Zou et al.

J perioperative science 2014,1:5

http://www.perioperative-science.com/content/01/05
Journal of Perioperative Science
OPEN ACCESS REVIEW

The Protective Effect of Propofol on Airway in Asthmatic Patients

Zou Yi, Xin Xin, Zhao Jing*

Abstract
Asthma is a chronic inflammatory disease of airway characterized by intermittent airway obstruction
and reversible airway hyperresponsiveness (AHR). It presents a major public health problem with
increasing prevalence rates and severity worldwide. Patients with no pretreatment suffered from
perioperative asthmatic attack and might result in severe complications (such as hypoxemia,
pneumonia, pneumothorax, pulmonary barotraumain, prolonged intubation, atelectasis, mucus plugging
and so on). Propofol, a widely used short-acting intravenous anaesthetic, is recognized as the ideal
sedative in asthmatic patients, Results from many clinical observations and laboratory studies strongly
support the notion that propofol exerts significant protective effect of asthmatic airways. The
mechanisms of airway protection by propofol are complicated, involving the direct relaxation of airway
smooth muscle, the attenuation of parasympathetic nerve acetylcholine release, the anti-inflammation
properties, the stimulation of ciliary motility and so on. Despite abundant studies about the protective
effect of propofol in asthmatic patients, the mechanisms remain to be further developed.
Keywords: Propofol; Asthma; Airway; Protective effect.

( J Perioper Sci 2014, 1:5 )

Introduction significantly during the past few decades [4,5].

Asthma is a chronic inflammatory disease of airway
characterized by intermittent airway obstruction and
reversible airway hyperresponsiveness (AHR). It
presents a major public health problem with
increasing prevalence rates and severity worldwide
[1]. According to the data from World Health
Organization (WHO) and Global Initiative for
Asthma (GINA), 235-300 million people currently
suffer from asthma as of 2011 and approximately
250,000 people die per year from asthma [2,3]. The
global prevalence of asthma have increased
From the *Department of Anesthesiology, Peking Union
Medical College Hospital, Peking Union Medical College,
Beijing, China
Accepted for publication July 20, 2014.
Reprints will not be available from the authors.
Address correspondence to Zhao Jing: Department of
Anesthesiology, Peking Union Medical College Hospital,
Peking Union Medical College, Beijing, China. Address e-mail
to zhaojing1009@aliyun.com.
According to national center for health statistics
(NCHS), asthma prevalence increased from 7.3% in
2001 to 8.4% in 2010 in the United States [6].
Surgeries may be inevitable in some asthmatic
patients. About 10.2% of asthmatic patients with no
pretreatment suffered from perioperative asthmatic
attack and might result in severe complications
(such as hypoxemia, pneumonia, pneumothorax,
pulmonary barotraumain, prolonged intubation,
atelectasis, mucus plugging and so on) [7]. The
incidence of these peri-operative complications in
asthmatic populations reaches up to 30%, which is
much higher than that in healthy patients [8,9].
Because of the airway hyperreactivity,
bronchospasm may easily be induced by direct
airway stimuli (such as laryngoscopy, tracheal
intubation, airway suctioning, tracheal extubation
and so on), drugs, inadequate depth of anesthesia,
surgical stimuli and perioperative complications
such as aspiration, infection, or trauma. Therefore,
apart from prophylactic treatment of asthma before
surgeries, it is vital for anesthesiologists to choose

Copyright © 2014 Journal of Perioperative Science

Zou et al. J perioperative science 2014,1:5
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the most appropriate anesthetics for asthmatic
patients.
Propofol, a widely used short-acting intravenous
anaesthetic, is recognized as the ideal sedative in
asthmatic patients [10,11]. Results from many
clinical observations and laboratory studies strongly
support the notion that propofol exerts significant
protective effect of asthmatic airways. The
mechanisms of airway protection by propofol are
complicated, involving the direct relaxation of
airway smooth muscle, the attenuation of
parasympathetic nerve acetylcholine release, the
anti-inflammation properties, the stimulation of
ciliary motility and so on. Despite abundant studies
about the protective effect of propofol in asthmatic
patients, the mechanisms remain to be further
developed.
Airway Protective Effect of Propofol
It is widely observed in vitro and in vivo studies that
propofol can attenuate the response to a variety of
bronchoconstrictor agents in both animals and
humans, with hyperreactive or normal reactive
airways.
the effect of propofol on normal airways
A growing body of laboratory and clinical studies
support the concept that propofol has
bronchodilation properties not only in asthmatic
airways but also in normal airways.
Results from many studies have shown that
propofol decreases airway resistance in patients or
animals with normal reactive airways. In normal rats
with no previous airway constriction, airway
resistance was found to decrease after the rats were
anaesthetized with propofol [12]. Likewise, propofol
appeared to be superior to thiopental and
thiobarbiturate in inhibiting the prevalence of
tracheal intubation-induced bronchoconstriction as
propofol has been shown to decrease the prevalence
of wheezing after the induction of anesthesia and
intubation of the trachea in normal patients [11,13].
Compared with thiopental and etomidate, propofol
was associated with decreased airway resistance in a
randomized trial involving nonasthmatic smokers
undergoing general anesthesia [14].
Moreover, it is observed that propofopl is shown
to have a direct airway smooth muscle (ASM) at
concentration of 10-4M and a greater direct relaxant
effect on distal ASM than on proximal ASM[15].
The decrease in airway resistance with propofol
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anaesthesia was supported by central airway dilation
observed at lung histology in normal rats[12].
the effect of propofol on asthmatic airways
A number of studies and reports suggest that
propofol may have properties beneficial to patients
with asthma. During anesthesia induction, it is
observed that the incidences of wheezing and the
airway resistance at 2 and 5 min post-intubation
were significantly lower in asthmatic patients
anesthetized with propofol than with thiopental11.
When used for sedation, propofol is reported to
inhibit postoperative bronchospasm in two patients
with hyperreactive airway disease[16]. Moreover,
rapid improvement of symptoms was observed in a
patient moribund with asthma, shortly after
induction of anesthesia with propofol[17]. In vivo
studies, intraperitoneal injection of propofol is
shown to decrease the airway resistance induced by
methacholine in asthmatic mice[18]. In vitro studies,
propofol was able to induce concentration-
dependent relaxations in precontracted, isolated
trachea smooth muscle of asthmatic airways[19,20].
Mechanisms of Airway Protective Effect
of Propofol
The Direct Relaxant Effects of Propofol on
Airway Smooth Muscle
It is well known that the concentration of
intracellular free Ca2+ plays a central role in the
regulation of ASM tone, therefore the inhibition of
Ca2+ mobilization, decrease of Ca2+ sensitivity, or
both may contribute to the ASM relaxant effects of
propofol.
The Effects of Propofol on Intracellular
Concentration of [Ca2+]i
The direct relaxing effect on smooth muscle of
propofol has been ascribed to a reduction in the
concentration of intracellular concentration of
[Ca2+]i[12,14]. The regulation of intracellular Ca2+
([Ca2+]i) is integrated by two mechanisms which
include Ca2+ release from the internal store
(sarcoplasmic reticulum, SR) and plasma membrane
Ca2+ influx. The mechanism underlying the
relaxant effects of propofol might be caused
inhibition of Ca2+ release from the internal store
and plasma membrane Ca2+ influx[21,22].
the effects of propofol on Ca2+ release from
internal store: Ca2+ release from intracellular
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stores is regulated by two mechanisms: inositol
phosphate (IP3)-induced Ca2+ release and Ca2+
induced Ca2+ release[23,24]. It is demonstrated that
propofol could attenuate the IP3 production induced
by carbachol[21]. IP3 is a second messenger in the
M3 receptor-coupled signaling pathway. This
finding indicates that propofol may interfere with
the components of receptor-G-protein-
phospholipase C pathway[21]. However, the precise
site of action is not known.
the effects of propofol on plasma membrane
Ca2+ influx: Ca2+ influx can occur through both
voltage-gated[25] and receptor gated channels[26].
The inhibition of Ca2+ influx may be caused by
blockade of L-type voltage-dependent Ca2+
channels[21,22,27]. As it is demonstrated in isolated
ASM, [Ca2+]i increase induced by KCl could be
inhibited by propofol and this inhibition was
blocked by verapamil (the voltage-operated calcium
channel blocker)[28].
However, it is demonstrated in some previous
studies that the inhibition effect of [Ca2+]i was
achieved at concentration higher than those
encountered clinically[27].
The Effects of Propofol on Sensitivity of [Ca2+]i
Airway smooth muscle contraction is not only
atttibuted to the increase in intracellular Ca2+
([Ca2+]i) on account of increased tension induced
by agonist at the same [Ca2+]i (increase in Ca2+
sensitivity). Evidence shows that propofol dilates
contracted ASM through reduction in intracellular
Ca2+ by inhibiting influx of Ca2+ and release of
intracellular stores, but not by decreased Ca2+
sensitivity[29]. However, conflicting evidence exists,
as the study from Grim et al shows propofol may
have an impact on Ca2+ sensitivity via RhoA/Rho-
kinase pathway[30].
The Effects of Propofol on Respiratory
Nerve System
It has been well known that parasympathetic
nervous system, adrenergic nerve system and
nonadrenergic noncholinergic (NANC) nerve
system together form the predominant neural
pathway and play an important role in the regulation
of airway diameter and resistance to airflow in
mammalian airway.
The Effects of Propofol on Parasympathetic
Nerve System
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Propofol was previously reported to be able to
decrease basal airway tone similarly to atropine and
attenuate histamine-induced bronchoconstriction
and it is maybe a reduction in vagal tone that
produce the relaxant effect[31]. Brown et al.[32]
found that propofol caused a dose-dependent
(8.4×10-5 M, 2.8×10-4 M, 8.4×10-4 M) attenuation
in the vagal nerve stimulation induced
bronchoconstriction. Furthermore, as the
spasmolytic effects of propofol did not differ
between normal dogs and vagotomized dogs, the
relaxant effect of propofol on methacholine-induced
bronchoconstriction may be a result of inhibition of
the peripheral vagal motor pathway instead of
central vagal pathway or direct inhibition of Ca2+
mobilization[33]. The concentrations (100μM)
required for these smooth muscle effects in the
above mentioned studies are above those typically
achieved clinically. Therefore, whether the clinically
relevant concentration of propofol relax ASM by
inhibiting the vagal motor pathway or not still needs
to be further explored.
The Inhibitory Effect of Propofol on
Nonadrenergic Noncholinergic Nerve System
Studies in humans and animal airway tissue models
demonstrated that propofol could attenuate
acetylcholine, histamine, and endothelin-1 induced
contractile responses, merely at concentrations
above those achieved clinically (1×10-4 M ~3×10-4
M)[21,22]. However, Gleason et al[34] indicated
that although propofol at clinically relevant
concentration could not attenuate acetylcholine
induced ASM contraction, it is able to inhibit
tachykinins A (neurotransmitter released by
nonadrenergic noncholinergic nerve) induced ASM
contraction. This finding suggests that propofol may
relax ASM by affecting nonadrenergic
noncholinergic (NANC) nerve system.
Studies suggesting a vagal nerve-mediated
mechanism for propofol have made two important
and perhaps incorrect assumptions of irritant
induced bronchoconstriction: (1) cholinergic nerves
are the primary airway efferent nerve and (2)
acetylcholine is the primary agonist. Nevertheless,
stimulated NANC nerves induce
bronchoconstriction in animals and humans by
liberated neurotransmitters (e.g., tachykinins).
Gleason et al [34] applied ten-second trains of
square wave direct current electrical field
stimulation (30-50 Hz, 24 V, 0.5ms pulse width) to
tracheal rings to induce contraction. These electrical
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stimuli induced a contractile response with two
distinct components: a rapid cholinergic contraction
followed by a more slowly developing contraction
classic for excitatory (procontractile) NANC
contractions. It is found that clinically relevant
concentrations of propofol relaxed the NANC
component of electrical field stimulation-induced
contraction mediated by tachykinins, while have no
effect on cholinergic component of electrical field
stimulation-induced contraction [34]. Therefore, it is
concluded that the mechanism of the protective
effect of propofol on irritant-induced
bronchoconstriction may be either by decreasing
NANC nerve transmission or by attenuating the
contractile effect of liberated tachykinins at the
neurokinin receptor on the airway smooth muscle
itself.
The Immunoregulatory Effect of Propofol on
Airway Inflammation
Airway inflammation has emerged as an important
contributor to mechanisms of asthma. The
immunologic-inflammatory pathways involved in
the pathogenesis of asthma are complex and include
lymphocytes (both Th1 and Th2), immunoglobulin
E, eosinophils, neutrophils, mast cells, leucotrienes,
and cytokines10. T-helper cell type (Th)
lymphocytes play an important role in the initiation,
progression and persistence of asthma. The
mechanism of action of the “Hygiene Hypothesis”
stated that insufficient stimulation of the Th1 arm,
stimulating the cell defence of the immune system,
leads to an overactive Th2 arm, stimulating the
antibody-mediated immunity of the immune systems
and playing an important role in induction and
aggravation of airway inflammation [35].
The immunoregulatory effect of propofol has
been shown in numerous studies that propofol not
only can preferably promote Th cells to differentiate
into Th1 cells [36,37] but also inhibit effects on
cytokines secreted by Th2 cells, such as interleukin
6 (IL-6) and IL-10 in some infectious animal models
or human [38,39]. Furthermore, it is currently
observed that propofol administration significantly
inhibited the elevation of cytokines secreted by Th2
cells (including IL-4, IL-5), while showed no effect
on IFN-γ (mainly secreted by in asthma mice, which
led to the down regulation of Th1/Th2 ratio18.
However, studies about the effect of propofol on
airway inflammation of asthma animals or human
are rare recently. Further investigations are yet
needed to be conducted.
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Other Potential Mechanisms of Protective
Effect of Propofol
The Effect of Propofol on Gamma-Aminobutyric
Acid (GABA)
It is found that low concentrations of propofol (20
μM) facilitated airway smooth muscle relaxation is
likely due to the signaling pathways regulating
relaxation rather than those regulating
contraction[40]. It is known that propofol is an
anesthetic with positive allosteric effects at the
GABAA channel. It has been a long-standing belief
that any potential GABAergic contribution to airway
tone is largely mediated by GABAA channels in the
brainstem [41] or by GABAB channels on
preganglionic cholinergic nerves in the lung [42].
Therefore, propofol may show relaxant effect by
acting on GABAA channels in the brainstem or
GABAB channels on preganglionic cholinergic
nerves in the lung. However, the airway smooth
muscle relaxation of propofol may be mediated by
enhancing the effect of GABA in the lung.
Endogenous GABA was also found to be existing in
the airway and plays an important role in
modulating airway smooth muscle tone by
facilitating smooth muscle relaxation via activation
of airway smooth muscle GABAA and GABAB
channels [40,41,43]. Gallos et al [40]demonstrated a
dose-dependent improvement in relaxation of a
substance P contraction by propofol, which was
partially reversed by low-dose GABAA channel
antagonism (gabazine, 5 μM). Therefore, the airway
smooth muscle relaxation of propofol may be
mediated by acting on this novel relaxation pathway.
Propofol Stimulates Airway Ciliary Motility
Clearance of foreign particles, such as dust and
bacteria and debris, from the respiratory tract by
airway cilia is an important host defense mechanism,
which is critical for asthmatic patients [44]. Because
the ciliary function is impaired in asthmatic patients,
they are predisposed to respiratory infection or
atelectasis. Therefore, the use of an anesthetic that
does not affect or that promotes ciliary motility may
benefit surgical patients with respiratory risk.
It is showed that ciliary beat frequency (CBF)
could be stimulated by propofol in a dose-dependent
manner (1-100 μM)45. It is suggested that propofol
stimulates CBF via the nitric oxide-cyclic guanosine
monophosphate (NO-cGMP) pathway in cultured rat
tracheal ciliated epithelial cells. As NO and the NO-
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cGMP signaling pathway play a pivotal role in
regulating ciliary motility in airway epithelium and
propofol is proved to be able to stimulate the release
of NO and cGMP in cultured tracheal epithelial cells.
Therefore, it is indicated that the promotion of
ciliary motility is associated with the effect of
propofol on the NO-cGMP pathway [45].
The Effects of Propofol on 5-HT
It is demonstrated that propofol could abolish 5-HT
induced contraction in a dose-dependent manner46.
It is well known that 5-HT causes contraction of
airway smooth muscle through two mechanisms.
One is mediated by a direct action of this agonist to
the 5-HT receptors of tracheal smooth muscle cell
membrane, and the other is by activation of 5-HT
receptors on parasympathetic nerve endings. It is
suggested that propofol at a higher concentration
(3×10-4 M) would abolish both kinds of action of 5-
HT [46].
The Effect of Preservatives in Propofol on
Airway Smooth Muscle
Currently, EDTA and metabisulfite are the most
used formulations as preservatives in propofol.
According to Nishiyama et al., the effect of propofol
on airways differs with the formulation of the drug
used [47]. The preservative used for propofol
formulation may alter the effects of propofol on the
total respiratory system resistance in smokers.
Previous work showed that the infusion of
propofol without metabisulfite could attenuated
bronchoconstriction in an animal model [48] and in
humans [13,22]. However, propofol with
metabisulfite had no effect on vagal nerve
stimulation-induced bronchoconstriction. Therefore,
it is estimated that the preservative (metabisulfite)
used for propofol can have a dramatic effect on its
ability to attenuate bronchoconstriction. As studied
in previous research, metabisulfite has been shown
to cause airway narrowing in asthmatic animals and
humans [49,50]. Because of the similarity of the
airway response to the VNS- and methacholine-
induced bronchoconstriction during metabisulfite
infusion, it is suggested that metabisulfite affects are
through direct airway smooth muscle mechanisms to
cause airway hyperresponsiveness [51].
On the contratry, the formulations of propofol
containing EDTA (ECP) or propofol without
preservatives (widely available outside of US) have
been reported previously to offer more protection
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Journal of perioperative Science
against tracheal intubation induced
bronchoconstriction than other induction agents (i.e.,
thiopental and etomidate) [14,51]. The total
respiratory system resistance measured repeatedly
for 10 min after tracheal intubation in patients with
smoking history or in sheep after metacholine
challenge is significantly decreased after induction
with EDTA-containing propofol-containing
propofol than after induction with sulfite [52].
Summary
Asthmatic patients who undergo surgeries may
suffer from perioperative asthmatic attack and might
result in severe complications. Propofol has shown
airway protection by attenuating concentration of
intracellular Ca2+, decreasing vagal motor tone,
stimulating airway ciliary motility, inhibiting airway
inflammation, the regulating effect of GABA
receptors, 5-HT and NANC nerve system and so on.
Propofol might show great strength as an anesthetic
or sedative in clinical practice for asthmatic patients.
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Journal of perioperative Science