대한마취과학회지 2007; 52: S 25～31 Korean J Anesthesiol Vol. 52, No. 6, June, 2007
□ 영문논문 □
Effects of Nitrous Oxide and Desflurane on Cardiovascular Responses to Endotracheal Intubation Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, *School of Dentistry, Chonnam National University Gwangju, Korea
Kyung Yeon Yoo, M.D., Ph.D., Nam Gi Park, M.D., Chang Yeong Jeong, M.D., Ph.D., Sung Su Chung, M.D., Ph.D.*, Myung Ha Yoon, M.D., Ph.D., Sang Hyun Kwak, M.D., Ph.D., Jung Il Choi, M.D., Ph.D., and Hong Beom Bae, M.D.
Background: Endotracheal intubation often results in hypertension and tachycardia. Desflurane and nitrous oxide (N2O) are known to augment the sympathetic nervous activity. We examined whether N2O and desflurane affect the cardiovascular responses to the intubation. Methods: One hundred-fifty patients were assigned randomly to receive one of six treatment regimens (n = 25 each): 2% sevoflurane (control), 6% desflurane or 12% desflurane with and without 75% N2O, respectively. General anesthesia was induced with intravenous thiopental (5-7 mg/kg), and tracheal intubation was facilitated with intravenous vecuronium (0.12 mg/kg). N2O was started 3 min before and desflurane soon after the intubation. Systolic arterial blood pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were determined. Results: The intubation increased SAP and HR in all groups within 1 min. A second increase was noted with 12% desflurane at 3 to 5 min after the intubation. N2O did not affect the tachycardiac response, but attenuated the pressor response to both intubation and 12% desflurane. The plasma concentrations of norepinephrine increased significantly at 1 min after the intubation in all groups with more pronounced rise in N2O groups, and increased further at 5 min in the 12% desflurane groups. Conclusions: A biphasic increase of SAP and HR was noted with 12% desflurane. The first increase may be related with the mechanical stimulus of the tracheal intubation and the second with the desflurane itself. Although N2O did not affect the tachycardiac responses and augmented norepinephrine release, it suppressed the pressor responses. (Korean J Anesthesiol 2007; 52: S 25～31) Key Words: catecholamine, desflurane, hypertension, intubation, nitrous oxide, tachycardia.
is rapidly increased after intravenous induction of anesthesia.5-7) Nitrous oxide (N2O) has been also demonstrated to augment
INTRODUCTION
the sympathetic nervous activities when used alone or in conLaryngoscopy and tracheal intubation are often associated
junction with other anesthetics.8,9) Although desflurane and N2O
with tachycardia, hypertension, and arrhythmias.1) Although these
are commonly used in combination for general anesthesia, pos-
hemodynamic changes have been in part attributed to a reflex
sible interaction among N2O and desflurane and endotracheal
sympathetic discharge caused by stimulation of the upper
intubation have not been clarified. We determined whether N2O
respiratory tract,2-4) their underlying mechanisms are not com-
affects the cardiovascular responses to laryngoscopy and endo-
pletely understood.
tracheal intubation and desflurane when desflurane was admin-
Desflurane has been known to cause sympathoexcitation,
istered soon after endotracheal intubation in subjects who un-
tachycardia, and hypertension, when its inspired concentration
derwent general anesthesia.
MATERIALS AND METHODS
Received：October 4, 2006 Corresponding to：Kyung Yeon Yoo, Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, 8, Hak-dong, Dong-gu, Gwangju 501-757, Korea. Tel: 82-62-220-6893, Fax: 82-62232-6294, E-mail:
[email protected]
After approval from the Ethics Committee of University Hospital and obtaining written informed consent, we studied S 25
Korean J Anesthesiol：Vol. 52. No. 6, 2007 Table 1. Patient Characteristics Groups Age (years) Height (cm) Weight (kg) Gender (F/M) Hemoglobin (g/dl) Without N2O 1-sevoflurane 46 ± 9 163 ± 8 64 ± 9 14/11 12 ± 1 1-desflurane 47 ± 8 160 ± 7 61 ± 8 16/9 13 ± 2 2-desflurane 48 ± 7 158 ± 7 60 ± 10 19/6 12 ± 1 With N2O 1-sevoflurane 45 ± 5 162 ± 6 63 ± 10 18/7 11 ± 2 1-desflurane 48 ± 5 160 ± 6 58 ± 7 22/3 11 ± 1 2-desflurane 46 ± 6 159 ± 5 60 ± 8 21/4 13 ± 1 Data are presented as mean ± SD or number. n: 25 patients per group. There were no statistically significant differences among the groups.
150 ASA grade I patients aged 35-60 yr, presenting for rou-
i.v., while patients were ventilated with oxygen with or with-
tine elective orthopedic, gynecological, or other general sur-
out N2O through an anesthesia facemask connected to a
gery, under general anesthesia. Patients were excluded if any
semi-closed anesthesia circuit (Dräger Kato Edition, Dräger,
of the followings applied: cardiovascular, pulmonary, or meta-
Lübeck, Germany). Thiopental was injected at a steady rate of
bolic diseases. Patients who took medications that would in-
10 mg/s until loss of consciousness, as assessed by loss of
fluence autonomic or cardiovascular responses to laryngoscopy
eyelash reflex. Vecuronium (0.12 mg/kg, i.v.) was used to
and intubation and patients in whom intubation required more
facilitate endotracheal intubation. Three minutes after induction,
than 15 s were also excluded. Sex ratio, age, body weight,
intubation was performed, and immediately thereafter vaporizer
height, and hemoglobin concentrations did not differ among the
setting was rapidly fitted at the designated concentration and
groups (Table 1).
maintained for 10 min. In the N2O-treated groups, 75 vol%
All patients were premedicated with 0.1 mg/kg midazolam
N2O (inspired) was given throughout the study period, begin-
orally 60 min before induction of anesthesia. Before arrival in
ning 3 min before tracheal intubation. The fresh gas flow rate
the operating room, all patients had an IV catheter placed to
was adjusted to 6 L/min (N2O 4.5 plus O2 1.5 or O2 6)
serve as a route for drug and fluid administration. Addi-
before and 4 L/min (N2O 3 plus O2 1 or O2 4) after
tionally, a 20-gauge catheter was placed into the radial artery
intubation. Lungs were mechanically ventilated to maintain
to continuously monitor the blood pressure and to take blood
end-tidal CO2 tension between 35 and 40 mmHg.
samples. For each patient, a rest period of at least 30 min
Routine monitoring included invasive measurements of sys-
was allowed to elapse between the time of cannulation and the
temic blood pressure, HR and rhythm by 5-lead ECG, and ox-
start of the study.
ygen saturation by pulse oximetry. Throughout the experiment,
The patients were randomly assigned to one of six groups
the inspired and end-tidal concentrations of desflurane, sevoflu-
according to a table of random numbers (n = 25 each): 2%
rane, N2O, and CO2 were measured using a gas analyzer
sevoflurane in 100% oxygen (control), 2% sevoflurane with
(Capnomac Ultima, Datex, Helsinki, Finland), which was cali-
75% N2O in oxygen, 6% desflurane in 100% oxygen, 6%
brated before each use.
desflurane with 75% N2O in oxygen, 12% desflurane in 100%
Arterial blood pressure (mmHg) and HR (beats/min) were
oxygen, or 12% desflurane with 75% N2O in oxygen. Anes-
continuously monitored. Hypertension was defined as a systolic
thetic concentration in each group was expressed in inspired
arterial blood pressure (SAP) higher than 130% of the basal
concentration. Those receiving 2% sevoflurane served as con-
value or ＞ 160 mmHg, whereas hypotension was defined as
10)
trol since it neither alters HR
nor causes cardiovascular
SAP ＜ 70% of the basal value or ＜ 90 mmHg. Secondary
stimulation during rapid increases of inspired anesthetic concen-
increase in SAP was defined as any increase in SAP more
trations in humans.5)
than 3 mmHg than before after first peak at 3 to 7 min of
After recording baseline measurements and breathing 100%
intubation, whereas secondary increase in HR more than 3
oxygen, anesthesia was induced with thiopental 5-7 mg/kg
beats/min. Tachycardia and bradycardia were defined as HR S 26
Kyung Yeon Yoo, et al：Effect of N2O and Desflurane on CV Responses to Intubation
more than 120 beats/min and ＜ 60 beats/min, respectively. A
plication rates among the groups were analyzed using the
dysrhythmia was defined as any ventricular or supraventricular
Chi-squared test where appropriate. A P value ＜ 0.05 was
premature beat or any sustained rhythm other than sinus.
considered statistically significant.
Arterial blood samples were drawn before the induction of anesthesia (baseline), 3 min after the induction with thiopental,
RESULTS
and 1 and 5 min after intubation. The samples were collected into prechilled tubes containing EDTA-Na and immediately
Laryngoscopy and tracheal intubation began 3 min after the
centrifuged at 3000 rpm for 15 min at 4oC. The plasma was
administration of thiopental and vecuronium, when the end-tidal
stored at －70oC until assayed for catecholamine concentrations.
N2O concentrations were 55 ± 5% in the N2O-treated groups.
Plasma concentrations of norepinephrine and epinephrine were
End-tidal concentrations of sevoflurane in patients given 2%
measured in duplicates using the technique of high-pressure
sevoflurane at 1 and 5 min after the intubation were 0.7 ±
liquid chromatography.11) The assay sensitivity was 10.0 pg/ml,
0.2% and 1.5 ± 0.2%, respectively. Those of desflurane in
and within-run precision coefficients of variation were 13.5%
patients given 6% and 12% desflurane at 1 min were 2.8 ±
and 14.2% for norepinephrine and epinephrine, respectively.
0.5% and 5.0 ± 1.3%, and at 5 min 4.2 ± 0.8% and 8.5 ± 0.8%, respectively, with no differences between the groups
The power calculation for including 25 patients was based
with and without N2O.
on being able to show a difference of 15% in SAP after intubation between the groups in our pilot study (16 in each
Figures 1 and 2 show SAP and HR before and after the
group for 80% power with P ＜ 0.05). All results are exp-
endotracheal intubation. Basal SAP and HR did not differ
ressed as mean ± SD. They were analysed using Stat View
among the groups. The induction of anesthesia with thiopental
software version 4.0 (Abacus Concepts, Berkeley, CA, USA)
with or without N2O significantly decreased SAP. The tracheal
on a Macintosh computer. Statistical analyses of the data were
intubation then resulted in an immediate increase of SAP in
performed by two-way ANOVA with repeated measures. A
all groups, the peak increase being noted within 1 min. The
Scheffé test was used for multiple pair-wise comparisons when
degree of peak increase was smaller in those with N2O than
a significant difference was indicated with ANOVA. Com-
without (Fig. 1). While SAP progressively returned toward the
Fig. 1. Systolic arterial pressure changes in patients given 2% sevoflurane, 6% desflurane, or 12% desflurane with and without 75% N2O before induction (baseline), immediately before intubation (Ind) and 1, 2, 3, 4 and 5 min postintubation. Data are presented as mean ± SD. *P ＜ 0.05 vs. baseline, †P ＜ 0.05 vs 2% sevoflurane with 0% N2O group.
Fig. 2. Heart rate changes in patients given 2% sevoflurane, 6% desflurane, or 12% desflurane with and without 75% N2O before induction (baseline), immediately before intubation (Ind) and 1, 2, 3, 4 and 5 min postintubation. Data are presented as mean ± SD. *P ＜ 0.05 vs. baseline, †P ＜0.05 vs. 2% sevoflurane with 0% N2O group.
S 27
Korean J Anesthesiol：Vol. 52. No. 6, 2007
Fig. 3. The first and second peak changes from postinduction values in systolic arterial blood pressure (ΔSAP) and heart rate (ΔHR) in † patients given 12% desflurane with 0% or 75% N2O. Data are presented as mean ± SD. *P ＜0.05 vs corresponding 0% N2O group, P ＜ 0.05 vs the first response.
Table 2. Incidence of Adverse Effects Tachycardia Bradycardia Groups Hypertension Hypotension Dysrhythmia (HR ＞ 120 beats/min) (HR ＜ 60 beats/min) Without N2O 1-sevoflurane 21 0 2 2 2 1-desflurane 18 0 0 4 4 2-desflurane 18 1 8* 1 1 With N2O 1-sevoflurane 14* 0 1 3 0 1-desflurane 14* 0 4 3 2 2-desflurane 11* 3 10* 0 1 Data are presented as number. n: 25 patients per group. HR: heart rate. *P ＜ 0.05 vs. 1 MAC sevoflurane 0% N2O group.
basal values thereafter in patients given 2% sevoflurane or 6%
frequent in those without N2O than with. Tachycardia was
desflurane, a secondary increase was noted in 12% desflurane
more common in those with 12% desflurane than with 2%
groups at 3-5 min after the intubation (48 ± 33 mmHg vs
sevoflurane. The incidence of hypotension, bradycardia, and
70 ± 24 mmHg from postinduction values, P ＜ 0.05; Fig. 3).
ventricular ectopic beats did not differ among the groups. The
The higher dose of desflurane delayed the return to the base-
arrhythmia disappeared spontaneously without treatment (Table
line blood pressure (6.1 ± 3.8 min with 12% vs 2.7 ± 1.3
2). None developed ECG changes suggestive of myocardial
min with 6%, P ＜ 0.05).
ischemia.
HR did not change significantly during induction of anes-
Table 3 shows the plasma catecholamine concentrations
thesia, but significantly increased following the intubation, the
before and after intubation. Basal concentrations of norepi-
degree of which did not differ among the six groups (Fig. 2).
nephrine and epinephrine were not different among the groups.
In addition, 12% desflurane elicited a second tachycardiac re-
They were not affected by anesthetic induction with thiopental
sponse, its magnitude being greater than that of the first (34
or N2O. Norepinephrine concentrations then increased, when
± 18 beats/min vs 23 ± 16 beats/min; Fig. 3). N2O signifi-
measured at 1 min after the intubation, in all groups. The
cantly attenuated the magnitude of both first and second pres-
increase was greater in 12% desflurane group than in 6%
sor responses and sped the restoration of basal blood pressure,
desflurane or control group. The norepinephrine concentrations
whereas it did not affect HR response. Hypertension was more
returned toward postinduction values at 5 min in 6% desS 28
Kyung Yeon Yoo, et al：Effect of N2O and Desflurane on CV Responses to Intubation Table 3. Plasma Concentration of Norepinephriene and Epinephrine Groups Baseline Induction PI-1 PI-5 PI-10 Norepinephrine Without N2O (pg/ml) 1-sevoflurane 205 ± 67 179 ± 54 216 ± 67† 194 ± 82 － 1-desflurane 218 ± 90 199 ± 75 254 ± 88*† 209 ± 93 － 2-desflurane 222 ± 45 181 ± 53 304 ± 75*†‡ 500 ± 204*†‡ 631 ± 238*† With N2O 1-sevoflurane 204 ± 59 176 ± 53 269 ± 88*†§ 250 ± 60†§ － † 1-desflurane 226 ± 99 188 ± 85 292 ± 103* 299 ± 142*†§ － 2-desflurane 202 ± 72 171 ± 63 390 ± 330*†‡ 607 ± 288*†‡ 730 ± 316*† Epinephrine (pg/ml)
Without N2O 1-sevoflurane 66 ± 26 62 ± 21 72 ± 41 63 ± 29 － 1-desflurane 64 ± 34 57 ± 26 64 ± 69 51 ± 34 － 2-desflurane 75 ± 23 66 ± 26 64 ± 24 77 ± 43 75 ± 48 With N2O 1-sevoflurane 64 ± 28 55 ± 15 57 ± 33 53 ± 28 － 1-desflurane 70 ± 31 57 ± 19 64 ± 35 62 ± 44 － †§ † † 2-desflurane 73 ± 28 55 ± 16 90 ± 54* 103 ± 69* 88 ± 44* Data are presented as means ± SD. n: 25 patients per group. Induction: 3 min after administration of thiopental with or without N2O. PI-1, † ‡ PI-5, PI-10: 1, 5 and 10 min after the onset of intubation. *P ＜ 0.05 vs. baseline and induction, P ＜ 0.05 vs. induction, P ＜ 0.05 vs. 1 § MAC sevoflurane with 0% N2O group, P ＜ 0.05 vs. corresponding 0% N2O groups.
Fig. 4. Changes at 1 and 5 min after intubation from postinduction values in plasma norepinephrine (ΔNE) and epinephrine (ΔE) concen† trations. Data are presented as mean ± SD. *P ＜ 0.05 vs. corresponding 0% N2O groups, P ＜0.05 vs 2% sevoflurane with 0% N2O.
flurane or control group but increased further in 12% de-
DISCUSSION
sflurane group. N2O augmented the norepinephrine response at 1 and 5 min after the intubation especially in the 2% sevoflurane and 6% desflurane groups (P ＜ 0.05). On the contrary,
Laryngoscopy and endotracheal intubation increased hemody-
the epinephrine concentration was not altered significantly in
namic variables, which peaked within 1 min in all groups.
any groups, except for the group receiving 12% desflurane
This change has been regarded as a response to mechanical
with N2O (Fig. 4).
stimulus of laryngoscopy and intubation.12-14) In addition, in the group given a higher dose of desflurane, a biphasic hemodyS 29
Korean J Anesthesiol：Vol. 52. No. 6, 2007
cal or chemical.
namic effect was noted, in which the second peak appeared at 3 to 5 min after the intubation. It has been known that
N2O did not affect basal plasma norepinephrine concen-
anesthetics themselves including desflurane may cause tachy-
trations. However, it augmented the norepinephrine response to
cardia and hypertension when their concentrations were rapidly
either mechanical or chemical stimuli, although it diminished
increased.
5,7,15)
Previous studies also have shown a delayed ef-
the pressor response. This finding is in line with that observed
fect of desflurane to cause sympathetic activation.7,15) In this
by Segawa et al.,19) in which isoflurane and sevoflurane
context, the second hemodynamic change may be a response
suppressed hemodynamic responses to surgical noxious stimuli
to desflurane itself. However, N2O attenuated first and second
along with an augmented norepinephrine response. N2O may
pressor although it did not affect tachycardiac responses and
not affect basal but augment stimulated sympathetic activity.
augmented norepinephrine release.
The decreased blood pressure response may then be attributed
The magnitude of the second HR response to 12% des-
to an attenuated cardiovascular response to catecholamines rath-
flurane was greater than the first (Fig. 3), in association with
er than to a suppressed sympathetic discharge. Alternatively,
a more pronounced norepinephrine release. This finding sug-
the larger unloading of arterial baroreceptor secondary to a
gests that the chemical stimulus of desflurane on the sym-
lowered blood pressure by N2O may have led to a larger
pathetic nervous system is more potent than the mechanical
efferent sympathetic discharge, resulting in an enhanced norep-
stimulus. The speculation may be in line with a previous ob-
inephrine release. However, a desflurane-mediated sympathetic
servation, in which high concentrations of isoflurane, although
activation still occurs in whom baroreceptor unloading and
being sufficient to block the neurocirculatory response to laryn-
hypotension was prevented by phenylephrine.20)
goscopy and tracheal intubation, failed to block the sym-
On the other hand, epinephrine concentrations were not
pathetic nervous activation from desflurane in young human
affected in either group except for that receiving 12% des-
volunteers.15) A rapid increase of end-tidal concentrations of
flurane with N2O. Previous studies demonstrated that tracheal
desflurane exceeding 1 minimum alveolar concentration may
intubation2,3) as well as desflurane inhalation19) was associated
even produce myocardial ischemia in patients with coronary
a small increase or no changes in plasma epinephrine concen-
artery disease.6)
trations. However, N2O augmented the increase of epinephrine
On the contrary, the magnitude of the second pressor effect
concentrations due to desflurane. Desflurane and N2O may
was smaller than that of the first (Fig. 3). The sympathetic
have additive effects on epinephrine release.
nervous activity triggered by desflurane is mainly responsible
Limitations of our study may include a virtual concentration
for both pressor and tachycardiac responses. However, the
of desflurane and N2O lower than designated. However, the
sympathetically-induced vasoconstriction may be counteracted
values may mimic those observed in the usual clinical practice.
by direct smooth muscle-relaxing effects of desflurane.16) The
Their concentrations would have been greater if the inflow gas
diminished pressor effect may thus be attributed to an
was primed with desflurane and N2O, if a high pressure was
attenuated vasoconstriction.
used to achieve rapid equilibration, or fresh gas flow was
Although N2O is also known to stimulate sympathetic ac-
increased. Another limitation may be associated with an in-
tivity,8,9) the impact of its interaction with desflurane on the
adequate depth of anesthesia during endotracheal intubation.
cardiovascular responses to tracheal intubation is unknown. It
However, although the light anesthesia may enhance the hemo-
was shown in the present study that N2O attenuated the
dynamic response to intubation, the depth of anesthesia was
pressor but not tachycardiac responses to tracheal intubation as
similar in all groups, so that it may have not influenced the
well as to desflurane, despite an augmented norepinephrine
results of our study.
release. This finding is in line with previous observations, in
In summary, a rapid increase of higher dose of desflurane
that N2O suppressed cardiovascular responses to tracheal in-
immediately after endotracheal intubation elicited biphasic car-
tubation in children17) and blunted the pressor response to
diovascular increases, in which N2O attenuated the first and
desflurane.18) Sympathomimetic effects of N2O have been ob-
the second pressor responses along with an augmented increase
served only when N2O is used in the absence of any other
of plasma norepinephrine concentrations. The potential unto-
noxious stimuli.8,9) It is thus likely that N2O should attenuate
ward cardiovascular effects due to desflurane may be of clin-
the cardiovascular responses to noxious stimuli, either mechani-
ical significance. S 30
Kyung Yeon Yoo, et al：Effect of N2O and Desflurane on CV Responses to Intubation 10. Ebert TJ, Harkin CP, Muzi M: Cardiovascular responses to sevoflurane: a review. Anesth Analg 1995; 81(6 Suppl): S11-22. 11. Holly JM, Makin HL: The estimation of catecholamines in human plasma. Anal Biochem 1983; 128: 257-74. 12. Dohi S, Gold MI: Pulmonary mechanics during general anaesthesia. The influence of mechanical irritation on the airway. Br J Anaesth 1979; 51: 205-14. 13. Dohi S, Nishikawa T, Ujike Y, Mayumi T: Circulatory responses to airway stimulation and cervical epidural blockade. Anesthesiology 1982; 57: 359-63. 14. Hickey S, Cameron AE, Asbury AJ, Murray GD: Timing of peak pressor response following endotracheal intubation. Acta Anaesthesiol Scand 1992; 36: 21-4. 15. Ebert TJ, Trotier TS, Arain SR, Uhrich TD, Barney JA: High concentrations of isoflurane do not block the sympathetic nervous system activation from desflurane. Can J Anaesth 2001; 48: 133-8. 16. Crystal GJ, Zhou X, Gurevicius J, Czinn EA, Salem MR, Alam S, et al: Direct coronary vasomotor effects of sevoflurane and desflurane in in situ canine hearts. Anesthesiology 2000; 92: 110313. 17. Swan HD, Crawford MW, Pua HL, Stephens D, Lerman J: Additive contribution of nitrous oxide to sevoflurane minimum alveolar concentration for tracheal intubation in children. Anesthesiology 1999; 91: 667-71. 18. Ghouri AF, White PF: Effect of fentanyl and nitrous oxide on the desflurane anesthetic requirement. Anesth Analg 1991; 72: 377-81. 19. Segawa H, Mori K, Murakawa M, Kasai K, Shirakami G, Adachi T, et al: Isoflurane and sevoflurane augment norepinephrine responses to surgical noxious stimulation in humans. Anesthesiology 1998; 89: 1407-13. 20. Ebert TJ, Perez F, Uhrich TD, Deshur MA: Desflurane-mediated sympathetic activation occurs in humans despite preventing hypotension and baroreceptor unloading. Anesthesiology 1998; 88: 1227-32.
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