multiple confounding
factors associated with critical illness.
An attractive area of research is the use of HRV
measurements to explore the role of ANS alterations in disease mechanisms, to enhance our understanding of pathophysiological phenomena and to
study the actions of specific medications in pharmacological studies.
Clinical benefit will become evident with increasing familiarity with this monitoring tool,
which will provide anesthesiologists with indexes
that could be used to guide a therapeutic intervention. A high-risk population will be the initial
beneficiary of HRV monitoring, and future studies

could help to determine which patient populations

more than others should be monitored for HRV
analysis in the perioperative and ICU setting.

Acknowledgements
This work was supported by the research fund of University of
Messina (ORME07Z49S).
The authors have no conflict of interest.

References
1. Matkabi MA. Basic and pharmacology of the autonomic
nervous system. In: Rogers MC, Tinker JH, Covino BG,
Longnecker DE, eds. Principle and practice of anesthesiology. St Louis: Mosby Year Book, 1993:14716.
2. Ebert TJ. Preoperative evalutation of the autonomic nervous system. In: Stoelting R, Barash P, Gallagher T., eds.
Advances in anesthesia. Chicago: Mosby Year Book,
1993:4968.
3. Schmidt HB, Werdan K, Muller-Werdan U. Autonomic
dysfunction in the ICU patient. Curr Opin Crit Care 2001;
7: 31422.
4. Gang Y, Malik M. Heart rate variability in critical care
medicine. Curr Opin Crit Care 2002; 8: 3715.
5. Goldstein B, Ellenby MS. Heart rate variability and critical
illness: potential and problems. Crit Care Med 2000; 28:
393940.
6. Laitio T, Jalonen J, Kuusela T, Scheinin H. The role of heart
rate variability in risk stratification for adverse postoperative cardiac events. Anesth Analg 2007; 105: 154860.
7. Ushiyama T, Nakatsu T, Yamane S, Tokutake H, Wakabayashi H, Ishimura K, Maeta H. Heart rate variability for
evaluating surgical stress and development of postoperative complications. Clin Exp Hypertens 2008; 30: 4555.
8. Goldstein B, Fiser DH, Kelly MM, Mickelsen D, Ruttimann
U, Pollack MM. Decomplexification in critical illness and
injury: relationship between heart rate variability, severity
of illness, and outcome. Crit Care Med 1998; 26: 3527.
9. Fan SZ, Cheng YJ, Liu CC. Heart rate variabilitya useful
non-invasive tool in anesthesia. Acta Anaesthesiol Sin 1994;
32: 516.
10. Baumert JH, Frey AW. Analysis of heart rate variability.
Background, method, and possible use in anesthesia.
Anaesthesist 1995; 44: 67786.
11. Ewing DJ, Martin CN, Young RJ, Clarke BF. The value of
cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8: 4918.
12. Task Force of the European Society of Cardiology and the
North American Society of Pacing and Electrophysiology.
Heart rate variability: standards of measurement, physiologic interpretation and clinical use. Circulation 1996; 93:
104365.
13. Ravits JM. AAEM minimonograph#48: autonomic nervous
system testing. Muscle Nerve 1997; 20: 91937.
14. Schroeder EB, Whitsel EA, Evans GW, Prineas RJ, Chambless LE, Heiss G. Repeatability of heart rate variability
measures. J Electrocardiol 2004; 37: 16372.
15. Mathias CJ, Bannister R. Investigation of autonomic disorders. In: Mathias CJ, Bannister R, eds. Autonomic failure:
a textbook of clinical disorders of the autonomic nervous
system. Oxford: Oxford University Press, 1999:16995.

807

A. T. Mazzeo et al.
16. Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of
autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol
2008; 51: 172533.
17. Nunan D, Sandercock GR, Brodie DA. A quantitative
systematic review of normal values for short-term heart
rate variability in healthy adults. Pacing Clin Electrophysiol 2010; 33: 140717.
18. Vita G, Princi P, Calabro R, Toscano A, Manna L, Messina C.
Cardiovascular reflex tests. Assessment of age-adjusted
normal range. J Neurol Sci 1986; 75: 26374.
19. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain.
Circulation 1991; 84: 48292.
20. Santamaria LB. La neuropatia autonomica come fattore di
rischio anestesiologico. Minerva Anestesiologica 1994; 60
(Suppl. 1): 1239.
21. Filipovic M, Jeger R, Probst C, Girard T, Pfisterer M, Gurke
L, Skarvan K, Seeberger MD. Heart rate variability and
cardiac troponin I are incremental and independent predictors of one-year all-cause mortality after major noncardiac surgery in patients at risk of coronary artery disease. J
Am Coll Cardiol 2003; 42: 176776.
22. Fujiwara Y, Sato Y, Shibata Y, Asakura Y, Nishiwaki K,
Komatsu T. A greater decrease in blood pressure after
spinal anaesthesia in patients with low entropy of the RR
interval. Acta Anaest Scand 2007; 51: 11615.
23. Hanss R, Bein B, Ledowski T, Lehmkuhl M, Ohnesorge H,
Scherkl W, Steinfath M, Scholz J, Tonner PH. Heart rate
variability predicts severe hypotension after spinal anesthesia for elective cesarean delivery. Anesthesiology 2005; 102:
108693.
24. Huang CJ, Kuok CH, Kuo TB, Hsu YW, Tsai PS. Preoperative measurement of heart rate variability predicts
hypotension during general anesthesia. Acta Anaesthesiol
Scand 2006; 50: 5428.
25. OFlaherty D. Heart rate variability and anaesthesia. Eur J
Anaesthesiol 1993; 106: 41932.
26. Knuttgen D, Trojan S, Weber M, Wolf M, Wappler F.
Pre-operative measurement of heart rate variability in
diabetics: a method to estimate blood pressure stability during anaesthesia induction. Anaesthesist 2005; 54:
4429.
27. Deschamps A, Denault A. Analysis of heart rate variability:
a useful tool to evaluate autonomic tone in the anesthetized
patient? Can J Anaest 2008; 55: 20813.
28. Neukirchen M, Kienbaum P. Sympathetic nervous system:
evaluation and importance for clinical general anesthesia.
Anesthesiology 2008; 109: 111331.
29. Haney MF, Wiklund U. Can heart rate variability become a
screening tool for anesthesia-related hypotension? Acta
Anaesthesiol Scand 2007; 51: 128991.
30. Chatzimichali A, Zoumprouli A, Metaxari M, Apostolakis
I, Daras T, Tzanakis N, Askitopoulou H. Heart rate variability may identify patients who will develop severe bradycardia during spinal anaesthesia. Acta Anaesthesiol
Scand 2011; 55: 23441.
31. Burgos LG, Ebert TJ, Asiddao C, Turner LA, Pattison CZ,
Wang-Cheng R, Kampine JP. Increased intraoperative cardiovascular morbidity in diabetics, with autonomic neuropathy. Anesthesiology 1989; 70: 5917.
32. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; 7: 146.
33. Tsueda K, Huang KC, Dumont SW, Wieman TJ, Thomas
MH, Heine MF. Cardiac sympathetic tone in anaesthetized
diabetics. Can J Anaesth 1991; 38: 203.

808

34. Yum MK, Kim HS. Prediction of severity of mean arterial

pressure elevation after tracheal intubation in hypertensive patients by preanesthetic recurrence quantification
analysis of heart rate. Acta Anaesthesiol Scand 2003; 47:
47581.
35. Laitio TT, Huikuri HV, Makikallio TH, Jalonen J, Kentala
ES, Helenius H, Pullisaar O, Hartiala J, Scheinin H. The
breakdown of fractal heart rate dynamics predicts prolonged postoperative myocardial ischemia. Anesth Analg
2004; 98: 123944.
36. Latson TW, Ashmore MD, Reinhart DJ, Klein KW, Giesecke
AH. Autonomic reflex dysfunction in patients presenting
for elective surgery is associated with hypotension after
anaesthesia induction. Anesthesiology 1994; 80: 32637.
37. Hanss R, Bein B, Francksen H, Scherkl W, Bauer M, Doerges
V, Steinfath M, Scholz J, Tonner PH. Heart rate variabilityguided prophylactic treatment of severe hypotension after
subarachnoid block for elective cesarean delivery. Anesthesiology 2006; 104: 63543.
38. Bertherat J, Lubetzki J, Lockhart A, Regnard J. Decreased
bronchial response to methacholine in IDDM patients with
autonomic neurophaty. Diabetes 1991; 40: 11006.
39. Kitamura A, Hoshino T, Kon T, Ogawa R. Patients with
diabetic neuropathy are at risk of greater intraoperative
reduction in core temperature. Anesthesiology 2000; 92:
13118.
40. Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients
with cardiovascular autonomic neuropathy and orthostatic
hypotension. Diabet Med 2003; 20: 11926.
41. Spallone V, Morganti R, Fedele T, DAmato C, Maiello MR.
Reappraisal of the diagnostic role of orthostatic hypotension in diabetes. Clin Auton Res 2009; 19: 5864.
42. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic
autonomic neuropathy. Diabetes Care 2003; 26: 155379.
43. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic
neuropathy. Circulation 2007; 115: 38797.
44. Mussalo H, Vanninen E, Ikaheimo R, Laitinen T, Laakso M,
Lansimies E, Hartikainen J. Heart rate variability and its
determinants in patients with severe or mild essential
hypertension. Clin Physiol 2001; 21: 594604.
45. Gribbin B, Pickering TG, Sleight P, Peto R. Effect of age and
high blood pressure on baroreflex sensitivity in man. Circ
Res 1971; 29: 42431.
46. Tanaka M, Kimura T, Goyagi T, Nishikawa T. Gender
differences in baroreflex response and heart rate variability
in anaesthetized humans. Br J Anaesth 2004; 92: 8315.
47. Di Leo R, Vita G, Messina C, Savica V. Autonomic function
in elderly uremics studied by spectral analysis of heart rate.
Kidney Int 2005; 67: 15215.
48. Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, Lee FA.
Effects of propranolol on recovery of heart rate variability
following acute myocardial infarction and relation to outcome in the Beta-Blocker Heart Attack Trial. Am J Cardiol
2003; 91: 13742.
49. Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G,
Melga P, Viviani GL, Esposito K, Morganti R, Cortelli P, on
behalf of the Diabetic Neuropathy Study Group of the
Italian Society of Diabetology. Recommendations for the
use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis 2011; 21: 69
78.
50. Estafanous FG, Brum JM, Ribeiro MP, Estafanous M, Starr
N, Ferrario C J. Analysis of heart rate variability to assess
hemodynamic alterations following induction of anesthesia. Cardiothorac Vasc Anesth 1992; 6: 6517.

Heart rate variability and anesthesiologist

51. Hanss R, Renner J, Ilies C, Moikow L, Buell O, Steinfath M,
Scholz J, Bein B. Does heart rate variability predict hypotension and bradycardia after induction of general anaesthesia in high risk cardiovascular patients? Anaesthesia
2008; 63: 12935.
52. Chamchad D, Arkoosh VA, Horrow JC, Buxbaum JL,
Izrailtyan I, Nakhamchik L, Hoyer D, Kresh JY. Using heart
rate variability to stratify risk of obstetric patients undergoing spinal anesthesia. Anesth Analg 2004; 99: 181821.
53. Haberthur C, Schachinger H, Seeberger M, Gysi CS. Effect
of non-hypotensive haemorrhage on plasma catecholamine
levels and cardiovascular variability in man. Clin Physiol
Funct Imaging 2003; 23: 15965.
54. Conte V, Guzzetti S, Porta A, Tobaldini E, Baratta P, Bello L,
Stocchetti N. Spectral analysis of heart rate variability
during asleep-awake craniotomy for tumor resection. J
Neurosurg Anesthesiol 2009; 21: 2427.
55. Toweill DL, Kovarik WD, Carr R, Kaplan D, Lai S, Bratton S,
Goldstein B. Linear and nonlinear analysis of heart rate
variability during propofol anesthesia for short-duration
procedures in children. Pediatr Crit Care Med 2003; 4: 30814.
56. Kanaya N, Hirata N, Kurosawa S, Nakayama M, Namiki A.
Differential effects of propofol and sevoflurane on heart
rate variability. Anesthesiology 2003; 98: 3440.
57. Luginbuhl M, Ypparila-Wolters H, Rufenacht M, PetersenFelix S, Korhonen I. Heart rate variability does not discriminate between different levels of hemodynamic responsiveness during surgical anaesthesia. Br J Anaesth 2007; 98:
72836.
58. Yum MK, Oh AY, Lee HM, Kim CS, Kim SD, Lee YS, Wang
KC, Chung YN, Kim HS. Identification of patients with
childhood moyamoya diseases showing temporary hypertension after anesthesia by preoperative multifractal Hurst
analysis of heart rate variability. J Neurosurg Anesthesiol
2006; 18: 2239.
59. Mamode N, Docherty G, Lowe GD, Macfarlane PW, Martin
W, Pollock JG, Cobbe SM. The role of myocardial perfusion
scanning, heart rate variability and D-dimers in predicting
the risk of perioperative cardiac complications after peripheral vascular surgery. Eur J Vasc Endovasc Surg 2001;
22: 499508.
60. Laitio TT, Huikuri HV, Kentala ES, Makikallio TH, Jalonen
JR, Helenius H, Sariola-Heinonen K, Yli-Mayry S, Scheinin
H. Correlation properties and complexity of perioperative
RR-interval dynamics in coronary artery bypass surgery
patients. Anesthesiology 2000; 93: 6980.
61. Stein PK, Schmieg RE Jr., El-Fouly A, Domitrovich PP,
Buchman TG. Association between heart rate variability
recorded on postoperative day 1 and length of stay in
abdominal aortic surgery patients. Crit Care Med 2001; 29:
173843.
62. Tsuchiya S, Kanaya N, Hirata N, Kurosawa S, Kamada N,
Edanaga M, Nakayama M, Omote K, Namiki A. Effects of
thiopental on bispectral index and heart rate variability. Eur
J Anaesthesiol 2006; 23: 4549.
63. Latson TW, McCarroll SM, Mirhej MA, Hyndman VA,
Whitten CW, Lipton JM. Effects of three anesthetics induction techniques on heart rate variability. J Clin Anesth 1992;
4: 26576.
64. Riznyk L, Fijalkowska M, Przesmycki K. Effects of thiopental and propofof on heart rate variability during fentanyl based induction of general anesthesia. Pharmacol Rep
2005; 57: 12834.
65. Picker O, Scheeren TW, Arndt JO. Inhalation anaesthetics
increase heart rate by decreasing cardiac vagal activity in
dogs. Br J Anaesth 2001; 87: 74854.

66. Haberthur C, Lehmann F, Ritz R. Assessment of depth of

midazolam sedation using objective parameters. Intensive
Care Med 1996; 22: 138590.
67. Agelink MW, Majewski TB, Andrich J, Mueck-Weymann
M. Short-term effects of intravenous benzodiazepines on
autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam and lorazepam. Crit
Care Med 2002; 30: 9971006.
68. Zickmann B, Hofmann HC, Pottkamper C, Knothe C, Boldt
J, Hempelmann G. Changes in heart rate variability during
induction of anesthesia with fentanyl and midazolam. J
Cardiothorac Vasc Anesth 1996; 10: 60913.
69. Michaloudis D, Kochiadakis G, Georgopoulou G, Fraidakis
O, Chlouverakis G, Petrou A, Pollard BJ. The influence of
premedication on heart rate variability. Anaesthesia 1998;
53: 44653.
70. Tirel O, Chanavaz C, Bansard JY, Carre F, Ecoffey C,
Senhadji L, Wodey E. Effect of remifentanil with and without atropine on heart rate variability and RR interval in
children. Anaesthesia 2005; 60: 9829.
71. Vettorello M, Colombo R, De Grandis CE, Costantini E,
Raimondi F. Effect of fentanyl on heart rate variability
during spontaneous and paced breathing in healthy volunteers. Acta Anaesthesiol Scand 2008; 52: 106470.
72. Tanaka M, Goyagi T, Kimura T, Nishikawa T. The effects of
cervical and lumbar epidural anesthesia on heart rate
variability and spontaneous sequence baroreflex sensitivity.
Anesth Analg 2004; 99: 9249.
73. Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations,
consequences, and treatment. J Clin Endocrinol Metab
2005; 90: 5896903.
74. Malik RA, Williamson S, Abbott C, Carrington AL, Iqbal J,
Schady W, Boulton AJ. Effect of angiotensin-convertingenzyme (ACE) inhibitor trandolapril on human diabetic
neuropathy: randomised double-blind controlled trial. Lancet 1998; 352: 197881.
75. Kaufman ES, Bosner MS, Bigger JT Jr., Stein PK, Kleiger RE,
Rolnitzky LM, Steinman RC, Fleiss JL. Effects of digoxin
and enalapril on heart period variability and response to
head-up tilt in normal subjects. Am J Cardiol 1993; 72: 959.
76. Keet SW, Bulte CS, Boer C, Bouwman RA. Reproducibility
of non-standardised autonomic function testing in the preoperative assessment screening clinic. Anaesthesia. 2011;
66: 104.
77. Kennedy HL. Heart rate variability a potential, noninvasive prognostic index in the critically ill patient. Crit Care
Med 1998; 26: 2134.
78. Winchell RJ, Hoyt DB. Spectral analysis of heart rate
variability in the ICU: a measure of autonomic function. J
Surg Res 1996; 63: 116.
79. Yien HW, Hseu SS, Lee LC, Kuo TB, Lee TY, Chan SH.
Spectral analysis of systemic arterial pressure and heart
rate signals as a prognostic tool for the prediction of patient
outcome in the intensive care unit. Crit Care Med 1997; 25:
25866.
80. Goldstein B, Kempski MH, Deking D, Cox C, DeLong DJ,
Kelly MM, Woolf PD. Autonomic control of heart rate
after brain injury in children. Crit Care Med 1996; 24:
23440.
81. Winchell RJ, Hoyt DB. Analysis of heart-rate variability: a
noninvasive predictor of death and poor outcome in
patients with severe head injury. J Trauma 1997; 43: 92733.
82. Biswas AK, Scott WA, Sommerauer JF, Luckett PM. Heart
rate variability after acute traumatic brain injury in children. Crit Care Med 2000; 28: 390712.

809

A. T. Mazzeo et al.
83. Mowery NT, Norris PR, Riordan W, Jenkins JM, Williams
AE, Morris JA. Jr. Cardiac uncoupling and heart rate
variability are associated with intracranial hypertension
and mortality: a study of 145 trauma patients with continuous monitoring. J Trauma 2008; 65: 6217.
84. Baillard C, Vivien B, Mansier P, Mangin L, Jasson S, Riou B,
Swynghedauw B. Brain death assessment using instant
spectral analysis of heart rate variability. Crit Care Med
2002; 30: 30610.
85. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF. Mechanisms in
neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2006; 5: 2439.
86. Samuels MA. The brain-heart connection. Circulation 2007;
116: 7784.
87. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation 2008; 118: 397409.
88. Kawahara E, Ikeda S, Miyahara Y, Kohno S. Role of
autonomic nervous dysfunction in electrocardiographic
abnormalities and cardiac injury in patients with acute
subarachnoid hemorrhage. Circ J 2003; 67: 7536.
89. Haji-Michael PG, Vincent JL, Degaute JP, Vande borne P.
Power spectral analysis of cardiovascular variability in
critically ill neurosurgical patients. Crit Care Med 2000;
28: 257883.
90. Claydon VE, Krassioukov AV. Clinical correlates of
frequency analyses of cardiovascular control after spinal
cord injury. Am J Physiol Heart Circ Physiol 2008; 294:
66878.
91. Ditor DS, Kamath MV, Macdonald MJ, Bugaresti J, McCartney N, Hicks AL. Reproducibility of heart rate variability
and blood pressure variability in individuals with spinal
cord injury. Clin Auton Res 2005; 15: 38793.
92. Moss J, Glick D. The autonomic nervous system. In: Miller
R. D., ed. Millers anesthesia. Philadelphia: Elsevier,
Churchill Livingstone, 2005:61777.
93. Flachenecker P, Reiners K. Twenty-four-hour heart rate
power spectrum for evaluation of autonomic dysfunction
in Guillain-Barre syndrome. J Neurol Sci 1999; 165: 144153.
94. Flachenecker P, Lem K, Mullges W, Reiners K. Detection of
serious bradyarrhythmias in GuillainBarre syndrome:
sensitivity and specificity of the 24-hour heart rate power
spectrum. Clin Auton Res 2000; 10: 18591.
95. Zollei E, Avramov K, Gingl Z, Rudas L. Severe cardiovascular autonomic dysfunction in a patient with Guillain
Barre syndrome: a case report. Auton Neurosci 2000; 86:
948.
96. Sykora M, Diedler J, Hacke W, Veltkamp R. Intrapulmonary
right-left shunts in GuillainBarre syndrome with severe
dysautonomia. Neurocrit Care 2008; 9: 3747.
97. Vita G, Fazio MC, Milone S, Blandino A, Salvi L, Messina C.
Cardiovascular autonomic dysfunction in multiple sclerosis is related to brainstem lesions. J Neurol Sci 1993; 120:
826.
98. Flachenecker P. Autonomic dysfunction in GuillainBarre
syndrome and multiple sclerosis. J Neurol 2007; 254:
96101.
99. Mahovic D, Lakusic N. Progressive impairment of autonomic control of heart rate in patients with multiple
sclerosis. Arch Med Res 2007; 38: 3225.
100. Meglic B, Kobal J, Osredkar J, Pogacnik T. Autonomic
nervous system function in patients with acute brainstem
stroke. Cerebrovasc Dis 2001; 11: 28.
101. Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllya VV.
Abnormal heart rate variability as a manifestation of
autonomic dysfunction in hemispheric brain infarction.
Stroke 1996; 27: 205963.

810

102. Makikallio AM, Makikallio TH, Korpelainen JT, Sotaniemi

KA, Huikuri HV, Myllyla VV. Heart rate dynamics predict
poststroke mortality. Neurology 2004; 62: 182226.
103. Gujjar AR, Sathyaprabha TN, Nagaraja D, Thennarasu K,
Pradhan N. Heart rate variability and outcome in acute
severe stroke: role of power spectral analysis. Neurocrit
Care 2004; 1: 34753.
104. Sander D, Winbeck K, Klingelhofer J, Etgen T, Conrad B.
Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke. Neurology 2001;
57: 8338.
105. Dougherty CM, Burr RL. Comparison of heart rate variability in survivors and nonsurvivors of sudden cardiac
arrest. Am J Cardiol 1992; 70: 4418.
106. Tiainen M, Parikka HJ, Makijarvi MA, Takkunen OS,
Sarna SJ, Roine RO. Arrhythmias and heart rate variability
during and after therapeutic hypothermia for cardiac
arrest. Crit Care Med 2009; 37: 4039.
107. Riker RR, Seder DB, Fraser GL. The Nina, the Pinta, and
heart rate variability: the search for prognostic indicators
after cardiac arrest. Crit Care Med 2009; 37: 7356.
108. Kleiger RE, Miller JP, Bigger JT Jr., Moss AJ. Decreased
heart rate variability and its association with increased
mortality after acute myocardial infarction. Am J Cardiol
1987; 59: 25662.
109. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz
PJ. Baroreflex sensitivity and heart rate variability in
prediction of total cardiac mortality after myocardial
infarction. Lancet 1998; 351: 47884.
110. Buccelletti E, Gilardi E, Scaini E, Galiuto L, Persiani R,
Biondi A, Basile F, Silveri NG. Heart rate variability and
myocardial infarction: systematic literature review and
metanalysis. Eur Rev Med Pharmacol Sci 2009; 13: 299
307.
111. Ewing DJ. Heart rate variability: an important new risk
factor in patients following myocardial infarction. Clin
Cardiol 1991; 14: 6835.
112. Odemuyiwa O, Malik M, Farrell T, Bashir Y, Poloniecki J,
Camm J. Comparison of the predictive characteristics of
heart rate variability index and left ventricular ejection
fraction for all-cause mortality, arrhythmic events and
sudden death after acute myocardial infarction. Am J
Cardiol 1991; 68: 4349.
113. Fetsch T, Reinhardt L, Makijarvi M, Bocker D, Block M,
Borggrefe M, Breithardt G. Heart rate variability in time
domain after acute myocardial infarction. Clin Sci (London) 1996; 91: 13640.
114. Fei L, Copie X, Malik M, Camm AJ. Short- and long-term
assessment of heart rate variability for postinfarction risk
stratification. Am J Cardiol 1996; 77: 6814.
115. Malik M, Camm AJ. Significance of long-term components
of heart rate variability for the further prognosis after
acute myocardial infarction. Cardiovasc Res 1990; 24: 793
803.
116. Schmidt HB, Hoyer D, Hennen R, Heinroth K, Rauchhaus
M, Prondzinsky R, Hottenrott K, Buerke M, Muller-Werdan U, Werdan K. Autonomic dysfunction predicts both 1and 2-month mortality in middle-aged patients with
multiple organ dysfunction syndrome. Crit Care Med
2008; 36: 96770.
117. Hoyer D, Friedrich H, Zwiener U, Pompe B, Baranowski R,
Werdan K, Muller-Werdan U, Schmidt H. Prognostic impact
of autonomic information flow in multiple organ dysfunction syndrome patients. Int J Card 2006; 108: 35969.
118. Godin PJ, Buchman TG. Uncoupling of biological oscillators: a complementary hypothesis concerning the patho-

Heart rate variability and anesthesiologist

119.

120.

121.

122.
123.
124.
125.
126.

127.

128.

129.

130.
131.

genesis of multiple organ dysfunction syndrome. Crit

Care Med 1996; 24: 110716.
Pontet J, Contreras P, Curbelo A, Medina J, Noveri S,
Bentancourt S, Migliaro ER. Heart rate variability as early
marker of multiple organ dysfunction syndrome in septic
patients. J Crit Care 2003; 18: 15663.
Papaioannou VE, Dragoumanis C, Theodorou V, Gargaretas C, Pneumatikos I. Relation of heart rate variability to
serum levels of C-reactive protein, interleukin 6, and 10 in
patients with sepsis and septic shock. J Crit Care 2009; 24:
625. e1-625.e7.
Tateishi Y, Oda S, Nakamura M, Watanabe K, Kuwaki T,
Moriguchi T, Hirasawa H. Depressed heart rate variability
is associated with high IL-6 blood level and decline in the
blood pressure in septic patients. Shock 2007; 28: 54953.
Barnaby D, Ferrick K, Kaplan DT, Shah S, Bijur P, Gallagher EJ. Heart rate variability in emergency department
patients with sepsis. Acad Emerg Med 2002; 9: 66170.
Garrard CS, Kontoyannis DA, Piepoli M. Spectral analysis
of heart rate variability in the sepsis syndrome. Clin
Auton Res 1993; 3: 513.
Chen WL, Kuo CD. Characteristics of heart rate variability
can predict impending septic shock in emergency department patients with sepsis. Acad Emerg Med 2007; 14: 3927.
Korach M, Sharshar T, Jarrin I, Fouillot JP, Raphael JC,
Gajdos P, Annane D. Cardiac variability in critically ill
adults: influence of sepsis. Crit Care Med 2001; 29: 138085.
Cooke WH, Salinas J, Convertino VA, Ludwig DA, Hinds
D, Duke JH, Moore FA, Holcomb JB. Heart rate variability
and its association with mortality in prehospital trauma
patients. J Trauma 2006; 60: 36370.
Grogan EL, Morris JA Jr., Norris PR, France DJ, Ozdas A,
Stiles RA, Harris PA, Dawant BM, Speroff T. Reduced
heart rate volatility: an early predictor of death in trauma
patients. Ann Surg 2004; 240: 54754.
Norris PR, Ozdas A, Cao H, Williams AE, Harrell FE,
Jenkins JM, Morris JA. Jr. Cardiac Uncoupling and heart
rate variability stratify ICU patients by mortality: a study
of 2088 trauma patients. Ann Surg 2006; 243: 80414.
Goto T, Fukushima H, Sasaki G, Matsuo N, Takahashi T.
Evaluation of autonomic nervous system function with
spectral analysis of heart rate variability in a case of
tetanus. Brain Dev 2001; 23: 7915.
Sykora M, Diedler J, Veltkamp R, Steiner T. Autonomic
impairment in tetanus: delayed baroreflex involvement. J
Neurol Sci 2008; 270: 2014.
ter Maaten JC, Strack van Schijndel RJ. Cyclic variability of
blood pressure and heart rate in tetanus. Intensive Care
Med 1996; 22: 12756.

132. Patural H, Goffaux P, Paricio C, Emeriaud G, Teyssier G,

Barthelemy JC, Pichot V, Roche F. Infant botulism intoxication and autonomic nervous system dysfunction. Anaerobe 2009; 15: 197200.
133. Vita G, Girlanda P, Puglisi RM, Marabello L, Messina C.
Cardiovascular-reflex testing and single-fibre electromyography in botulism. A longitudinal study. Arch Neurol
1987; 44: 2026.
134. Tanaka M, Nagasaki G, Nishikawa T. Moderate hypothermia depresses arterial baroreflex control of hearth rate
during, and delays its recovery after, general anesthesia in
humans. Anesthesiology 2001; 95: 515.
135. Novak V, Novak P, De Champlain J, Le Blanc AR, Martin
R, Nadeau R. Influence of respiration on heart rate and
blood pressure fluctuations. J Appl Physiol 1993; 74: 617
26.
136. Brown TE, Beightol LA, Koh J, Eckberg DL. Important
influence of respiration on human R-R interval power
spectra is largely ignored. J Appl Physiol 1993; 75: 23107.
137. Kasaoka S, Nakahara T, Kawamura Y, Tsuruta R, Maekawa T. Real-time monitoring of heart rate variability in
critically ill patients. J Crit Care 2010; 25: 3136.
138. Poyhonen M, Syvaoja S, Hartikainen J, Ruokonen E,
Takala J. The effect of carbon dioxide, respiratory rate
and tidal volume on human heart rate variability. Acta
Anaesthesiol Scand 2004; 48: 93101.
139. Mathias CJ, Bannister R. Investigation of autonomic disorders. In: Mathias CJ, Bannister R, eds. Autonomic failure: a textbook of clinical disorders of the autonomic
nervous system, 4th edn. Oxford: Oxford University Press,
1999:16995.
140. Omboni S, Parati G, Di Rienzo M, Wieling W, Mancia G.
Blood pressure and heart rate variability in autonomic
disorders: a critical review. Clin Auton Res 1996; 6: 17182.
141. Pinna GD, Maestri R, Torunski A, Danilowicz-Szymanowicz L, Szwoch M, La Rovere MT, Raczak G. Heart rate
variability measures: a fresh look at reliability. Clin Sci
(London) 2007; 113: 13140.

Address:
Dr Anna Teresa Mazzeo
Anestesia e Neurorianimazione
AOU Policlinico G. Martino
Via Consolare Valeria
98125 Messina
Italy
e-mail: annateresamazzeo@unime.it

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