CLINICAL INVESTIGATION

EEG Entropy Values During Isoflurane, Sevoflurane and

Halothane Anesthesia With and Without Nitrous Oxide
Hemanshu Prabhakar, MD, Zulqar Ali, MD, Parmod K. Bithal, MD,
Gyaninder P. Singh, MD, Pradip K. Laithangbam, MD,
and Hari H. Dash, MD

Abstract: We hypothesized that like bispectral index, entropy

may be anesthetic agent specic. We carried out a study to assess
the entropy values of dierent anesthetics at equi-minimal
alveolar concentrations (MACs) with air and nitrous oxide as
carrier gases. Thirty adult patients undergoing spine surgery
were randomized to receive halothane, isourane, or sevourane, in 2 stages, (a) with air/oxygen mixture (2:1) and (b) in
nitrous oxide/oxygen (2:1). Heart rate, mean arterial blood
pressure, response entropy (RE), and state entropy (SE) were
noted at 1.0 and 1.5 MACs for each agent. Statistical analysis
was done using the 2-way analysis of variance followed by
Bonferroni correction and Student t test for paired data. P value
of less than 0.05 were considered signicant. The demographics
and baseline values of heart rate, mean arterial blood pressure,
RE, and SE were comparable. Changing from air/oxygen as
carrier gas to 66% nitrous oxide in oxygen resulted in signicant
increase in both RE and SE at 1.0 MAC for all the agents
(P<0.05). Among the agents, it was found that both RE and SE
values were signicantly higher during halothane anesthesia as
compared with sevourane and isourane (P<0.05). At 1.5
MAC for all agents, after addition of nitrous oxide, there was an
insignicant reduction in both RE and SE (P>0.05). Again the
values of RE and SE remained high for halothane as compared
with isourane and sevourane. In conclusion, our data suggest
a possibility of misinterpretation of anesthetic hypnosis when
entropy values increase with addition of nitrous oxide to 1 MAC
isourane and sevourane.
Key Words: isourane, sevourane, halothane, nitrous oxide,
minimum alveolar concentration, entropy values, hypnosis.
(J Neurosurg Anesthesiol 2009;21:108111)

inimal alveolar concentration (MAC) has traditionally been used to measure potency of inhalational
anesthetics. Therefore, equi-MAC concentrations of

Received for publication June 11, 2008; accepted October 27, 2008.
From the Department of Neuroanaesthesiology, Neurosciences Center
All India Institute of Medical Sciences, New Delhi, India.
Reprints: Hemanshu Prabhakar, MD, Department of Neuroanesthesiology, Neurosciences Center, 7th oor, All India Institute of Medical
Sciences, New Delhi 110029, India (e-mail: prabhakarhemanshu@
redimail.com).
Copyright r 2009 by Lippincott Williams & Wilkins

108

dierent anesthetics should have a similar potency in

suppressing responses to painful stimuli. Recent studies
have shown that bispectral index (BIS) values at equiMAC concentrations are not similar.1,2 BIS values may
be drug specic depending on the ability of the anesthetic
to suppress the electroencephalogram (EEG) signals.
However, no such data are available with the use of
entropy. At the same time, nitrous oxide has shown to
decrease MAC requirement of inhalational anesthetics.
We hypothesized that entropy indices [response entropy
(RE) and state entropy (SE)] may also dier at equi-MAC
concentrations of halothane, isourane, and sevourane.
Furthermore, due to the variable eect of nitrous oxide
on EEG, its presence could also aect entropy values. No
study to date has compared the 3 anesthetics in terms of
their equi-MAC entropy values, both in the absence and
presence of nitrous oxide. The aim of this prospective and
randomized preliminary study was to compare entropy
indices (RE and SE) at equi-MAC concentrations of
commonly used anesthetics, halothane, isourane, and
sevourane. We also tried to assess the inuence of
nitrous oxide on entropy indices.

MATERIALS AND METHODS

After approval from the institutes ethics committee
and informed consent from the patient, 30 adult patients
(ASA physical status I and II) ages 18 to 60 years
undergoing lumbar spine surgery were enrolled for the
study. Exclusion criteria included patients with body
weight more than 20% of ideal body weight, patients on
hypnotics and antidepressants, patients with cardiac
diseases and neurologic disorders, and those receiving
b-blocker drugs. All patients were premedicated with intramuscular glycopyrrolate 0.2 mg 1 hour before surgery.
In the operation theater, standard monitoring of electrocardiogram, pulse oximetry and noninvasive blood
pressure was started. The entropy sensor, disposable
(Datex-Ohmeda, Instrumentarium Corporation, Helsinki, Finland) was applied on the right forehead of
the patient after skin preparation in accordance with
the manufacturers instruction and connected to the
entropy monitor (Datex-Ohmeda S/5 Entropy module).
The indices RE and SE were read manually and recorded. General anesthesia was induced with fentanyl
2 mcg/kg and thiopentone sodium 4 to 5 mg/kg. Tracheal
J Neurosurg Anesthesiol

Volume 21, Number 2, April 2009

J Neurosurg Anesthesiol

Volume 21, Number 2, April 2009

Entropy Varies for Air/Nitrous Oxide Anesthesia

intubation was facilitated with rocuronium 1 mg/kg. A

nasopharyngeal temperature probe was placed and right
dorsalis pedis artery cannulated for invasive blood
pressure monitoring. Mechanical ventilation was started
to adjust EtCO2 between 34 and 36 mm Hg. Intermittent
boluses of fentanyl 1 mcg/kg hourly [whenever heart rate
(HR) and mean blood pressure exceeded 20% of baseline]
and rocuronium 0.05 mg/kg hourly were administered to
assist ventilation. Baseline HR and mean arterial blood
pressure (MAP) were recorded along with RE and SE
before induction of general anesthesia. On the basis of
a computer-generated randomization table, patients
received halothane, isourane, or sevourane for maintenance of anesthesia in oxygen and air mixture
(FiO20.4) (stage 1). A constant fresh gas ow of 3 L/min
was maintained throughout the study period. The
surgery was allowed to start before recording of data.
The HR, MAP, RE, and SE were noted at the end-tidal
concentration of inhaled anesthetics 1.0 MAC (end-tidal
concentrations isourane1.1%, sevourane2%, halothane0.7%) and 1.5 MAC (end-tidal concentration
isourane1.7%, sevourane3%, halothane1.1%). A
steady state of 10 minutes was allowed at each target
MAC concentration before data were recorded, to ensure
equilibration of the anesthetic to the brain. Arterial blood
pressure (from dorsalis pedis artery with the transducer
xed at the level of mastoid bone) was increased with
bolus injection of mephentermine sulfate if values
decreased by 20% from the initial MAP.
In stage 2, air was discontinued and nitrous oxide
introduced. At steady state of nitrous oxide, values were
again noted as in stage 1, keeping the end-tidal
concentration of volatile agents constant at 1.0 (end-tidal
concentrations isourane0.6%, sevourane1%, halothane0.3%) and 1.5 MAC (end-tidal concentrations
isourane1.3%, sevourane2%, halothane0.7%).
Data were analyzed using software STATA 9.0
(College Station, TX). Data are expressed as mean (SD).
Mean age, body weight, and sex of patients and the
baseline values of HR, MAP, RE, and SE in the 3 groups
were compared by 2-way analysis of variance followed by
Bonferroni correction. At each MACfraction for each

volatile agent, the parameters tabulated during air/oxygen were compared with those during nitrous oxide/oxygen using Student t test for all paired data. A P value of
less than 0.05 was considered signicant.

RESULTS
All patients completed the study and none were
excluded from nal analysis. The groups did not dier in
demographic characteristics and baseline values of HR,
MAP, RE, and SE (Table 1). The HR and MAP during
both stages of anesthesia are tabulated (Table 2). With
air/oxygen as the carrier gas, isourane and sevourane
resulted in comparable RE and SE, whereas during 1.0
MAC, halothane RE and SE were signicantly higher.
Addition of 66% of nitrous oxide resulted in signicant
increase in both RE and SE at 1.0 MAC of all 3 agents
(P<0.05). At 1.5 MAC, RE, and SE decreased although
the change was not signicant (P>0.05) (Table 3). The
use of mephentermine sulfate did not dier between the
groups. Four patients in halothane group and 3 patients
each in isourane and sevourane groups required
vasopressor at 1.5 MAC concentrations.

DISCUSSION
Entropy has been eectively used in monitoring the
depth of hypnosis.3,4 In our study, we found that entropy
values in the halothane group remained high as compared
with isourane and sevourane group at all MAC
concentrations. It was also noted that entropy values
between isourane and sevourane groups were comparable at equi-MAC concentrations. In a study, Rao et al1
also showed that equi-MAC concentrations of isourane
and halothane do not produce similar BIS values. They
found BIS values signicantly lower under isourane
compared with halothane anesthesia at similar MAC
concentrations. Schwab et al2 had similar observations
while using sevourane and halothane at equal MAC
multiples. Our study diers from the earlier ones as none
have compared the 3 agents together.
A potential confounding factor in our study could
be the nonrandomized sequence of the carrier gases used.

TABLE 1. Patient Demographics and Baseline Values Measured Before Induction of General
Anesthesia

Age (years)
Weight (kg)
Male/female
HR
MAP
RE
SE

Isourane Group
(n = 10)

Sevourane Group
(n = 10)

Halothane Group
(n = 10)

38.1 (16.5)
55.0 (10.6)
8/2
88.8 (12.3)
99.8 (8.1)
98 (2)
88 (3)

38.2 (12.8)
56.9 (7.6)
6/4
84.4 (12.6)
102.8 (9.5)
98 (1)
90 (1)

38.2 (10.5)
62.7 (13.6)
7/3
81.0 (12.3)
105.4 (8.2)
98 (1)
87 (3)

NS
NS
NS
NS
NS
NS
NS

Data are mean (SD) or numbers.

HR, heart rate; MAP, mean arterial pressure; n, number of patients; NS, not signicant; RE, response entropy;
SE, state entropy.

2009 Lippincott Williams & Wilkins

109

J Neurosurg Anesthesiol

Prabhakar et al

Volume 21, Number 2, April 2009

TABLE 2. Heart Rate and Blood Pressure Measurement for All Study Groups, Without and
With Nitrous Oxide
Isourane

Sevourane

Halothane

A
N
P
A
N
P

82.3 (11.8)
77.7 (18.2)

75.4 (17.2)
69.9 (13)
0.007*
78.1 (18.1)
69.9 (12.5)
0.001w

67.5 (12.1)
63.6 (8.4)

0.19

69.6 (10.6)
63.2 (6.9)

0.03

A
N
P
A
N
P

78.2 (15.8)
83.1 (12.3)

81.6 (15.1)
90.1 (13.1)
0.50
73.0 (12.5)
76.1 (15.4)
0.02*

81.1 (12.6)
86.9 (15.2)

0.08

78.9 (11.1)
83.9 (15.5)

0.23

MAC
Heart rate
1.0
1.5

89.0 (12.4)
81.7 (15.0)

Mean arterial pressure

1.0
1.5

68.4 (7.9)
72.2 (12.0)

Data are presented as mean (SD).

*Isourane versus halothane group.
wIsourane versus Sevourane and halothane group.
A, air group; MAC, minimum alveolar concentration; N, nitrous oxide group; NS, not signicant.

All patients received air/oxygen and then nitrous oxide/

oxygen. Some other factors could also possibly inuence
our study results. We did not adjust the MAC values of
the inhaled anesthetics to the age of the patient. However,
it must be mentioned that the age-corrected MAC values
as suggested by Eger5 is derived from meta-analysis,
which may not be clinically relevant for individual
patients. The authors share the same opinion as Schwab
et al2 in this regard. In our study, mean age of patients
was comparable in all the 3 groups. Ropcke et al6 have
shown that surgical stimulus shifts EEG concentrationresponse relationship of desurane and therefore aects
BIS values. We believe that the same may hold true for

entropy values also. We therefore, recorded all parameters after the surgery started. Opioids and muscle
relaxants are known to aect the EEG and thereby the
interpretations of EEG signal-based monitors like BIS
and entropy. We attempted to minimize such eects by
administering fentanyl and rocuronium at uniform doses
and intervals.
The dierence in entropy values can be explained on
the basis of dierential eects of halothane, isourane,
and sevourane on EEG. Halothane produces fast EEG
rhythms whereas isourane and sevourane produce
mainly slow waves. Halothane produces persistent 8 to
14 Hz activity despite increasing depth, whereas isourane

TABLE 3. Response Entropy and State Entropy Values for All Study Groups, Without and
With Nitrous Oxide
Isourane

Sevourane

Halothane

A
N
P
A
N
P

40.6 (9.9)
55.1 (18.4)
0.02*
30.8 (12.6)
30.1 (12.9)
0.004w

39.6 (11.9)
53.3 (22.3)

59.1 (14.5)
61.5 (19.2)

0.02

31.1 (18.9)
27.6 (13.4)

49.8 (10.2)
34.7 (17.8)

0.05

A
N
P
A
N
P

38.9 (8.5)
53.5 (18.5)
0.009w
28.5 (10.6)
29.1 (12.3)
0.002w

35.9 (10.6)
51.3 (20.9)

57 (14.2)
60.6 (19.4)

0.009

28.2 (5.8)
27.6 (12.7)

48.3 (17.7)
33.1 (17.4)

0.11

MAC
Response entropy
1.0
1.5
State entropy
1.0
1.5

Data are presented as mean (SD).

*Sevourane versus halothane group.
wIsourane versus halothane and sevourane versus halothane group.
A, air group; MAC, minimum alveolar concentration; N, nitrous oxide group; NS, not signicant.

110

2009 Lippincott Williams & Wilkins

J Neurosurg Anesthesiol

Volume 21, Number 2, April 2009

and sevourane result in progressive slowing leading to

burst suppression as depth increases. The values of
entropy recorded during the stage of nitrous oxide
anesthesia were higher at all MAC values for all the 3
agents. This can be explained by the fact that nitrous
oxide produces stimulatory changes at lower and higher
frequency ranges of EEG, as noted by Rampil and
colleagues.7 At 1.0 MAC, it was observed that there was a
signicant rise in entropy values in sevourane and
isourane groups. At 1.5 MAC variable eects were
observed on the entropy values. This may be due to
incompletely understood mechanisms of nitrous oxide.
The suppressant eect of the anesthetics on EEG may
have been counteracted by the stimulatory eect of
nitrous oxide, thereby resulting in comparable entropy
values. In another study by Yli-Hankala,8 with isourane
or halothane anesthesia, nitrous oxide signicantly
decreased the EEG power of a and b ranges and increased
the power in d and y ranges. The mechanism of action of
nitrous oxide is not completely understood and is partly
believed to be due to the release of endorphin and
norepinephrine.9 At any given depth of hypnosis, the
dierences in EEG eects produced by nitrous oxide or
other anesthetics may be a result of dierent mechanisms
involved.
An interesting observation made during this study,
when comparing the entropy values for volatile agents
with air and nitrous oxide as additives, the RE and SE
values for all study agents at 1.0 MAC increased with
introduction of nitrous oxide and signicance was noted
only for isourane and sevourane. At 1.5 MAC, RE,
and SE remained comparable for isourane and sevourane but decreased signicantly in halothane group.
Our data support our hypothesis that similar to
dierential BIS values at equi-MAC concentrations of
various anesthetic agents; entropy values also dier. It is
clear that at same concentrations, isourane and sevourane produce greater hypnotic eect than halothane. It
is known that MAC indicates the ability of an agent to
cause immobility during the surgery and has poor
correlation with the degree of hypnosis caused by the
agent. Anesthetic agents variably aect the spinal
mechanisms of immobility and cerebral mechanisms of
hypnosis.10 This may be responsible for dierences in
entropy values observed between agents at equi-MAC
concentrations. Jinks et al10 showed that halothane,
through its spinal mechanisms caused greater degree of
analgesia and immobility when compared with isourane.
Our work diers from earlier studies in that we
recorded entropy values of 3 volatile agents for comparison and also noted the eect of nitrous oxide. Most of
the previously published studies have compared only 2
agents using BIS.1,2 Besides, through entropy, we
measured 2 indices; SE which quanties the cortical
cerebral activity (hypnosis) and has been shown to be

2009 Lippincott Williams & Wilkins

Entropy Varies for Air/Nitrous Oxide Anesthesia

similar to BIS value, and RE, which evaluates the

electromyographic activity (subcortical component).
The clinical implication of our study is that
adjusting the administration of anesthetic agents based
on entropy values may not ensure the same degree of
hypnosis. Halothane produces fast EEG rhythms and has
a predominant spinal eect whereas the cortical eect of
isourane and sevourane produce mainly slow waves.
Therefore, clinicians may administer excessive halothane
in an attempt to achieve adequate entropy values. This
may indirectly aect the systemic and intracranial
hemodynamics. In a previous similar studies using BIS
monitor, absence of surgical stimulus was a limitation.2 A
limitation in our study could be that we recorded entropy
values at single nitrous oxide concentration (66%). This
would probably be insucient to generalize the observed
eects of nitrous oxide on entropy values. It is suggested
that at a constant MAC value, varying concentration of
nitrous oxide may be used and changes in entropy, if any,
be recorded. Further studies may be needed to determine
the role of entropy monitoring in clinical practice when 1
or more anesthetic agents are used simultaneously.
In conclusion, our data suggest a possibility of
misinterpretation of anesthetic hypnosis when entropy
values increase with addition of nitrous oxide to 1 MAC
isourane and sevourane. Likewise, addition of nitrous
oxide to 1.5 MAC halothane results in lowering of
entropy value that could be interpreted as greater
hypnosis.
REFERENCES
1. Rao GSU, Ali Z, Ramamoorthy M, et al. Equi-MAC concentrations of halothane and isourane do not produce similar bispectral
index values. J Neurosurg Anesthesiol. 2007;19:9396.
2. Schwab HS, Seeberger MD, Eger E II, et al. Sevourane decreases
bispectral index values more than does halothane at equal MAC
multiples. Anesth Analg. 2004;99:17231727.
3. Takamatsu I, Ozaki M, Kazama T. Entropy indices vs the bispectral
index for estimating nociception during sevourane anesthesia.
Br J Anaesth. 2006;96:620626.
4. Martorano PP, Falzetti G, Pelaia P. Bispectral index and spectral
entropy in neuroanesthesia. J Neurosurg Anesthesiol. 2006;18:205210.
5. Eger EL II. Age, minimum alveolar anesthetic concentration, and
minimum alveolar anesthetic concentration-awake. Anesth Analg.
2001;93:947953.
6. Ropcke H, Rehberg B, Koenen-Bergmann M, et al. Surgical
stimulation shifts EEG concentration-response relationship of
desurane. Anesthesiology. 2001;94:390399.
7. Rampil IJ, Kim JS, Lenhardt R, et al. Bispectral EEG index during
nitrous oxide administration. Anesthesiology 1998;89:671677.
8. Yli-Hankala A. The eect if nitrous oxide on EEG Spectral power
during halothane and isourane anesthesia. Acta Anaesthesiol
Scand. 1990;34:579584.
9. Gou TZ, Poree L, Golden W, et al. Antinociceptive response to
nitrous oxide is mediated by supraspinal opiate and spinal alpha-2
adrenergic receptors in the rat. Anesthesiology. 1996;85:846852.
10. Jinks SL, Martin JT, Carstens E, et al. Peri-MAC depression of a
nociceptive withdrawal reex is accompanied by reduced dorsal
horn activity with halothane but not isourane. Anesthesiology.
2003;98:11281138.

111