British Journal of Anaesthesia 1998; 81: 203207

Effects of thiopental on airway calibre in dogs: direct visualization

method using a superfine fibreoptic bronchoscope
K. HIROTA, N. OHTOMO, Y. HASHIMOTO, T. KUDO, M. KUDO, H. ISHIHARA AND A. MATSUKI

Summary
Induction of anaesthesia with thiopental sometimes
causes
bronchospasm.
Although
the
mechanism by which thiopental induces bronchospasm may involve cholinergic stimulation,
direct spastic effect and histamine release, the
spastic effects of thiopental have not been comprehensively defined. In this study, we have
assessed the effect of thiopental on in vivo airway smooth muscle tone using direct visualization
method
with
a
superfine
fibreoptic
bronchoscope as previously reported. Twentyone mongrel dogs were anaesthetized with pentobarbital (30 mg kg91) and paralysed with pancuronium (200 g kg91 h91). The trachea was
intubated with a tube that had a second lumen
for insertion of the bronchoscope (od: 2.2 mm)
to continuously measure bronchial cross-sectional area. The tip of the bronchoscope was
placed between the second and third bronchial
bifurcation of the right lung. The dogs were allocated to three groups of seven: group T, A;T,
H;T. In group T, thiopental 0 (saline), 0.1,1.0 and
10 mg kg91 was given i.v. In group A;T, saline i.v.,
5 min later atropine 0.1 mg kg91 i.v., and 5 min
later thiopental 10 mg kg91 was administered. In
group H;T, bronchoconstriction was produced
with histamine 10 g kg91 i.v. followed by infusion
at 500 g kg91 h91. Thirty minutes later, thiopental
0, 1.0 and 10 mg kg91 were given. Arterial blood
sampling was performed for measurement of
plasma catecholamines and histamine. In group
T, thiopental significantly reduced bronchial
cross-sectional area (maximally by 28.7 (5.6% at
0.5 min after thiopental 10 mg kg91), which
returned to the baseline in 3 min, while any
changes in plasma concentrations of catecholamines and histamine were not observed
except norepinephrine level at 1 min following
thiopental 10 mg kg91 i.v. Atropine pretreatment
completely prevented thiopental-induced bronchospasm in group A;T. In group H;T, thiopental 10 mg kg91 transiently but significantly
decreases
bronchial
cross-sectional
area.
Therefore, the present study indicates that
the mechanism of thiopental bronchospasm
may result from cholinergic nerve stimulation.
(Br. J. Anaesth. 1998; 81: 203207)
Keywords: anaesthetics i.v., thiopental; complications, bronchospasm; histamine; measurement techniques, fibreoptic
bronchoscope

Induction doses of thiopental do not abolish airway

reflexes and hence tracheal intubation sometimes
causes bronchospasm.1 Baker and colleagues2
reported that induction doses of thiopental produced
a significant decrease in the angle formed by the vocal
cords. In addition they observed complete glottic closure in four of 14 patients. As the entire motor innervation to the laryngeal muscles is supplied by two
branches of the vagus nerve: the superior and recurrent laryngeal nerves,3 the reduction in angle between
the vocal cords including laryngospasm may be
caused by vagal stimulation by thiopental. Thiopental
related allergic reactions may be partially because of
bronchospasm, as thiopental causes histamine release
from leucocytes.46 Several in vitro studies7 8 have also
shown direct spastic effects of thiopental on tracheal
smooth muscle. The use of thiopental in asthmatic
patients is controversial. Shnider and Papper9
reported that thiopental in itself did not cause bronchospasm in asthmatic patients, while Pizov and
colleagues10 described that both asthmatic and nonasthmatic patients receiving thiobarbiturates had a
greater incidence of wheezing (45%, 13%, respectively) than did asthmatic and non-asthmatic patients
receiving propofol (0%, 3%, respectively).
We have recently developed a new direct method
for quantification of bronchial calibre using a
superfine fibreoptic bronchoscope, and have shown
that this direct method may be more specific
than conventional measurements such as airway pressure, airway resistance or dynamic pulmonary compliance.1115 In the present study, we have used this
method to evaluate the in vivo effects of thiopental on
bronchial smooth muscles in dogs.

Methods
Our study design was approved by Animal Care and
Use Committee of the University of Hirosaki School
of Medicine. Twenty-one mongrel dogs (812 kg)
were anaesthetized with pentobarbital 30 mg kg91 i.v.
and paralysed with pancuronium at 200 g kg91 h91.
The tracheas were intubated with tubes (id: 7.0 mm,
Univent tube, Fuji System, Tokyo) that have a second
lumen for the insertion of a superfine fibreoptic bronchoscope. The lungs were mechanically ventilated
KAZUYOSHI HIROTA, MD, NORIAKI OHTOMO, MD, YOSHIO HASHIMOTO,
MD, TSUYOSHI KUDO, MD, MIHOKO KUDO, MD, HIRONORI ISHIHARA,
MD, AKITOMO MATSUKI, MD, Department of Anesthesiology,
University of Hirosaki School of Medicine, Hirosaki 036, Japan.
Accepted for publication: March 6, 1998.
Correspondence to K. H.

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British Journal of Anaesthesia

using a volume-controlled respirator (Servo 900C)

with oxygen and the end-tidal carbon dioxide maintained at 4.04.5%. The femoral artery was cannulated to monitor arterial pressure and to obtain
arterial blood samples. The femoral vein was also cannulated to insert a Swan-Ganz catheter (Baxter
Health Co., Tokyo) via its sheath to avoid potentiation
of histamine-induced bronchospasm by flushing histamine from the dead space of a single i.v. catheter.
IMAGING AND ANALYSIS OF AIRWAY

We inserted a superfine fibreoptic bronchoscope (od

2.2 mm: AF type 22A, Olympus, Tokyo) through the
second lumen of the tracheal tube placing the tip
between the second and third bronchial bifurcation

of the right bronchus in order to continuously monitor bronchial cross-sectional area at the third bifurcation. The image at the third bifurcation was printed
out with a videoprinter (VY-170, Hitachi, Tokyo)
after expiration and before inspiration. The printed
image was imported into a Macintosh computer
(Power Macintosh 7100/80 AV, Apple Computer
Inc., California) using a scanner (Scan-Jet 4c,
Hewlett Packard Co, Colorado) to measure the
bronchial cross-sectional area with the NIH Image
program, which is a public domain image processing
and analysis program (Wayne Rasband, US National
Institutes of Health, available from Internet by
anonymous ftp from zippy.nimh.nih.gov or on floppy
disk from NTIS, 5285 Port Royal RD., Springfield,
VA 22161, part number PB93504868).

Figure 1 Effect of thiopental on basal bronchial cross-sectional area with (B) and without atropine (Atrop)
pretreatment (A). Pre: before thiopental or saline i.v., Thiop: thiopental, *P:0.05, **P:0.01 compared with Pre. All
values are expressed as mean (SEM).

Thiopental and bronchoconstriction

PROCEDURE

205

1: EFFECT OF THIOPENTAL ON THE BASAL

AIRWAY TONE

Fourteen dogs were allocated to two groups:

thiopental administration group (group T, n:7) and
atropine-thiopental administration group (group
A;T, n:7). One hour after the placement of a
superfine fibreoptic bronchoscope, the experiment
was started. This reduces the effect of pentobarbital
induction as pentobarbital in itself decreases
bronchial cross-sectional area.13 However, dogs
remained anaesthetized until the following procedure started (confirmed by electroencephalography
in another 7 dogs).
In group T, after the basal bronchial crosssectional area was measured, each thiopental dose:
0 (saline), 0.1, 1.0, 10 mg kg91 was given in this order
at 5-min intervals. The bronchial cross-sectional area
was measured at 0.5, 1, 2, 3, 4 and 5 min after each
thiopental dose i.v.
In group A;T, saline was given to confirm that the
bronchoscope was well-fixed without any significant
changes in bronchial cross-sectional area, 5 min later
atropine 0.1 mg kg91 was given i.v. and then 5 min
later thiopental 10 mg kg91 was administered. The
bronchial cross-sectional area was measured at 0 and
5 min after atropine i.v. and 0.5, 1, 2, 3, 4 and 5 min
after thiopental i.v.
PROCEDURE

2: EFFECTS OF THIOPENTAL ON

HISTAMINE-INDUCED BRONCHOCONSTRICTION

Seven dogs were studied. The basal bronchial

cross-sectional area measurement was performed
before the induction of bronchoconstriction by continuous infusion of histamine at 500 g kg91 h91 following a bolus injection of 10 g kg91 via pulmonary
arterial catheter until the end of the experiment.
Systolic arterial pressure was maintained above
80 mm Hg with fluid (lactate Ringers solution:
50 ml kg91) and with continuous phenylephrine infusion at 0.592.0 g kg91 min91, the rate of which was
dependent on systolic arterial pressure. Thirty minutes
after the start of histamine infusion, thiopental: 0
(saline), 1.0,10 mg kg91 was given in this order at 5-min
intervals. The bronchial cross-sectional area was measured at 0.5, 1, 2, 3, 4 and 5 min after each thiopental
dose i.v. The bronchial cross-sectional area is presented
as % of basal bronchial cross-sectional area.
PLASMA CATECHOLAMINES AND HISTAMINE ASSAY

Blood samples (6 ml) were taken through the arterial

cannula at 1 and 5 min after each dose of thiopental
i.v. and were immediately centrifuged at 3000 rpm
for 10 min at 910 C to separate plasma which
was then frozen at 70 C until assayed. The plasma

concentrations of epinephrine and norepinephrine

were determined by gas chromatography mass spectrometry in all groups. The coefficient of variation of
the assay was 8.4% for epinephrine and 11.3% for
norepinephrine. Plasma histamine concentrations in
group T were measured by radioimmunoassay. The
minimal detection limit was 0.2 nmol litre91 and the
intra- and inter-assay coefficient of variations were
7.2% and 7.8%, respectively. The antiserum showed
no significant cross-reactivity with L-histidine,
methyl-histamine, imidazole or methyl-imidazole.
STATISTICAL ANALYSIS

All data were expressed as mean (SEM). Data were

analysed statistically using repeated measures analysis
of variance followed by Fishers protected least significant difference test using Stat View 2.0 for
Macintosh. A P:0.05 was considered significant.

Results
PROCEDURE

Thiopental (91.0 mg kg91) significantly reduced

bronchial cross-sectional area, which spontaneously
returned to the baseline within 3 min (group T, fig.
1A). With the exception of norepinephrine at 1 min
after thiopental 10 mg kg91 i.v., plasma concentrations
of epinephrine, norepinephrine and histamine did
not change significantly after thiopental i.v. (table 1).
In group A;T, atropine significantly increased
bronchial cross-sectional area, and this preadministration blocked thiopental-induced decrease in the
bronchial cross-sectional area (fig. 1B). Moreover,
thiopental significantly increased atropine-pretreated
bronchial cross-sectional area (fig. 1B).
PROCEDURE

Histamine decreased the bronchial cross-sectional

area by 34.1% (2.6%) of basal bronchial crosssectional area. The bronchial cross-sectional area
decreased transiently but significantly after thiopental 10 mg kg91 (fig. 2). Plasma catecholamines did not
change (table 2).

Discussion
The present study demonstrates that thiopental transiently but significantly increased basal bronchial
smooth muscle tone, which was completely inhibited
by atropine pretreatment. Several reports2 16 suggest
that thiopental may increase upper airway reflex sensitivity to produce laryngospasm. This finding supports the notion that thiopental increases vagal tone
to produce bronchospasm.

Table 1 Changes in plasma catecholamine and histamine concentrations 1 and 5 min following thiopental (T) i.v., mean (SEM). **P:0.01
compared with before thiopental
T 0.1 mg kg91

ml91)

Norepinephrine (pg
Epinephrine (pg ml91)
Histamine (nmol litre91)

T 1.0 mg kg91

T 10 mg kg91

Before

1 min

5 min

1 min

5 min

1 min

5 min

121 (27)
159 (15)
1.7 (0.2)

158 (31)
129 (13)
1.6 (0.2)

136 (32)
127 (23)
1.6 (0.2)

143 (24)
119 (14)
1.6 (0.2)

151 (35)
122 (19)
1.9 (0.2)

240 (75)
167 (22)
1.9 (0.3)

186 (41)
131 (10)
1.8 (0.2)

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British Journal of Anaesthesia

Table 2 Changes in plasma catecholamine concentrations 1 and 5 min after thiopental (T) i.v. in presence of histamine
(H) infusion at 500 g kg91 h91, mean (SEM). H30: 30 min after the start of histamine infusion

Norepinephrine (pg ml91)

Epinephrine (ng ml91)

T 1.0 mg kg91

T 10 mg kg91

H30

Saline

1 min

5 min

1 min

5 min

237 (91)
3.78 (1.53)

202 (57)
3.16 (1.18)

321 (122)
7.82 (5.91)

306 (140)
4.84 (2.64)

453 (296)
7.38 (6.37)

293 (137)
16.5 (15.9)

Figure 2 Effect of thiopental on histamine (H)-induced bronchoconstriction assessed by changes in bronchial cross-sectional area. Pre:
before start of H infusion. H30:30 min after the start of H infusion, *P:0.05 compared with H30. All values are expressed as mean (SEM).

In vitro studies indicate that thiobarbiturates, but

not oxybarbiturates, directly produce airway smooth
muscle contraction7 which may result from the production of thromboxane A2.8 However, our previous
report13 showed that pentobarbital, an oxybarbiturate, increased bronchial smooth muscle tone.
Moreover, the present study shows that thiopentalinduced bronchospasm was completely blocked by
atropine. Therefore, the production of thromboxane
A2 by thiopental may not be the primarily cause of
bronchospasm in vivo.
Hirshman and colleagues4 reported that thiopentalcaused anaphylactic shock which may be because of
histamine release from leucocytes. They also showed
that thiopental induces histamine release in human
skin mast cells.5 In addition, Lorenz and colleagues6
found increases in plasma histamine concentrations
after i.v. administration of thiopental even in normal
subjects. These findings suggest that histamine
release may be involved in the mechanism of
thiopental-induced bronchospasm. However, in the
present study, as the plasma concentration of histamine did not change after i.v. thiopental, histamine
release may not contribute to bronchospasm.
As thiopental inhibits sympathetic neural outflow,17
it may cause bronchospasm.18 However, in the present
study, plasma level of catecholamines were not altered
by thiopental i.v. with and without histamine infusion
that increased plasma catecholamine concentration.
Therefore, it is unlikely that sympatholytic effect of
thiopental caused the bronchospasm in the present
study.
In the present study, after atropine administration,

thiopental unexpectedly produced a relaxant effect.

Yamakage and colleagues19 reported that thiopental
inhibits voltage sensitive Ca2; channels in porcine tracheal smooth muscle cells. It has been suggested that
block of Ca2; channels causes airway relaxation.20
Taken together, the relaxant effect of thiopental following vagal denervation might be because of inhibition of Ca2; influx.
In conclusion, the present study indicates that
thiopental should be used carefully in patients with
hyper-reactive airway as thiopental produced and
worsened bronchospasm via vagal stimulation, and
that atropine might protect from thiopental-induced
bronchospasm.

References
1. Wedley JR. Thiopentone induced bronchospasm. Anaesthesia
1973; 28: 318319.
2. Baker P, Langton JA, Wilson IG, Smith G. Movements of the
vocal cords on induction of anaesthesia with thiopentone or
propofol. British Journal of Anaesthesia 1992; 69: 2325.
3. Stone DJ, Gal TJ. Airway management. In: Miller RD, ed.
Anesthesia, 4th Edn. New York: Churchill Livingstone, 1994;
14031436.
4. Hirshman CA, Peter J, Cartwright-Lee BC. Leukocyte histamine release to thiopental. Anesthesiology 1982; 56: 6467.
5. Hirshman CA, Edelstein RA, Ebert JM, Hanifin JM.
Thiobarbiturate-induced histamine release in human skin
mast cells. Anesthesiology 1985; 63: 353356.
6. Lorenz W, Doenicke A, Meyer R, Reimann HJ, Kusche J,
Barth H, Geesing H, Hutzel M, Weissenbacher B. Histamine
release in man by propranidid and thiopentone:
Pharmacological effects and clinical consequences. British
Journal of Anaesthesia 1972; 44: 355368.

Thiopental and bronchoconstriction

7. Lenox WC, Mitzner W, Hirshman CA. Mechanism of
thiopental-induced constriction of guinea pig trachea.
Anesthesiology 1990; 72: 921925.
8. Curry C, Lenox WC, Spannhake EW, Hirshman CA.
Contractile responses of guinea pig trachea to oxybarbiturates
and thiobarbiturates. Anesthesiology 1991; 75: 679683.
9. Shnider SM, Papper EM. Anesthesia for the asthmatic
patient. Anesthesiology 1961; 22: 886892.
10. Pizov R, Brown RH, Weiss YS, Baranov D, Hennes H, Baker
S, Hirshman CA. Wheezing during induction of general anesthesia in patients with and without asthma. Anesthesiology
1995; 82: 11111116.
11. Hashimoto Y, Hirota K, Ohtomo N, Ishihara H, Matsuki A. In
vivo direct measurement of the bronchodilating effect of
sevoflurane using a superfine fibreoptic bronchoscope: comparison with enflurane and halothane. Journal of
Cardiothoracic and Vascular Anesthesia 1996; 10: 213216.
12. Otomo N, Hirota K, Sato T, Hashimoto Y, Ishihara H. In vivo
assessment of droperidol-induced bronchial relaxation in
dogs using a superfine fibreoptic bronchoscope. British
Journal of Anaesthesia 1997; 78: 579582.
13. Otomo N, Hirota K, Hashimoto Y, Kushikata T, Sato T,
Ishihara H, Matsuki A. Measurement of bronchodilation
using a superfine fibreoptic bronchoscope. British Journal of
Anaesthesia 1997; 78: 583585.
14. Hirota K, Ohtomo N, Hashimoto Y, Kudo T, Ishihara H,

207

15.

16.
17.
18.
19.

20.

Matsuki A. Midazolam reverses histamine-induced bronchoconstriction in dogs. Canadian Journal of Anaesthesia 1997;
44: 11151119.
Hirota K, Hashimoto Y, Sakai T, Sato T, Ishihara H, Matsuki
A. In vivo spasmolytic effect of ketamine and adrenaline on
histamine-induced airway constriction. Direct visualization
method with a superfine fibreoptic bronchoscope. Acta
Anaesthesiologica Scandinavica 1998; 42: 184188.
Ruth HS, Tovell RM, Milligan AA, Chareleroy DK. Pentothal
sodium is its growing popularity justified? Journal of the
American Medical Association 1939; 113: 18641868.
Ebert TJ, Kanitz DD, Kampine JP. Inhibition of sympathetic
neural outflow during thiopental anesthesia in humans.
Anesthesia and Analgesia 1990; 71: 319326.
Gal TJ. Bronchial hyperresponsiveness and anesthesia: physiologic and therapeutic perspectives. Anesthesia and Analgesia
1994; 78: 559573.
Yamakage M, Hirshman CA, Croxton TL. Inhibitory effects
of thiopental, ketamine, and propofol on voltage-dependent
Ca2; channels in porcine tracheal smooth muscle cells.
Anesthesiology 1995; 83: 12741282.
Weichman BM, Muccitelli RM, Tucker SS, Wasserman MA.
Effect of calcium antagonists on leukotriene D4-induced contractions of the guinea-pig trachea and lung parenchyma.
Journal of Pharmacology and Experimental Therapeutics 1983;
225: 310315.