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Zou et al.

J perioperative science 2014,1:5


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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].


According to national center for health statistics
Asthma is a chronic inflammatory disease of airway (NCHS), asthma prevalence increased from 7.3% in
characterized by intermittent airway obstruction and 2001 to 8.4% in 2010 in the United States [6].
reversible airway hyperresponsiveness (AHR). It Surgeries may be inevitable in some asthmatic
presents a major public health problem with patients. About 10.2% of asthmatic patients with no
increasing prevalence rates and severity worldwide pretreatment suffered from perioperative asthmatic
[1]. According to the data from World Health attack and might result in severe complications
Organization (WHO) and Global Initiative for (such as hypoxemia, pneumonia, pneumothorax,
Asthma (GINA), 235-300 million people currently pulmonary barotraumain, prolonged intubation,
suffer from asthma as of 2011 and approximately atelectasis, mucus plugging and so on) [7]. The
250,000 people die per year from asthma [2,3]. The incidence of these peri-operative complications in
global prevalence of asthma have increased asthmatic populations reaches up to 30%, which is
much higher than that in healthy patients [8,9].
From the *Department of Anesthesiology, Peking Union Because of the airway hyperreactivity,
Medical College Hospital, Peking Union Medical College, bronchospasm may easily be induced by direct
Beijing, China airway stimuli (such as laryngoscopy, tracheal
Accepted for publication July 20, 2014. intubation, airway suctioning, tracheal extubation
Reprints will not be available from the authors. and so on), drugs, inadequate depth of anesthesia,
Address correspondence to Zhao Jing: Department of surgical stimuli and perioperative complications
Anesthesiology, Peking Union Medical College Hospital, such as aspiration, infection, or trauma. Therefore,
Peking Union Medical College, Beijing, China. Address e-mail
to zhaojing1009@aliyun.com. 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
http://www.perioperative-science.com/content/01/05

the most appropriate anesthetics for asthmatic anaesthesia was supported by central airway dilation
patients. observed at lung histology in normal rats[12].
Propofol, a widely used short-acting intravenous
the effect of propofol on asthmatic airways
anaesthetic, is recognized as the ideal sedative in
A number of studies and reports suggest that
asthmatic patients [10,11]. Results from many
propofol may have properties beneficial to patients
clinical observations and laboratory studies strongly
with asthma. During anesthesia induction, it is
support the notion that propofol exerts significant
observed that the incidences of wheezing and the
protective effect of asthmatic airways. The
airway resistance at 2 and 5 min post-intubation
mechanisms of airway protection by propofol are
were significantly lower in asthmatic patients
complicated, involving the direct relaxation of
anesthetized with propofol than with thiopental11.
airway smooth muscle, the attenuation of
When used for sedation, propofol is reported to
parasympathetic nerve acetylcholine release, the
inhibit postoperative bronchospasm in two patients
anti-inflammation properties, the stimulation of
with hyperreactive airway disease[16]. Moreover,
ciliary motility and so on. Despite abundant studies
rapid improvement of symptoms was observed in a
about the protective effect of propofol in asthmatic
patient moribund with asthma, shortly after
patients, the mechanisms remain to be further
induction of anesthesia with propofol[17]. In vivo
developed.
studies, intraperitoneal injection of propofol is
shown to decrease the airway resistance induced by
Airway Protective Effect of Propofol
methacholine in asthmatic mice[18]. In vitro studies,
It is widely observed in vitro and in vivo studies that propofol was able to induce concentration-
propofol can attenuate the response to a variety of dependent relaxations in precontracted, isolated
bronchoconstrictor agents in both animals and trachea smooth muscle of asthmatic airways[19,20].
humans, with hyperreactive or normal reactive
airways. Mechanisms of Airway Protective Effect
the effect of propofol on normal airways of Propofol
A growing body of laboratory and clinical studies
support the concept that propofol has The Direct Relaxant Effects of Propofol on
bronchodilation properties not only in asthmatic Airway Smooth Muscle
airways but also in normal airways.
It is well known that the concentration of
Results from many studies have shown that
intracellular free Ca2+ plays a central role in the
propofol decreases airway resistance in patients or
regulation of ASM tone, therefore the inhibition of
animals with normal reactive airways. In normal rats
Ca2+ mobilization, decrease of Ca2+ sensitivity, or
with no previous airway constriction, airway
both may contribute to the ASM relaxant effects of
resistance was found to decrease after the rats were
propofol.
anaesthetized with propofol [12]. Likewise, propofol
appeared to be superior to thiopental and The Effects of Propofol on Intracellular
thiobarbiturate in inhibiting the prevalence of Concentration of [Ca2+]i
tracheal intubation-induced bronchoconstriction as The direct relaxing effect on smooth muscle of
propofol has been shown to decrease the prevalence propofol has been ascribed to a reduction in the
of wheezing after the induction of anesthesia and concentration of intracellular concentration of
intubation of the trachea in normal patients [11,13]. [Ca2+]i[12,14]. The regulation of intracellular Ca2+
Compared with thiopental and etomidate, propofol ([Ca2+]i) is integrated by two mechanisms which
was associated with decreased airway resistance in a include Ca2+ release from the internal store
randomized trial involving nonasthmatic smokers (sarcoplasmic reticulum, SR) and plasma membrane
undergoing general anesthesia [14]. Ca2+ influx. The mechanism underlying the
Moreover, it is observed that propofopl is shown relaxant effects of propofol might be caused
to have a direct airway smooth muscle (ASM) at inhibition of Ca2+ release from the internal store
concentration of 10-4M and a greater direct relaxant and plasma membrane Ca2+ influx[21,22].
effect on distal ASM than on proximal ASM[15]. the effects of propofol on Ca2+ release from
The decrease in airway resistance with propofol internal store: Ca2+ release from intracellular

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stores is regulated by two mechanisms: inositol Propofol was previously reported to be able to
phosphate (IP3)-induced Ca2+ release and Ca2+ decrease basal airway tone similarly to atropine and
induced Ca2+ release[23,24]. It is demonstrated that attenuate histamine-induced bronchoconstriction
propofol could attenuate the IP3 production induced and it is maybe a reduction in vagal tone that
by carbachol[21]. IP3 is a second messenger in the produce the relaxant effect[31]. Brown et al.[32]
M3 receptor-coupled signaling pathway. This found that propofol caused a dose-dependent
finding indicates that propofol may interfere with (8.4×10-5 M, 2.8×10-4 M, 8.4×10-4 M) attenuation
the components of receptor-G-protein- in the vagal nerve stimulation induced
phospholipase C pathway[21]. However, the precise bronchoconstriction. Furthermore, as the
site of action is not known. spasmolytic effects of propofol did not differ
the effects of propofol on plasma membrane
between normal dogs and vagotomized dogs, the
Ca2+ influx: Ca2+ influx can occur through both
relaxant effect of propofol on methacholine-induced
voltage-gated[25] and receptor gated channels[26]. bronchoconstriction may be a result of inhibition of
The inhibition of Ca2+ influx may be caused by the peripheral vagal motor pathway instead of
blockade of L-type voltage-dependent Ca2+ central vagal pathway or direct inhibition of Ca2+
channels[21,22,27]. As it is demonstrated in isolated mobilization[33]. The concentrations (100μM)
ASM, [Ca2+]i increase induced by KCl could be required for these smooth muscle effects in the
inhibited by propofol and this inhibition was above mentioned studies are above those typically
blocked by verapamil (the voltage-operated calcium achieved clinically. Therefore, whether the clinically
channel blocker)[28]. relevant concentration of propofol relax ASM by
However, it is demonstrated in some previous inhibiting the vagal motor pathway or not still needs
studies that the inhibition effect of [Ca2+]i was to be further explored.
achieved at concentration higher than those The Inhibitory Effect of Propofol on
encountered clinically[27]. Nonadrenergic Noncholinergic Nerve System
Studies in humans and animal airway tissue models
The Effects of Propofol on Sensitivity of [Ca2+]i demonstrated that propofol could attenuate
Airway smooth muscle contraction is not only acetylcholine, histamine, and endothelin-1 induced
atttibuted to the increase in intracellular Ca2+ contractile responses, merely at concentrations
([Ca2+]i) on account of increased tension induced above those achieved clinically (1×10-4 M ~3×10-4
by agonist at the same [Ca2+]i (increase in Ca2+ M)[21,22]. However, Gleason et al[34] indicated
sensitivity). Evidence shows that propofol dilates that although propofol at clinically relevant
contracted ASM through reduction in intracellular concentration could not attenuate acetylcholine
Ca2+ by inhibiting influx of Ca2+ and release of induced ASM contraction, it is able to inhibit
intracellular stores, but not by decreased Ca2+ tachykinins A (neurotransmitter released by
sensitivity[29]. However, conflicting evidence exists, nonadrenergic noncholinergic nerve) induced ASM
as the study from Grim et al shows propofol may contraction. This finding suggests that propofol may
have an impact on Ca2+ sensitivity via RhoA/Rho- relax ASM by affecting nonadrenergic
kinase pathway[30]. noncholinergic (NANC) nerve system.
Studies suggesting a vagal nerve-mediated
The Effects of Propofol on Respiratory mechanism for propofol have made two important
Nerve System and perhaps incorrect assumptions of irritant
It has been well known that parasympathetic induced bronchoconstriction: (1) cholinergic nerves
nervous system, adrenergic nerve system and are the primary airway efferent nerve and (2)
nonadrenergic noncholinergic (NANC) nerve acetylcholine is the primary agonist. Nevertheless,
system together form the predominant neural stimulated NANC nerves induce
pathway and play an important role in the regulation bronchoconstriction in animals and humans by
of airway diameter and resistance to airflow in liberated neurotransmitters (e.g., tachykinins).
mammalian airway. Gleason et al [34] applied ten-second trains of
square wave direct current electrical field
The Effects of Propofol on Parasympathetic stimulation (30-50 Hz, 24 V, 0.5ms pulse width) to
Nerve System tracheal rings to induce contraction. These electrical

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stimuli induced a contractile response with two


distinct components: a rapid cholinergic contraction Other Potential Mechanisms of Protective
followed by a more slowly developing contraction Effect of Propofol
classic for excitatory (procontractile) NANC
The Effect of Propofol on Gamma-Aminobutyric
contractions. It is found that clinically relevant Acid (GABA)
concentrations of propofol relaxed the NANC It is found that low concentrations of propofol (20
component of electrical field stimulation-induced μM) facilitated airway smooth muscle relaxation is
contraction mediated by tachykinins, while have no likely due to the signaling pathways regulating
effect on cholinergic component of electrical field relaxation rather than those regulating
stimulation-induced contraction [34]. Therefore, it is contraction[40]. It is known that propofol is an
concluded that the mechanism of the protective anesthetic with positive allosteric effects at the
effect of propofol on irritant-induced GABAA channel. It has been a long-standing belief
bronchoconstriction may be either by decreasing that any potential GABAergic contribution to airway
NANC nerve transmission or by attenuating the tone is largely mediated by GABAA channels in the
contractile effect of liberated tachykinins at the brainstem [41] or by GABAB channels on
neurokinin receptor on the airway smooth muscle preganglionic cholinergic nerves in the lung [42].
itself. Therefore, propofol may show relaxant effect by
The Immunoregulatory Effect of Propofol on acting on GABAA channels in the brainstem or
Airway Inflammation GABAB channels on preganglionic cholinergic
Airway inflammation has emerged as an important nerves in the lung. However, the airway smooth
contributor to mechanisms of asthma. The muscle relaxation of propofol may be mediated by
immunologic-inflammatory pathways involved in enhancing the effect of GABA in the lung.
the pathogenesis of asthma are complex and include Endogenous GABA was also found to be existing in
lymphocytes (both Th1 and Th2), immunoglobulin the airway and plays an important role in
E, eosinophils, neutrophils, mast cells, leucotrienes, modulating airway smooth muscle tone by
and cytokines10. T-helper cell type (Th) facilitating smooth muscle relaxation via activation
lymphocytes play an important role in the initiation, of airway smooth muscle GABAA and GABAB
progression and persistence of asthma. The channels [40,41,43]. Gallos et al [40]demonstrated a
mechanism of action of the “Hygiene Hypothesis” dose-dependent improvement in relaxation of a
stated that insufficient stimulation of the Th1 arm, substance P contraction by propofol, which was
stimulating the cell defence of the immune system, partially reversed by low-dose GABAA channel
leads to an overactive Th2 arm, stimulating the antagonism (gabazine, 5 μM). Therefore, the airway
antibody-mediated immunity of the immune systems smooth muscle relaxation of propofol may be
and playing an important role in induction and mediated by acting on this novel relaxation pathway.
aggravation of airway inflammation [35].
Propofol Stimulates Airway Ciliary Motility
The immunoregulatory effect of propofol has
Clearance of foreign particles, such as dust and
been shown in numerous studies that propofol not bacteria and debris, from the respiratory tract by
only can preferably promote Th cells to differentiate
airway cilia is an important host defense mechanism,
into Th1 cells [36,37] but also inhibit effects on which is critical for asthmatic patients [44]. Because
cytokines secreted by Th2 cells, such as interleukin
the ciliary function is impaired in asthmatic patients,
6 (IL-6) and IL-10 in some infectious animal models
they are predisposed to respiratory infection or
or human [38,39]. Furthermore, it is currently atelectasis. Therefore, the use of an anesthetic that
observed that propofol administration significantly does not affect or that promotes ciliary motility may
inhibited the elevation of cytokines secreted by Th2 benefit surgical patients with respiratory risk.
cells (including IL-4, IL-5), while showed no effect It is showed that ciliary beat frequency (CBF)
on IFN-γ (mainly secreted by in asthma mice, which
could be stimulated by propofol in a dose-dependent
led to the down regulation of Th1/Th2 ratio18.
manner (1-100 μM)45. It is suggested that propofol
However, studies about the effect of propofol on
stimulates CBF via the nitric oxide-cyclic guanosine
airway inflammation of asthma animals or human
monophosphate (NO-cGMP) pathway in cultured rat
are rare recently. Further investigations are yet tracheal ciliated epithelial cells. As NO and the NO-
needed to be conducted.
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cGMP signaling pathway play a pivotal role in against tracheal intubation induced
regulating ciliary motility in airway epithelium and bronchoconstriction than other induction agents (i.e.,
propofol is proved to be able to stimulate the release thiopental and etomidate) [14,51]. The total
of NO and cGMP in cultured tracheal epithelial cells. respiratory system resistance measured repeatedly
Therefore, it is indicated that the promotion of for 10 min after tracheal intubation in patients with
ciliary motility is associated with the effect of smoking history or in sheep after metacholine
propofol on the NO-cGMP pathway [45]. challenge is significantly decreased after induction
The Effects of Propofol on 5-HT
with EDTA-containing propofol-containing
It is demonstrated that propofol could abolish 5-HT propofol than after induction with sulfite [52].
induced contraction in a dose-dependent manner46.
It is well known that 5-HT causes contraction of Summary
airway smooth muscle through two mechanisms.
Asthmatic patients who undergo surgeries may
One is mediated by a direct action of this agonist to
suffer from perioperative asthmatic attack and might
the 5-HT receptors of tracheal smooth muscle cell
result in severe complications. Propofol has shown
membrane, and the other is by activation of 5-HT
airway protection by attenuating concentration of
receptors on parasympathetic nerve endings. It is
intracellular Ca2+, decreasing vagal motor tone,
suggested that propofol at a higher concentration
stimulating airway ciliary motility, inhibiting airway
(3×10-4 M) would abolish both kinds of action of 5-
inflammation, the regulating effect of GABA
HT [46].
receptors, 5-HT and NANC nerve system and so on.
Propofol might show great strength as an anesthetic
The Effect of Preservatives in Propofol on
or sedative in clinical practice for asthmatic patients.
Airway Smooth Muscle
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Journal of perioperative Science