ORIGINAL PAPER

Further Pieces of Evidence to the Pulmonary Originof Sevoflurane Escaping to the Operating Room During GeneralAnaesthesia

Zhanhong Xu • Min Dong • Ran Dong •

Shuyan Li • Shangjin Cui

� Springer Science+Business Media New York 2014

Abstract The purpose of this study was to investigate

whether the previously described per oral escape of sevo-

flurane during general anaesthesia is influenced by the

method of cuff inflation and the intra-cuff pressures

achieved. A total of 30 patients undergoing intracranial

surgery participated in the study. Cuffs were inflated under

manual control of the pilot balloon (n = 15) or using a

standardised pressure gauge (n = 15). Sevoflurane con-

centration at the patients’ mouth was captured by absorbers

and quantified by chromatography. We also addressed

whether plateau pressure, breathing frequency, end-tidal

volume, compliance or alveolar concentration of the vol-

atile anaesthetic monitored throughout the anaesthesia was

related to the sevoflurane concentration at the patient’s

mouth. Mean (± SD) intra-cuff pressures achieved by

empirical inflations were significantly higher compared

with the gauge-controlled inflations (53 ± 17 versus

27.7 ± 1.8 cm H2O, P \ 0.001). Despite these pressure

differences, the mean (± SD) concentrations of sevoflu-

rane at the patients’ mouth were comparable (1.77 ± 2.24

versus 2.04 ± 2.31 ppm, P = 0.78). Of the monitored

parameters, only the mean alveolar sevoflurane concen-

tration seemed to be related to the magnitude of escape

(r = 0.51, P \ 0.05). The results provide further evidence

that sevoflurane captured at the patients’ mouth originates

from the lung, and the escape is possibly due to the pre-

viously described presence of longitudinal folds in the

polyvinyl chloride cuff wall, which are not eliminated by

increasing the intra-cuff pressure beyond the recommended

cuff pressure of 25 cm H2O, at least not in the pressure

range covered by this study.

Keywords Method of cuff inflation � Sevoflurane �The intra-cuff pressures

Introduction

Volatile anaesthetics remain the preferred choice for the

maintenance of general anaesthesia. While their use is

intended for patients undergoing surgery, numerous studies

highlight simultaneous exposure of the staff and in par-

ticular, the anaesthesiologist [1, 2]. Since possible health

hazards from long-term exposure to trace concentrations of

inhalational anaesthetics cannot yet be definitely excluded

[3], the National Institute of Occupational Safety and

Health (NIOSH) recommends not to exceed a threshold

value of 2 parts per million (ppm) for volatile anaesthetic

agents without concomitant nitrous oxide exposure [4]. In

order to minimise occupational exposure, better under-

standing of the sources of airborne anaesthetics remains of

paramount importance. We have previously reported that

the concentration of the commonly used volatile anaes-

thetic agent sevoflurane was highest in the proximity of the

intubated patient’s mouth [5]. This observation contradicts

the core function of the cuff, which is to seal the upper-

airway and maximise positive pressure ventilation and

prevent the aspiration of fluid or pharyngeal contents.

Z. Xu � R. Dong � S. Li

The First Affiliated Hospital of Harbin Medical University,

Harbin 150001, China

M. Dong

The Affiliated Hospital of Guilin Medical University,

Guilin 541001, China

S. Cui (&)

State Key Laboratory of Veterinary Biotechnology, Harbin

Veterinary Research, Institute of Chinese Academy of

Agricultural Sciences, Harbin 150001, China

e-mail: drshangjincui@163.com

123

Cell Biochem Biophys

DOI 10.1007/s12013-014-0080-8

Ideally, this sealing occurs at intra-cuff pressures that do

not exceed the safety margin of 25–30 cm H2O, at which

the risk of blocking mucosal capillary blood flow by

compression and the occurrence of various post-procedural

complications is minimal [6, 7]. Nevertheless, numerous

in vitro studies highlight the possibility of fluid micro-

leakage and its dependence on intra-cuff pressure [8–11].

However, less is known about whether the inflation pro-

cedure influences the per oral escape of the volatile

anaesthetic.

To obtain insights, we sought to answer the following

questions:

(1) Does the release of sevoflurane differ when the

endotracheal balloon is inflated under manual con-

trol (palpation of the pilot balloon) versus when it is

set to the recommended tracheal cuff pressure of

25–30 cm H2O with the help of a pressure gauge?

(2) If yes, can differences in intra-cuff pressure explain

the differences in sevoflurane release?

(3) And can associations of sevoflurane release at the

patient’s mouth provide hints to the origin of the

release?

Methods

Subjects

A total of 30 patients undergoing craniotomy for the

removal of intra-cerebral tumours participated in the study.

Participants were both women and men with a mean

(± SD) age of 58 ± 12 years. All patients gave written

consent to participation, and the study protocol was

approved by the local Investigational Review Board and

Ethics Committee (registration number: DEOEC RKET/

IKET 2483-2006).

Procedures-Cuff Inflation

Tracheal tubes were armoured RuschFlex tracheal tubes

with a low-pressure cuff made of polyvinyl chloride (PVC)

(Teleflex Medical GmbH, Kernen, Germany). Size of the

tube chosen for men and women was 8.5 and 7.5, respec-

tively. The so-called barrel cuff makes this model partic-

ularly suitable for sealing. In both the groups, the position

of the endotracheal tube was ascertained under visual

control using the black indicator mark on the tube, which

was to be positioned between the vocal cords.

In the first series involving 15 patients, tracheal cuffs

were inflated under controlled conditions using the Rusch

Endotest system (Teleflex Medical GmbH, Kernen, Ger-

many), which is an easy-to use and read pressure gauge

able to fill, read, monitor and adjust the cuff pressure of the

low-pressure endotracheal tube. Using this equipment,

intra-cuff pressure was set to a pressure between 25 and

30 cm H2O.

In the second series involving another 15 patients, tra-

cheal cuffs were inflated empirically, i.e. while estimating

intra-cuff pressure based on the hardness of the pilot bal-

loon. In these latter cases, the anaesthesiologists/assistants

were not made aware of the intended control of intra-cuff

pressure, which was obtained by a trained independent

person.

General Anaesthesia Using Sevoflurane

For the induction of anaesthesia, we used propofol

(1–2.5 mg/kg), whereas for maintenance we used the

combination of fentanyl-rocuronium and sevoflurane. Ro-

curonium was given via perfusor to ensure sustained

compliance and airway pressure throughout the anaesthe-

sia. The sevoflurane-air mixture was administered via an

anaesthesia machine (Zeus, Drager Medical AG & Co. KG,

Lubeck, Germany) using a low-flow technique (2 L/min

fresh gas flow). All operations were performed in recently

built operating theatres equipped with modern ventilation

and air-conditioning systems. The operating theatre was

also equipped with a scavenging system compliant with

international standards.

Air was continuously circulated in the room and chan-

ged or refilled at a rate of approximately 50 m3/min.

Monitored Parameters of Ventilation

During anaesthesia, we monitored peak pressure, plateau

pressure, minute volume and alveolar concentration of

sevoflurane in order to explore possible relations to the

degree of anaesthetic escape and thereby obtain hints to the

origin of the release.

Quantification of Volatile Sevoflurane

For the detection of sevoflurane, we used a detection setup

that consisted of a portable air sampling pump (224-51TX

Air Sampling Pump, SKC, Dorset, England), an integrated

tube system and an absorber ampoule coupled to the tube

system. During the sampling, the distal part of the tube

containing the absorber was placed in the close proximity

of the patient’s mouth. A suction pump attached to the

sample collector ensured that samples were flowing

through the absorber where the anaesthetic was collected

for later quantification. Sampling of sevoflurane at the

patient’s mouth was restricted to the time period starting

from reaching steady state conditions to the beginning of

skin closure.

Cell Biochem Biophys

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After the termination of sample collection, the ampoule

containing the absorber was hermetically sealed and sent to

the laboratory for chromatographic assessment, as descri-

bed previously in detail [5, 12]. The chromatographic

assessment was performed by an independent chemist

(Cs.P.), who was blinded to the origin of the sample and

other key variables of the study. The concentration cap-

tured by chromatography (in ppm) is considered to be a

surrogate of the time-weighted average present over the

entire sampling period.

Data Analysis

Data shown are mean ± SD, unless otherwise indicated.

Mean sevoflurane concentrations were compared using

Mann–Whitney U test, while differences in balloon pres-

sure were tested with Student’s unpaired t test. Differences

were considered statistically significant if P \ 0.05. Given

the broad range and none normal distribution of sevoflu-

rane concentrations measured at the patients’ mouth the

relationship with the different functional parameters of

ventilation was explored following logarithmic transfor-

mation of the respective datasets. Calculations were carried

out using the Statistical for Windows software (StatSoft,

Tulsa, OK, USA).

Results

Baseline Characteristics of the Two Patient Cohorts

Baseline characteristics of the two patient cohorts are

shown in Table 1. Under controlled conditions, intra-cuff

pressures were successfully inflated to a pressure between

25 and 30 cm H2O. The mean (± SEM) pressure in the

group of 15 patients was 27.7 ± 0.5 cm H2O. In contrast,

when cuffs were inflated under manual control, only intra-

cuff pressures were significantly higher (53 ± 4.4 cm H2O,

P \ 0.001).

Sevoflurane concentrations captured at the patients’

mouth showed a considerable variation in both the groups

(Fig. 1). However, when comparing the two mean sevo-

flurane concentrations between the two groups, there were

no statistically significant differences. Thus, when inflating

the endotracheal cuffs under manometer or manual control,

the mean (± SD) sevoflurane concentrations at the

patients’ mouth were 2.04 ± 2.31 and 1.77 ± 2.24 ppm,

respectively (P = 0.78). Given that the sevoflurane data

did not show normal distribution, we have also calculated

the medians and interquartile ranges for each group

(Fig. 1).

When investigating the relationship between different

parameters of ventilation and the concentration of sevo-

flurane measurable at the patient’s mouth, we found no

association with peak or plateau pressure, ventilation rate

and end-tidal volume (Table 2). Of the different parameters

of ventilation, only the mean alveolar concentration of

sevoflurane showed a relationship to the concentration of

Table 1 Key baseline characteristics

Group 1

(manual

control)

Group 2

(manometer

control)

Number of subjects 15 15

Gender distribution (M/F) 8/7 9/6

Body mass index (kg/m2) 25.6 ± 4.8 26.4 ± 6.2

Intra-cuff pressure(cm H2O) 53 ± 17 27.7 ± 1.8

Sevoflurane concentration

at patient’s mouth (ppm)

1.77 ± 2.24 2.04 ± 2.31

Minute volume (ml) 7,155 (750) 7,015 (970)

Data shown are mean ± SD

Fig. 1 Concentration of volatile sevoflurane captured at the patients’

mouth (in ppm), when cuffs of endotracheal tubes were inflated either

empirically (manual control of the pilot balloon) or to an optimal

pressure under guidance by a pressure gauge. Data show the

minimum, maximum and median concentration as well as the

respective interquartile ranges (bars) for the two scenarios. Mean

intra-cuff pressures (± SD) measured were 53 ± 17 and

27.7 ± 1.8 cm H2O, respectively (P = 0.78)

Table 2 Associations between numerous ventilation parameters and

the concentration of sevoflurane measured at the patients’ mouth

Sevoflurane concentration at patient’s mouth

versus N R P Plateau pressure

Minute

volume

30 30

-0.10 -0.12

0.6 0.5

Cell Biochem Biophys

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sevoflurane detectable at the patients’ mouth (R2 = 0.27,

P = 0.004). The relationship following logarithmic trans-

formation of the respective parameters is illustrated in

Fig. 2.

Discussion

The present study asked the question whether the mode of

cuff inflation and the related intra-cuff pressures have

implications for the concentration of sevoflurane measur-

able at the patient’s mouth during general anaesthesia. Our

findings highlight that when cuffs are inflated empirically,

intra-cuff pressure frequently exceeds the recommended

limits from 25 to 30 cm H2O. This observation is in line

with numerous reports from independent groups [13–15].

This finding is important, in particular, when considering

time-demanding operations where prolonged intubation

with unnecessarily high intra-cuff pressures may pose risks

for post-procedural complications via unwanted impact on

the tracheal tissue [6, 7]. To avoid these complications,

cuff inflation should be performed under guidance by a

manometer to ensure the ideal cuff pressure of 25–30 cm

H2O.

When comparing the two modes of inflation, the con-

centration of sevoflurane measured at the patients’ mouth

did not show significant differences. These concentrations

were comparable with those previously found at the

patient’s mouth, which at the same time represents the zone

of the highest concentration during anaesthesia [5, 16]. Our

observations have underscored that inflating the cuff with

pressures exceeding 25–30 cm H2O did not diminish sig-

nificantly the mean sevoflurane concentrations at the

patients’ mouth and hence did not achieve complete sealing

in the trachea.

In in vitro investigations performed in bench-top mod-

els, Young et al. [8] as well as Dullenkopf et al. [6]

described considerable fluid leakage past the endotracheal

cuff, which was detectable even at 60 cm H2O. The fluid

leakage could be ascribed to the presence of longitudinal

folds within the cuff wall.

Importantly, fold formation is particularly common in

cuff walls made of PVC [6]. Since the endotracheal cuffs

used in the present study are also made of PVC and the

higher cuff pressures (* 60 cm H2O) accompanying

purely empirical inflations did not eliminate the per oral

escape of sevoflurane, and it seems reasonable to assume

that the involvement of contributing factors is similar to

those described in bench-top models.

Anticipating considerable differences in trachea calibre

between men and women, we used tubes with size of 8.5

and 7.5, respectively. Despite this consideration, (i.e.

trying to account for differences in gender-specific anat-

omy of the upper-airways) a fairly broad range of sevo-

flurane concentration was measured at the patients’

mouth. Even when focusing on patients who received the

same balloon inflated to the same intra-cuff pressure,

there was considerable variation in the measured sevo-

flurane concentrations, which seems to point the addi-

tional factors influencing the escape of sevoflurane.

Indeed, numerous studies indicate that the relationship

between the diameter of the trachea and the cuff (or tra-

cheal tube) size [17] together with the material and shape

of the cuffs [18, 19] has an influence on the rise of folds

in the cuff wall. The study by Hwang et al. [20] clearly

demonstrates that larger versus smaller balloons inflated

in the same trachea are associated with more folds within

the cuff wall. Thus, when trachea diameter is smaller than

anticipated just by gender, the same tracheal cuff may

turn out to be too large for the individual patient leading

to increased number of longitudinal folds, and thereby a

more pronounced escape of sevoflurane during the

anaesthesia.

To explore potential further hints to the underlying

mechanisms of the apparent escape of the volatile anaes-

thetic, we also investigated the association between sevo-

flurane concentration at the patients’ mouth and various

key parameters of the actual ventilation. Of these latter

ones plateau pressure, compliance, end-tidal volume and

breathing frequency did not seem to be modifiers of

sevoflurane escape. The only parameter that could be

related to the sevoflurane concentration at the patient’s

mouth was the alveolar sevoflurane concentration. This

latter observation provides further support to the previously

raised notion that the origins of the volatile anaesthetic at

the patient’s mouth are the ventilated lungs.

Fig. 2 Association between sevoflurane concentrations measured at

the patients’ mouth and the alveolar concentrations of the volatile

anaesthetic in 30 intubated patients undergoing craniotomy for the

removal of intracranial tumours. Note that the relationship was

visualised with log-transformed data (base 10)

Cell Biochem Biophys

123

Sevoflurane concentrations at the patient’s mouth as

captured by the absorber (average overtime) exceeded the

clinically significant threshold value of 2 ppm in some

cases [4]. In theory, exposure of the personnel is expected

to decrease with increased distance from the patient’s

mouth (dilution), yet several studies [3, 21, 22] failed to

demonstrate this consistently. What is more, staff members

working outside the area of protective laminar airflow were

actually the subject of the highest level of exposure [23].

Importantly, location and/or placement of instrument tables

and containers may abolish the laminar airflow and create

turbulence, which in turn can lead to a 15-fold higher

exposure level compared to that in areas of laminar air flow

[19]. Intuitively, obtaining complete sealing of airways

during endotracheal intubation could be an important

contributor to the elimination of leakage. Our study sug-

gesting that more pronounced inflation cannot per se

eliminate or diminish the magnitude of leakage, when

using PVC balloons calls on further comparative investi-

gations addressing whether non-PVC balloon material

could contribute to further reduction or even elimination of

this source of airborne sevoflurane.

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