British Journal of Anaesthesia 95 (3): 4069 (2005)

doi:10.1093/bja/aei175

Advance Access publication June 10, 2005

Assessment of the cough reflex after propofol anaesthesia

for colonoscopy
J. Guglielminotti1*, T. Rackelboom1, A. Tesniere1, X. Panhard2, F. Mentre2,
M. Bonay3, J. Mantz1 and J. M. Desmonts1
1

Service dAnesthesiologie et de Reanimation Chirurgicale, 2Departement dEpidemiologie, Biostatistique et

Recherche Clinique and 3Service des Explorations Fonctionnelles, Hopital Bichat, Assistance Publique,
Hopitaux de Paris, 46 rue Henri Huchard, F-75018 Paris, France
*Corresponding author. E-mail: jean.guglielminotti@bch.ap-hop-paris.fr
Background. Dysfunction of the cough reflex as a result of the lingering effects of anaesthetics
may lead to aspiration pneumonia or retained secretions after general anaesthesia. It is unknown
whether low concentrations of propofol alter the cough reflex in the early period after anaesthesia. The objective of this study was to investigate the effect of low concentrations of propofol
on the cough reflex sensitivity as assessed by the cough reflex threshold to an inhaled irritant.
Methods. Fifteen, ASA III, non-smoking patients undergoing elective colonoscopy were studied.
Anaesthesia was induced and maintained with a blood target-controlled propofol infusion. Cough
reflex threshold was measured with citric acid. Increasing concentrations of nebulized citric acid
(2.5, 5, 10, 20, 40, 80, 160, 320, and 640 mg ml 1) were delivered during inspiration until a cough
was evoked. The citric acid concentration eliciting one cough (C1) was defined as the cough reflex
threshold. C1 was log transformed for statistical analysis (Log C1). Log C1 was measured before
anaesthesia and during the recovery period with estimated decreasing propofol concentrations of
1.2, 0.9, 0.6, and 0.3 mg ml 1.
Results. Log C1 (median; interquartile range) measured with propofol concentrations of 1.2, 0.9,
0.6, 0.3, and 0 mg ml 1 were 1.9 (0.6), 1.9 (1.0), 1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml 1 (NS),
respectively. However, light sedation was observed with propofol concentrations of 1.2 and
0.9 mg ml 1.
Conclusion. This study indicates that residual sedation after propofol anaesthesia for
colonoscopy does not adversely affect the cough reflex.
Br J Anaesth 2005; 95: 4069
Keywords: anaesthetics i.v., propofol; citric acid; colonoscopy; complications, aspiration;
complications, pneumonia; cough
Accepted for publication: May 16, 2005

Cough reflex is the main mechanism of airway defence. It

protects the lungs from inhalation of foreign particles and
clears the airways of retained secretions. However, residual
concentration of anaesthetics and residual sedation observed
after general anaesthesia may depress this reflex.14 This
impairment may lead to adverse respiratory events like
aspiration pneumonia or retained secretions.
Propofol is often used in general anaesthesia for day-case
surgery. In this setting, early recovery of airway reflexes is
essential to allow safe resumption of fluid intake before
hospital discharge. However, propofol is a potent depressant
of airway reflexes at hypnotic concentrations,4 5 but the
effects of low concentrations of this drug, such as those
observed during recovery from general anaesthesia, have
not been assessed. We therefore conducted this study to

assess the effect of the low propofol concentrations observed

during recovery from general anaesthesia on the cough
reflex sensitivity assessed by the cough reflex threshold to
an inhaled irritant.

Methods
The study was conducted in the Anaesthesia Department
of Bichat Hospital, a 1200-bed University Hospital. It was
approved by the Ethics Committee of Saint-Antoine
Hospital and written informed consent was obtained from
each patient.
ASA III non-smoking patients undergoing elective
colonoscopy under general anaesthesia were scheduled for
the study. Any of the following excluded the patient from the

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Cough reflex after propofol for colonoscopy

study: age less than 18 or more than 55 yr, diabetes mellitus,

central nervous system disease, epilepsy, medication with
psychotrops or ACE inhibitors, pregnancy, anaesthesia or
tracheal intubation during the preceding month, allergic
rhinitis, upper airways or bronchopulmonary infection
during the preceding month, chronic respiratory disease
(asthma, COPD, bronchiectasis), chronic cough (more than
3 months per yr during 2 consecutive yr) or chronic upper
airways disease.
The patients did not receive any pre-anaesthetic medication and no anaesthetic drug other than propofol was administered during colonoscopy. Anaesthesia was induced and
maintained with a blood target controlled propofol infusion
(Diprifusor
device, Astra-Zeneca Laboratory, France). The
software running the device uses the Marsh pharmacokinetic
model.6 It has a precision of 18.2% (median absolute prediction error) and a bias of 7% (median prediction error).7
The initial blood target for induction was 6 mg ml 1. Thereafter, the target was modified according to the depth of
anaesthesia as assessed by the motor response to endoscopic
stimulation and arterial pressure and heart rate variations.
During anaesthesia, patients were spontaneously breathing
with supplemental oxygen administered through nasal
prongs to keep pulse oxygen saturation above 95%. Airway
management was limited to manual jaw thrust and mandibular advancement. After anaesthesia, the patient was transferred to the post anaesthesia care unit while the propofol
infusion was maintained with a blood target concentration of
1.2 mg ml 1.
The cough reflex threshold was determined by delivering
increasing concentrations of nebulized citric acid (2.5, 5, 10,
20, 40, 80, 160, 320, and 640 mg ml 1) during inspiration
until cough was evoked. The concentration eliciting one
cough (C1) was defined as the cough reflex threshold8 provided that cough was also elicited by the immediately
greater concentration.9 The order of administration of citric
acid solutions was always the same, from the lowest to
the highest concentration. No saline was interspersed with
increasing concentrations of citric acid. If cough was not
evoked with the concentration of 640 mg ml 1, C1 was
arbitrarily defined as 1280 mg ml 1. All measurements
were performed in the morning to minimize the diurnal
variation of the cough reflex, as the threshold is increased
in the afternoon.
For the challenge, the patient was in the sitting position
and wore a nose-clip and was asked to exhale to functional
residual capacity and then inhale to total lung capacity
through a mouthpiece (single-breath inhalation technique).
Each concentration of tussive agent was inhaled five
times with a 30-s pause between each inhalation. A breathactivated jet nebulizer was used (Nebulizer dosimeter
MEDIPRON F.D.C. 88, MEDIPROM, Paris, France) which
delivered a constant volume of solution (8 mg breath 1).
Citric acid solutions were prepared by the Pharmacy of
Bichat Hospital. Normal saline was used as solvent. Solutions were used no more than 48 h after their preparation.

C1 was measured before anaesthesia (blood propofol

concentration of 0 mg ml 1) and during the recovery
period with decreasing blood target propofol concentrations of 1.2, 0.9, 0.6, and 0.3 mg ml 1. Blood concentrations were estimated with the Diprifusor
software, but
were not measured. Each measurement at a given concentration was performed once and was started 5 min after
the blood and brain propofol concentrations had reached
equilibrium.
Before each challenge, sedation was assessed with
the Observers Assessment of Awareness/Sedation Scale
(OAA/S).10 It is a five point scale, which takes into
account responsiveness, speech, facial expression, and
eyes (see Appendix). It ranges from 5 to 1, a score of 5
corresponding to an alert state and a score of 1 to a deep
sleep state. The same unblinded investigator assessed the
OAA/S score and conducted the cough challenge.
Fifteen subjects were required to show a 50% increase
of Log C1 at a propofol concentration of 1.2 mg ml 1
when compared with the preoperative value (nQuery
Advisor software, Statistical Solutions Company, Saugus,
MA, USA). C1 was Log transformed for statistical analysis
(Log C1). A Wilcoxon sign rank test was used for comparisons. Results were expressed as the median (interquartile
range).

Results
From July 2001 to October 2002, 17 patients were included.
Two patients withdrew their consent on the day of colonoscopy. So, 15 patients were studied and their characteristics
are presented in Table 1.
OAA/S scores measured before colonoscopy and with
propofol concentrations of 1.2, 0.9, 0.6, 0.3, and 0 mg ml 1
were 4 (2), 5 (1), 5 (0), 5 (0), and 5 (0), respectively. Scores
measured at 1.2 and 0.9 mg ml 1 were significantly different
from the score measured at 0 mg ml 1 (P=0.002 and
P=0.016, respectively).
Log C1 measured with estimated propofol concentrations
of 1.2, 0.9, 0.6, 0.3, and 0 mg ml 1 were 1.9 (0.6), 1.9 (1.0),
1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml 1, respectively. Log
C1 value measured at 1.2 mg ml 1 did not differ from that
measured at 0 mg ml 1 (P=0.10). Individual variations of
Log C1 values are presented in Figure 1. One patient was
not able to cough with the highest concentration tested
(640 mg ml 1) at each of the five challenges.

Table 1 Demographic and anaesthetic characteristics of the 15 patients. Results

are expressed as median (interquartile range) unless otherwise stated
Age (yr)
Weight (kg)
Height (cm)
Male patients
Duration of anaesthesia (min)
Dose of propofol received (mg)

407

40
64
167
6/15
25
290

(19)
(14)
(12)
(40%)
(17)
(232)

Guglielminotti et al.

3.5

Log C1 (mg ml1)

3.0
2.5
2.0
1.5
1.0
0.5
0
1.2

0.9
0.6
0.3
0.0
Blood propofol concentration (g ml1)

Fig 1 Individual variations of the cough reflex threshold as assessed by the

Log C1 to citric acid with decreasing blood propofol concentration.

Discussion
Despite residual light sedation observed after discontinuation of propofol anaesthesia, the cough reflex threshold
measured with increasing concentrations of an inhaled irritant was not modified during the early postoperative period
compared with the pre-anaesthetic period. Sensitivity of the
cough reflex therefore did not appear to be modified by
estimated propofol concentrations less than 1.2 mg ml 1.
Previous studies have suggested that postoperative
impairment of the cough reflex may lead to aspiration
pneumonia or retained secretions. Indeed, an increase of
the cough reflex threshold was observed in medical patients
who developed aspiration pneumonia or recurrent pneumonia.11 12 Moreover, a decrease of the cough threshold
induced by ACE inhibitors may be protective against aspiration pneumonia.13 Consequences of cough reflex depression
after general anaesthesia may be worse in patients with
pulmonary disease like COPD patients. Indeed, cough contributes to up to 60% of total pulmonary clearance in COPD
patients but only to 8% in healthy patients.14
Little is known about the effects of anaesthetics on the
cough reflex and especially the effect of subhypnotic concentrations of anaesthetics like those observed in the recovery period. Nishino and Tagaito reported that enflurane and
propofol depress the cough reflex.2 3 However, both studies
addressed the effects of high, hypnotic concentrations of
these drugs, that is 0.7 MAC enflurane and 3 mg ml 1 propofol concentrations. Dilworth and colleagues reported an
increase of the cough reflex threshold elicited by citric
acid and capsaicin until the first day after upper abdominal
surgery. Drugs administered during anaesthesia may have
been responsible for that increase.8
In the present study, we investigated the effect of lingering concentrations of propofol and the associated residual
sedation observed in the post anaesthesia care unit, in view
of the high risk of adverse respiratory events during the
early postoperative period.15 16 We observed a small but
significant decrease of the OAA/S score indicating light

levels of sedation with blood propofol concentrations of

1.2 and 0.9 mg ml 1. However, we did not observe any
effect of low propofol concentration on the cough reflex
threshold. The cough reflex appears more resistant to the
effect of anaesthetic agents than pharyngeal reflexes. Indeed,
venous blood propofol concentration of 0.9 mg ml 1 deeply
impairs pharyngeal reflexes.4 Differential sensitivity of both
reflexes towards the same anaesthetic drug seems to be
related to a differential sensitivity of each neural pathway
in the brain.3 However, we cannot rule out that our negative
results were related to a type II statistical error. Since the
number of subjects included in the study was calculated to
demonstrate a 50% increase in Log C1, a smaller Log C1
change may not have been detected.
Preservation of the cough reflex after propofol anaesthesia
may be clinically relevant for the management of ambulatory patients. It may allow early and safe resumption of oral
fluid intake before hospital discharge, that is without aspiration of fluid into the trachea. Colonoscopy is the most frequent procedure conducted under general anaesthesia in
France. More than 800 000 procedures are performed
each year in France accounting for 10% of all anaesthetics.17 Owing to the number of cases and the ambulatory
nature of the procedure, safety is a primary concern. So,
knowing that the concentrations of propofol observed in
the recovery period do not impair airway protective reflexes
is rather reassuring for the management of the patient. These
results could also be extended to all procedures conducted
under propofol sedation with or without topical anaesthesia
or local anaesthetic infiltration, that is with no or little
systemic resorption of local anaesthetics (cataract and ocular
surgery, dental extractions, extracorporeal shock-wave lithotripsy, angiography, cosmetic surgical procedures, in vitro
fertilization procedures, etc.).
In this study, patients only received propofol without
upper airway instrumentation. Our findings can therefore
not be extrapolated to other anaesthetic protocols using different anaesthetic agents or airway manipulation, as opioids,
volatile agents, and muscle relaxants impair upper airway
function.2 3 18 Similarly, upper airway reflexes are depressed
after tracheal intubation or laryngeal mask airway insertion.19 20 We chose not to insert a laryngeal mask airway
or a tracheal tube because that is not the usual practice in
our Institution. The patients in this study were young nonsmoking patients and the procedure was a colonoscopy,
which does not interfere with lung function. In contrast,
patients with abnormal upper airway function, for example
diabetic patients, smokers or elderly, may have a different
postoperative course.2123 However, these conditions are
associated with an increase of the cough reflex threshold.
If we had included these patients, we may have overlooked
an increase of the cough reflex threshold caused by low
propofol concentrations because of the high basal threshold
of the patients. The surgical procedure may also influence
the cough threshold, as described after upper abdominal
surgery.8

408

Cough reflex after propofol for colonoscopy

Measurement of the cough threshold evoked by a tussive

agent like citric acid is the gold standard for assessing the
cough reflex sensitivity. It has been used to assess the effect
of many conditions on this reflex, for example asthma,24
smoking,22 chronic obstructive lung disease,25 or diabetes.21
It is also routinely used to test the efficacy of anti-tussive
drugs.9 Capsaicin is the other tussive agent used in cough
challenge. Theoretically, the results may have been different
if capsaicin had been used instead of citric acid. However,
this is probably not the case. Indeed, doseresponse curves
to citric acid and capsaicin are similar in humans.26 Moreover, studies that have used both citric acid and capsaicin as
tussive agent in serial cough challenges have shown similar
evolution of the cough reflex threshold whatever the tussive
agent used.8
In conclusion, propofol concentrations observed during
recovery from general anaesthesia for colonoscopy and
associated sedation do not appear to adversely affect the
cough reflex.

Acknowledgements
We would like to thank Dr V. Leclerc (Societe Aster-Cephac) and
Dr A. C. Cremieux (Centre dInvestigation Clinique, Hopital Bichat) for
their help in conducting this study.

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Appendix
Assessment categories included in the OAA/S.10
Score

Reactivity

Speech

Face expression

Eyes

5
4
3
2
1
0

Response readily to name spoken in normal tone

Lethargic response to name spoken with a normal tone
Responds only after name is called loudly and/or repeatedly
Response after gentle hand stimulation
Responds only after mild prodding or shaking
Does not respond to mild prodding or shaking

Normal
Mild slowing or thickening
Slurring or prominent slowing
Few recognizable words

Normal
Mild relaxation
Marked relaxation

Clear, no ptosis
Glazed or mild ptosis
Glazed and marked ptosis

409