Online Monitoring of Intraoperative Exhaled Propofol by Acetone

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Online Monitoring of Intraoperative Exhaled Propofol by Acetone-Assisted Negative Photoionization Ion Mobility Spectrometry Coupled with Time-Resolved Purge Introduction Dandan Jiang, Enyou Li, Qinghua Zhou, Xin Wang, Hanwei Li, Bangyu Ju, Lei Guo, Desheng Liu, and Haiyang Li Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b00171 • Publication Date (Web): 23 Mar 2018 Downloaded from http://pubs.acs.org on March 24, 2018

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Analytical Chemistry

Online Monitoring of Intraoperative Exhaled Propofol by Acetone-Assisted Negative Photoionization Ion Mobility Spectrometry Coupled with Time-Resolved Purge Introduction Dandan Jiang,†, ‡ Enyou Li,§ Qinghua Zhou,†, ‡ Xin Wang,† Hanwei Li‖, Bangyu Ju,† Lei Guo,§ Desheng Liu,§ and Haiyang Li*† †

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical

Physics, Chinese Academy of Sciences, Dalian, Liaoning, 116023, People’s Republic of China ‡

University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China

§

Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin,

Heilongjiang, 150001, People’s Republic of China ‖

College of Instrumentation & Electrical Engineering, Jilin University, Changchun, Jilin, 130026,

People’s Republic of China

1

ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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ABSTRACT Online monitoring of exhaled propofol concentration is important for anesthetists to provide adequate anesthesia as propofol concentrations in plasma and breath are correlated reasonably well. Exhaled propofol could be detected by

63

Ni ion mobility

spectrometry in negative ion mode, however, the radioactivity of 63Ni source restricts its clinical application due to safety, environmental, and regulatory concerns. An acetone-assisted negative photoionization ion mobility spectrometer (AANP-IMS) using a side-mounted vacuum ultraviolet (VUV) lamp in the unidirectional (UD) flow mode was developed for sensitively measurement of exhaled propofol by producing high percentage of O2-(H2O)n. An adsorption sampling and time-resolved purge introduction system was developed to eliminate the interference of residual inhaled anesthetic sevoflurane based on their different adsorptions between propofol and sevoflurane on the inwall of the fluorinated ethylene propylene (FEP) sample loop. The effects of the inner diameter and the length of the sample loop on the signal intensity of propofol and the time-resolution between propofol and sevoflurane were theoretically and experimentally investigated. A sample loop with 3 mm i.d. and 150 cm length allowed sensitive measurement of exhaled propofol with a response time of 4 s, a linear response range for propofol was achieved to be 0.2 to 14 ppbv with a limit of detection (LOD) of 60 pptv, and the quantification of propofol was not influenced by the change of the sevoflurane concentration. Finally, the performance of monitoring exhaled propofol during surgery was demonstrated on a patient undergoing laparoscopic distal pancreatectomy combined with cholecystectomy. INTRODUCTION Propofol, as an intravenous anesthetic agent, has the advantages of short duration, quick recovery with a high satisfaction for patients. Whereas, sevoflurane is an inhaled anesthetic with the low gas partition coefficient (0.69). In balanced anesthesia, propofol and sevoflurane were often used in combination to achieve a better anesthetic effect.1,2 Real-time monitoring of exhaled propofol could make possible an objective measure of the depth of anesthesia to complement existing clinical 2


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observations.3 Thus, rapid response time and high sensitivity detection methods were needed for closed-loop target controlled infusion (TCI) anesthesia with propofol in the presence of sevoflurane. Generally, several methods have been used for monitoring the concentration of exhaled propofol, such as proton transfer - reaction mass spectrometry (PTR-MS),4,5 ion molecular reaction - mass spectrometry (IMR-MS),6-8 electron ionization - mass spectrometry (EI-MS),9,10 selected ion flow tube - mass spectrometry (SIFT-MS),11 gas chromatography - mass spectrometry (GC-MS)1,12-15 and photoacoustic spectroscopy (PAS).16 Beyond that, Dong et al. developed a non-invasive method utilizing a fast gas chromatography combined with a surface acoustic wave sensor (Fast GC-SAW) to simultaneously monitor sevoflurane and propofol in patients’ exhaled gas.17 The concentration of sevoflurane was calibrated by a GC-MS, which ensured the reliability and accuracy of the fast GC-SAW system. Ion mobility spectrometry (IMS), with the advantage of high sensitivity, comparatively inexpensive acquisition, good portability and rapid response since spectra are available in the milliseconds range, has been developed for non-invasive analysis methods for clinical application,18 especially in human exhaled air for the diagnosis of diseases or measurement of exposure to anesthetic gases, such as propofol, sevoflurane, enflurane.19-21 The size of IMS apparatus developed in this study was about 38 cm×40 cm×18 cm and the weight was less than 15 kg. Compare to larger PTR and SIFT mass spectrometers, IMS apparatus was more suitable for application in a quiet and narrow operation theater, as IMS could work at ambient pressure without using bulk and noisy vacuum pumps. Although IMS has been used for the detection of exhaled propofol, there are still some problems to be solved. The radioactive 63Ni ionization source used in these methods significantly limited their clinical application. In negative ion mode of 63

Ni-IMS, with the reactant ion of O2-(H2O)n (K0 = 2.30 cm2 V-1 s-1) propofol formed

three kinds of product ions (M-H)-, M∙O2-, and (M2-H)-.22 The reduced mobility of O2-(H2O)n was determined with the moisture kept below 1 ppm and the temperature 3



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was kept at 120 oC. In our study the product ion of M∙O2- was used for the qualitative and

quantitative

detection

of

exhaled

propofol.

Dopant-assisted

negative

photoionization ion mobility spectrometry (DANP-IMS) has been developed for the detection of explosives.23 However, the reactant ions and the formation mechanism in DANP source were different from

63

Ni ionization source. In order to get high

percentage of O2-(H2O)n reactant ions, the conditions needed to be controlled strictly in unidirectional (UD) flow mode.24 However, the reactant ions were mainly CO3-(H2O)n (K0 = 2.44 cm2 V-1 s-1) in bidirectional (BD) flow mode. In the ionization region of DANP-IMS, low-energy electrons were produced by vacuum ultraviolet photoionization of acetone as reaction 1. Simultaneously, O3 was also generated due to the high concentration of O2 molecules at 123.5 nm, and the low heat of formation for O3 (34.1 kcal/mol) (reaction 2 and 3). Then, the O2 and O3 molecules in the ionization region could capture the low-energy electron and form O2- and O3- ions, which would further cluster water molecules to form their hydrated anions under ambient pressure (reaction 4-7). Besides, a part of hydrated O3- could be transformed from O2-(H2O)n through charge-transfer reaction 8. As there is about 300 ppm CO2 present in the carrier gas, the O3-(H2O)n could react with the CO2 in air as the reaction 9 and convert to CO3-(H2O)n in only about 0.4 µs due to the negative Gibbs free energy of reaction 9 (< -8.3 kcal/mol) and its rate constant k = 5.5×10-10 cm3 s-1. Moreover, in the UD flow mode of the axial-mounted vacuum ultraviolet (VUV) lamp the low-energy electrons and the O3 could present in the whole ionization chamber under the action of electric field and carrier gas, which accelerated the conversion of O2-(H2O)n. In addition, the formation of CO3-(H2O)n was easily influenced by the high concentration of moisture, CO2 and the complex components of exhaled breath. As a result, DANP-IMS based on axial-mounted VUV lamp was not very appropriate for the measurement of exhaled propofol. Therefore the structure of ionization region should be optimized for achievement of high percentage of O2-(H2O)n to ionize exhaled propofol.

acetone + hν → e − 4


1

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O2 + hν → O + O

2

O + O2 → O3

3

e − + O2 + M → O2 − + M ( M = N 2 , O2 , H 2O, etc.)

4

e − + O3 + M → O3− + M

5

O2 − + nH 2O + M → O2 − ( H 2O )n + M

6

O3− + nH 2O + M → O3− ( H 2O )n + M

7

O2 − ( H 2O ) n + O3 → O3− ( H 2O )m + O2 + (n − m) H 2O

8

O3− ( H 2O ) n + CO2 → CO3− ( H 2O )m + (n − m) H 2O + O2

9

In addition, the high moisture in exhaled breath and the inhaled anesthetic sevoflurane in the anesthetic breathing circuit interfere the detection of propofol seriously. Recently, IMS coupled with a range of sample introduction methods has been used for the measurement of exhaled propofol. Baumbach et al. developed multi-capillary column ion mobility spectrometry (MCC-IMS) to measure exhaled propofol. The MCC provides the possibility to work within humid environment.25,26 In our group, membrane inlet ion mobility spectrometry (MI-IMS), trap and release membrane inlet ion mobility spectrometry (TRMI-IMS), and time-resolved dynamic dilution introduction ion mobility spectrometry (TRDD-IMS) have been developed to monitor end-tidal propofol.27-29 However, in actual clinical environment, the anesthesia was not only total intravenous anesthesia (TIVA) environment, often combined with residual inhaled anesthetic sevoflurane. Though the major volatile organic compounds in exhaled air, including acetone, ethanol, ammonia, and isoprene molecules, did not interfere with the detection of exhaled propofol in the negative ion mode of IMS, the residual sevoflurane in the anesthetic breathing circle still made the ion mobility spectrum complex and confusing. Without sample pre-separation, it was difficult to overcome the influence of moisture and sevoflurane. In addition to this, the analysis time of membrane inlet and MCC was relatively long, it was difficult to meet the requirement of clinical closed-loop TCI. In order to reflect the plasma 5



propofol concentration in time, the analysis time also needs to be further shortened. In this paper, in order to reduce the formation of CO3-(H2O)n and measure exhaled propofol accurately, a side-mounted VUV lamp based on acetone-assisted negative photoionization ion mobility spectrometry (AANP-IMS) was designed to achieve a high percentage of O2-(H2O)n reactant ions in the UD flow mode at a wide range of flow rate, which reduced the concentration and the spatial diffusion of O3 in the reaction region, further improved the percentage of O2-(H2O)n. Moreover, an adsorption sampling and time-resolved purge introduction system was applied to eliminate the influence of exhaled moisture and inhaled anesthetic sevoflurane simultaneously. With the different inner diameter and length of the sample loop the different adsorption properties of propofol and sevoflurane and their time-resolution were studied in detail. The exhaled breath was sent into the AANP-IMS device through the fluorinated ethylene propylene (FEP) sample loop with a response time of 4 s. Under the optimized conditions, the separation effect and repeatability were satisfactory and this method was tested on a patient during laparoscopic distal pancreatectomy combined with cholecystectomy to demonstrate its capacity for the measurement of exhaled propofol in the presence of inhaled anesthetic sevoflurane. EXPERIMENTAL SECTION Apparatus. A side-mounted VUV lamp based on AANP-IMS coupled with adsorption sampling and time-resolved purge introduction system, as shown in Figure 1, including (a) the sampling process and (b) the injection process, was developed. A commercial low-pressure krypton discharge lamp (Kr10.6-B12X50 PID lamp, Steven Sepvest Corporation) with a photon flux of about 5×1011 photons s-1 was used as the ultraviolet light source. The VUV lamp was side-mounted instead of axial-mounted and with radio frequency (RF) power supply. The IMS tube was constructed with a series of stacked stainless steel guard rings separated by Teflon insulating rings. It was operating at 90 oC and the applied electric field was 393 V cm-1. The reactant ions generation zone was 23 mm long with inner diameter of 6 mm and the applied voltage was 812 V. The reaction region was 14 mm long with inner diameter of 14 6


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mm and the drift region was 72 mm long with inner diameter of 18 mm. The ion gate was a Bradbury-Nielson type with an injection pulse width of 200 µs. Reactant ions were generated in the side-mounted VUV lamp region and then reacted with the exhaled sample to product ions, which were separated in the drift region and detected by the Faraday plate. The duration of acquisition time for an ion mobility spectrum was 15 ms; then, an output spectrum was obtained by averaging 20 initial IMS spectra, so 3 averaged spectra could be recorded within 1 s. An UD flow mode was used in the IMS. The dopant and carrier gas were introduced through the port near the BNG separately, and the drift gas was introduced from the back of the Faraday plate. Both the carrier and drift gases flowed through the ionization region and were exhausted through the front port of the reactant ions generation zone. The clean air gas, purified and filtrated by silica gel, activated carbon and freshly baked 13X molecular sieve, was used for the carrier and drift gases. The moisture of the purified air was kept below 1 ppm, which was monitored by a dew point detector (DP300, CS Instrument GMH). The flow rate of the dopant carrier gas, the carrier gas and the drift gas were set at 50 mL min-1, 500 mL min-1 and 200 mL min-1, respectively.

Figure 1. Schematic diagram of the side-mounted VUV lamp based on acetone-assisted negative photoionization ion mobility spectrometer coupled with (a) the sampling process and (b) the injection process. Adsorption Sampling and Time-Resolved Purge Introduction. In order to eliminate the interference of residual inhaled anesthetic sevoflurane in the breathing

7



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circuit, the time-resolved purge introduction system was developed here based on the different adsorptions between propofol and sevoflurane on the inwall of the sample loop, schematically as shown in Figure 1. It was composed of a FEP sample loop (kept

at

30

o

C),

a

sampling

pump

and

three-way

solenoid

valves

(MTV-3R-M6FHT-24, Takasago Electric). The sample loop was made of 150 cm FEP tube (3 mm i.d.), with a hollow volume of 10.6 mL. In the sampling process, the exhaled breath samples were drawn into the sample loop by the pump while the carrier gas was directly introduced into IMS, as shown in Figure 1a. After the sampling process, the pump was turned off and the carrier gas was infused into the sample loop by switching the valves, followed by the injection of samples into IMS, as shown in Figure 1b. The sampling parameters were optimized to suit the patient respiration. From a T-piece connected between the endotracheal tube and the breathing circuit exhaled gas was sampled, and through a 1.5 m long with an inner diameter of 2 mm, polytetrafluoroethylene (PTFE) tube connected to the third valve of the IMS. In the clinical application, a CO2 sensor (C200, National Medical Co. Ltd., China) was used to measure the exhaled CO2. When the CO2 sensor signal located at the peak of the alveolar platform of CO2 respiration curve, the end-tidal breath was sampled by controlling the three solenoid valves synchronously. Then a clean carrier gas was switched into the sample loop to purge the end-tidal breath gas injection into the reaction region of the ion mobility spectrometer. The injection process was last 10 s, the moisture, sevoflurane and propofol in the breath gas were separated in time for better quantitative measurements of the concentration of propofol. After the injection process, the three solenoid valves were switched back to let the breath gas flush the sample loop for about 20 s, and the clean carrier gas was also directly introduced into IMS to stabilize the IMS system for a new measurement. The flow rate for sampling the exhaled gas was about 1000 mL min-1. The theory of adsorption sampling and time-resolved purge introduction is simplified from the theory of chromatography. In the sampling process, gaseous substances in the sample loop are absorbed on the inwall, and the surface concentration of analyte is uniform distributed in whole tubing. Meanwhile assuming 8


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that the distribution of a substance between the gas phase and loop inwall is instantly equalized, its average concentration in the gas (Cg, cm3 cm-3) and on the loop inwall (Cs, cm3 cm-2) can be related as in Eq. (1), where K is the distribution coefficient (cm3 cm-2). Cs =K Cg

(1)

In the injection process, the amount of substance lost in the sample loop, dn, can be described as Eq. (2) as well as Eq. (3), where t is the time for carrier gas flushing the sample loop (s), f is the flow rate of carrier gas (mL s-1), S is the total surface of the sample loop inwall (cm2), and V is the volume of sample loop (mL).

dn = VdCg + SdCs

(2)

dn = −Cg fdt

(3)

Combining Eq. (2) and Eq. (3) yields Eq. (4).

−(VdCg + SdCs ) = Cg fdt

(4)

According to Eq. (1), the relation of dC s = KdC g is valid, so Eq. (4) can be simplified to Eq. (5).

dC g

Cg

=−

f dt V + KS

(5)

Solving Eq. (5), the average concentration in the carrier gas, C g , can be described 0

by Eq. (6), where Cg is the initial average concentration in sample loop.

Cg = Cg0 exp( −

ft ) V + KS

(6)

V (mL) and S (cm2) can be described as Eq. (7) and Eq. (8), respectively, where

d is the inner diameter of the sample loop (cm) and l is the length of the sample

loop (cm).

d V = π ( )2 l 2

9


(7)


S = π dl

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(8)

Substituting Eq. (7) and Eq. (8) into Eq. (6) yields Eq. (9).

Cg = Cg0 exp( −

4 ft / π l ) d 2 + 4 Kd

(9)

I g is the IMS signal intensity of the substance in the gas phase ( I g , mV). Due to 0 0 I g and I g is proportional to Cg and Cg , respectively. Eq. (9) could be expressed

as Eq. (10). From Eq. (10), it is clear that the IMS signal intensity I g is related with f , t , d and l .

I g = I g0 exp( −

4 ft / π l ) d 2 + 4 Kd

(10)

From Eq. (6), it is clear that the decay rate of concentration is determined by the term of (V + KS) / f , which is defined as the decay factor, τ (s), as Eq. (11).

τ=

V + KS f

(11)

The separation efficiency between propofol and sevoflurane is determined by the term of τ propofol / τ sevoflurane , which is defined as the time resolution factor α, as Eq. (12).

α=

τ propofol τ sevoflurane

(12)

Substituting Eq. (7), (8) and (11) into Eq. (12) yields Eq. (13). From Eq. (13), it can be seen that the time resolution factor α between propofol and sevoflurane is related with the inner diameter d and their distribution coefficient K .

α=

d + 4 K propofol d + 4 K sevoflurane

; ( K propofol＞Ksevoflurane )

(13)

Dopant and Sample Gases Preparation Method. Acetone was analytical grade and purchased from Tianjin Kermel Chemicals Co. Ltd. (Tianjin, China). Acetone was first placed inside a 5 mL vial (Agilent Technologies Inc., Santa Clara, CA, USA)

10


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sealed at one end by a porous capsule. The vial was placed in a 6 mL bottle, which was kept at 30 oC constant temperature and dopant carrier gas was employed to purge the headspace of the bottle to generate a carrier air flow with concentration of 20 ppm, which could provide enough reactant ions and avoid excess consumption of acetone.23 Propofol was purchased from J & K Scientific Ltd. (Beijing, China). Sevoflurane for inhalation was purchased from Shanghai Hengrui Pharmaceutical Co. Ltd. (Shanghai, China). A mother gas of propofol and sevoflurane was prepared by the permeating method,28 and the details are described as follows: 1 mL pure liquid propofol or sevoflurane was sealed in a 2 mL vessel; then its silicone cap was drilled with a fine sharp needle to allow the propofol or sevoflurane gas to diffuse out; the propofol or sevoflurane gas was immediately carried away by purified air at a constant flow rate; after several days, the mass loss of this vessel was weighed; at a constant temperature of 28 oC, their concentration of propofol and sevoflurane was calculated to be 50 ppbv and 2 ppmv, respectively. To make lower concentration of propofol or sevoflurane mixture, the mother gas of propofol or sevoflurane was diluted with clean air, which had been passed through the sevoflurane or propofol gas. RESULTS AND DISCUSSION The Side-Mounted VUV Lamp Based on AANP-IMS. In order to achieve high percentage of O2-(H2O)n for the detection of propofol, a side-mounted VUV lamp based on AANP-IMS was designed and UD flow mode was developed in this study as shown in Figure 1. Because the different percentage of dominant reactant ions O2-(H2O)n and CO3-(H2O)n is related to the chemical reactions initialized by the ultraviolet light. Furthermore, the light intensity decays with the increase of distance

x (mm) from the MgF2 window, according to the equation ln( I / I 0 ) = −0.46 x in air30 and would lose 90% of its intensity at the 5 mm distance and 99% at the 10 mm distance.24 In previous study, with axial-mounted VUV lamp a stainless steel extraction electrode with a hole (4 mm diameter) at the center was mounted at a 10 mm distance from the lamp window to improve the percentage of O2-(H2O)n in the 11



unidirectional mode. Thus, the formation of ozone from photochemical reaction of oxygen and electrons from the photoionization of acetone occurred mainly in the region between the VUV lamp and the extraction electrode (10 mm).24 With the side-mounted VUV lamp design, the inner diameter of reactant ions generation region was reduced to 6 mm, and at the same time, O3 generated by VUV light were more efficiently removed out from reaction region compare to the axis-mounted structure in the UD flow mode. Moreover, the diffusion of O3 in the axial and radial direction was reduced. Thus, the ozone molecules mainly existed in the region of the side-mounted VUV lamp, which would limit the formation region of O3-(H2O)n, thus a reduced formation of CO3-(H2O)n. Meanwhile, the low-energy electrons was captured by oxygen molecules to form O2-(H2O)n, which were forced to the reaction region behind the side-mounted VUV lamp by the high electric field. In addition, the dilution effect of the drift gas on the concentration of ozone in the UD mode would be another reason for the reduction of CO3-(H2O)n and the dominance of O2-(H2O)n. The reduced generation area, the reduced spatial distribution and the dilution of O3 concentration lead to the dominant O2-(H2O)n reactant ions in the UD flow mode with the design of side-mounted VUV lamp. Importantly, the side-mounted VUV lamp could effectively avoid the contamination of the MgF2 window from the exhaled breath, including exhaled CO2, moisture, aerosol, macromolecular and other interferent components. Furthermore, UD flow mode will be useful for the dilution of moisture and the interferent components of exhaled breath. Thus, the ion mobility spectrum of propofol will be simple and the sensitivity could be improved. With this design the evolution of O2-(H2O)n in the UD flow mode with carrier gas and drift gas flow rates from 100 to 1000 mL min-1 were depicted in Figure 2a-b, respectively. The percentage of O2-(H2O)n remained stable above 85% with a wide range of carrier gas and drift gas flow rate. The percentage of O2-(H2O)n was calculated by the ratio of the signal intensity of O2-(H2O)n to the total signal intensity of O2-(H2O)n and CO3-(H2O)n. Due to the dilution of the carrier gas and drift gas, the signal intensity O2-(H2O)n slightly decreased with the increase of their flow rates. At last, coupled with adsorption sampling and time-resolved purge introduction 500 mL 12


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min-1 and 200 mL min-1 was chosen as the flow rate of the carrier gas and drift gas respectively for better separation and sensitivity of propofol. This method demonstrated the feasibility of the side-mounted VUV lamp based on AANP-IMS in UD flow mode for the detetion of propofol, nicely solved the problem of the

63

Ni

radioactive contamination.

Figure 2. The percentage of O2-(H2O)n in the unidirectional flow mode by the side-mounted VUV lamp based on acetone-assisted negative photoionization ion mobility spectrometer for (a) carrier gas and (b) drift gas flow rate. The Influence of Sevoflurane with Direct Introduction. The effect of the different concentration of sevoflurane on the sensitivity of 5 ppbv propofol with direct introduction method was studied. With direct introduction the sample of propofol and sevoflurane was injected into the reaction region simultaneously. The ion mobility spectra of 5 ppbv propofol with different concentration of sevoflurane was shown in Figure 3a, with K0 of 1.38 and 1.61cm2 V-1 s-1, respectively. The signal intensity of sevoflurane related peak was increased almost linearly, when its concentration was increased from 10 to 237 ppbv in the presence of 5 ppbv propofol, as shown in Figure3b. The intensity difference between sevoflurane only and sevoflurane with 5 ppb propofol might be related to the competitive ionization between sevoflurane and propofol. As shown in Figure 3c, the signal variation observed in propofol only experiments was only 8 mV, its relative standard deviation (RSD) was about 1.5%, which originated from the random error caused by measurement. However, the signal intensity of 5 ppbv propofol rose with the increasing concentration of sevoflurane.

13



Although the peaks are fully resolved as shown in Figure 3a, the signal intensity of propofol in IMS was affected by the presence of sevoflurane using direct introduction method, so quantitative determination of propofol concentration in the exhaled gas might be influenced when the concentration of sevoflurane in the exhaled gas was changed.

Figure 3. With direct introduction (a) the ion mobility spectra of 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv, (b) the signal intensities of different concentration of sevoflurane from 10 to 237 ppbv only (blue square) and sevoflurane with 5 ppbv propofol (red circle), (c) the signal intensities of 5 ppbv propofol only (blue square) and 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv (red circle). Time-Resolved Purge Introduction for Eliminating the Influence of Sevoflurane. In order to eliminate the influence of sevoflurane, adsorption sampling and time-resolved purge introduction was developed here. Based on their different adsorptions on the inwall of the FEP sample loop, the effects of the inner diameter and the length of the sample loop on the signal intensity of propofol and their time 14


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resolution factor α between propofol and sevoflurane were theoretically and experimentally investigated. When the length of the sample loop was 150 cm, the time-resolved profiles of propofol and sevoflurane with the inner diameter of 1 mm, 3 mm and 6 mm, were shown in Figure 4a-c, respectively. The time-resolved profiles of propofol and sevoflurane were obtained by recording the peak intensities of propofol (K0 = 1.38 cm2 V-1 s-1) and sevoflurane (K0 = 1.61cm2 V-1 s-1) from 120 IMS spectra during the 40 s injection process. In Figure 4a, with the inner diameter of 1 mm, the time-resolution is the best while the signal intensity was the lowest. In Figure 4b, with the inner diameter of 3 mm the concentration of propofol and sevoflurane has realized the time-resolution, and the signal intensity of propofol became higher. In Figure 4c, with the inner diameter of 6 mm, although the signal intensity of propofol was higher, the time-resolution was the lowest. According to the adsorption sampling and time-resolved purge introduction theory, from Eq. (10), it can be seen when the f , t and l was constant, the IMS signal intensity of propofol I g was related with the inner diameter d . As shown in Figure 4d, with the increase of the inner diameter d , the signal intensity of propofol increased. When 4 ft / π l is equal to A, Eq. (10) could be written to Eq. (14). I g = I g0 exp( −

A ) d 2 + 4 K propofol d

(14)

0 The experimental result was fitted by the Eq. (14), yielded I g = 68.63 , A = 0.70 ,

K propofol = 1.43 , and I g could be expressed by Eq. (15). The adjusted coefficient of

determination R2 calculated by the data fitting with origin software was 0.98 and the experimental results agree well with the theoretical derivation.

I g = 68.63exp( −

0.7 ) d + 5.72d 2

(15)

With the increase of the inner diameter, the time resolution factor α between propofol and sevoflurane decreased, as shown in Figure 4d. According to Eq. (13), the time resolution factor α was related with the inner diameter d and fitted with the 15



experimental data to α =

d + 5.76 . The adjusted coefficient of determination R2 d + 0.06

could reach to 0.99, K propofol = 1.44 and K sevoflurane = 0.015 , which shows a good correlation. At last, in consideration of the signal intensity of propofol and the time-resolution, 3 mm was chosen as the optimal inner diameter of the sample loop.

Figure 4. The time-resolved profiles of 2 ppbv propofol and sevoflurane with the inner diameter of (a) 1 mm, (b) 3 mm, (c) 6 mm, and (d) the signal intensities of 2 ppbv propofol and the time resolution factor α between 2 ppbv propofol and sevoflurane with the inner diameter of sample loop from 1 mm to 6 mm. When the inner diameter of the sample loop was 3 mm, the time-resolved profiles of propofol and sevoflurane with the length of 50 cm, 150 cm and 250 cm, were shown in Figure 5a-c, respectively. No matter how long the sample loop was, it had a good and certain time resolution factor α between propofol and sevoflurane, as shown in Figure 5d. According to the Eq. (13), the time resolution factor α was only related with the inner diameter d and the distribution coefficient K , which has nothing to do with the length. The time resolution factor α = 25.23 fitted by the Eq. (13), which agreed with the experimental result. With the increase of the length, the signal 16


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intensity of the propofol increased to be stable. According to Eq. (10), I g could be

B 4 ft / π expressed as I g = I g0 exp( − ) , and B = 2 . The signal intensity of propofol l d + 4 Kd was

fitted

by

I g = 59.5exp( −

the

equation

with

the

experimental

data

and

yielded

10.5 ) . At last, in consideration of the signal intensity of propofol and l

the time-resolution, 150 cm was chosen as the optimal length of the sample loop.

Figure 5. The time-resolved profiles of 2 ppbv propofol and sevoflurane with the length of (a) 50 cm, (b) 150 cm, (c) 250 cm, and (d) the signal intensities of 2 ppbv propofol and the time resolution factor α between 2 ppbv propofol and sevoflurane with the length of sample loop from 25 cm to 250 cm. Resolution, Repeatability and Sensitivity. Under the above optimized conditions, the signal intensities of 5 ppbv propofol, with different concentration of sevoflurane from 10 to 237 ppbv, were illustrated in Figure 6a. The signal intensities of the propofol with different concentration of sevoflurane were almost the same as the constant concentration of propofol. Thus the signal intensity of propofol was not 17



influenced by the concentration variation of sevoflurane when the time-resolved purge introduction method was employed, as sevoflurane and propofol could be well separated in time during the purging process. As shown in Figure 6b, 2 ppbv propofol with sevoflurane was measured five times, which demonstrated a good repeatability with a relative standard deviation (RSD) of 1.6%. Linearity of the method was investigated in the concentration range from 0.2 to 14 ppbv at the limit of detection (LOD) of 60 pptv.

Figure 6. With time-resolved purge introduction (a) the signal intensities of 5 ppbv propofol only and 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv, (b) five measurements of 2 ppbv propofol with sevoflurane. Clinical Application. The protocol of this study was approved by the Ethics Committee at Harbin Medical University (protocol no. 201314) and written informed consent was also obtained from the patient involved (female, age of 47, height of 165 cm, weight of 80 kg), who was scheduled to undergo laparoscopic distal pancreatectomy combined with cholecystectomy conducted at the First Affiliated Hospital of Harbin Medical University, Harbin, China. The patient was anesthetized with 6 µg mL-1 propofol given by the TCI system for the induction of anesthesia. Then the patient was intubated using endotracheal tube and anesthesia was maintained by continuous intravenous application of propofol and remifentanil. After intubation, the lung was ventilated with a commercially available anaesthesia machine (Dräger Fabius GS, Lübeck, Germany). During surgery, anesthesia was maintained by continuous administration of 3.5 µg mL-1 and 4 µg mL-1 18


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propofol by the TCI system. The ventilator frequency for this patient was 16 per minute. A PTFE tube (kept at a room temperature of 21 ~ 22 oC) was attached to the T-piece connected between the endotracheal tube and the breathing circuit. The end-tidal air was sampled and injected into the reaction region of the IMS for monitoring the exhaled propofol concentration. Throughout the monitoring process, the end-tidal propofol was measured with an interval of seven respirations and its signal at the 4th s spectrum after sample injection was utilized to measure its concentration, as shown in Figure 7a. In contrast, with direct introduction method the ion mobility spectrum was complex with the interference of exhaled moisture and sevoflurane in the middle of the surgery, which was difficult to discriminate the product ion peak of exhaled propofol, as shown in Figure 7b. In Figure 7c, every measured concentration characterizes the end-tidal propofol 4 s before, realizing the online monitoring of exhaled propofol in the presence of sevoflurane. Furthermore, the increase and decrease of exhaled propofol concentration was a result of the change of plasma propofol concentration set by TCI, which shows a good correlation (r = 0.79), as shown in Figure S-1a. Moreover, the total blood loss was 100 mL during the operation. The hemodynamic data including the mean arterial pressure (MAP) and the heart rate (HR) had been added as Figure S-2. The bispectral index (BIS) is used as a surrogate to represent the propofol effect in the clinic. Trends of the exhaled propofol concentration were highly accordant with the BIS index. A linear relationship was also found between exhaled propofol intensity and BIS index values (r = -0.76), as shown in Figure S-1b. The relationship between the exhaled propofol and the BIS index indicates that the exhaled propofol concentration may reflect the effects of anesthesia in the brain, to some degree, which may help to improve the safety of propofol anesthesia. Exhaled propofol and blood concentrations show good correlation for an individual, however, the exhaled propofol concentration is affected by other clinic factors, such as the tidal volume and the cardiac output, etc. So, before the propofol monitor is used for daily care, the measured exhaled propofol concentrations must be well standardized, and a reliable population pharmacokinetic model for exhaled propofol 19



needs to be established. In order to meet this goal, simple, reliable, rapid and clinic friendly analysis methods need to be developed. BIS monitor processes a single frontal electroencephalographic signal to calculate a dimensionless number that provides a measure of the patient’s level of consciousness. The BIS index as a surrogate to represent the propofol effect is effective in most monitoring situations, but the value can be influenced by many factors.31,32Anesthesia awareness occurred even when BIS values were within the target ranges.33 Therefore, it would be best to combine BIS with the online monitoring techniques to ensure the safety of anesthesia.

Figure 7. (a) The time-resolved ion mobility spectra of the 10 s purge introduction, (b) the comparison between the 4th s ion mobility spectrum of the time-resolved purge introduction and the ion mobility spectrum of the direct introduction, and (c) the measured temporal profiles of exhaled propofol and sevoflurane, the BIS and the plasma propofol concentration set by TCI for a patient undergoing laparoscopic distal pancreatectomy combined with cholecystectomy. 20


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CONCLUSIONS In conclusion, we demonstrated an acetone-assisted negative photoionization ion mobility spectrometer for the online monitoring of exhaled propofol under the interference of inhaled anesthetic sevoflurane. The side-mounted VUV lamp in the unidirectional flow mode could provide high percentage of O2-(H2O)n in the ion source at a wide range of applied conditions to react with propofol. Meanwhile, the time-resolved purge introduction developed in this work could eliminate the influence of moisture and low concentration of inhaled sevoflurane, which shows good feasibility for rapid online monitoring of exhaled propofol. The AANP-IMS could allow continuous and noninvasive monitoring of expiratory propofol and sevoflurane levels simultaneously in patients undergoing general anesthesia in the future.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Correlation analysis between exhaled propofol intensity and plasma propofol concentration set by TCI, and BIS; the temporal profiles of MAP and HR (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Fax: +86-411-84379517. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work is partly supported by DICP (Grant No. DICP ZZBS201709), the National High-Tech Research and Development Plan (No. 2017YFC0806601-1), and the National Natural Science Foundation of China (Grants: 21675155, 21707138).

REFERENCES (1) Dong, H.; Zhang, F. J.; Wang, F. Y.; Wang, Y. Y.; Guo, J.; Kanhar, G. M.; Chen, J.; Liu, J.; Zhou, C.; Yan, M.; Chen, X. J. Chromatogr. A 2017, 1506, 93-100. (2) Tonner, P. H. Best Pract. Res. Cl. Anaesth. 2005, 19, 475-484. (3) Colin, P.; Eleveld, D. J.; van den Berg, J. P.; Vereecke, H. E.; Struys, M. M.; Schelling, G.; Apfel, C. C.; Hornuss, C. Clin. Pharmacokinet. 2016, 55, 849-859. (4) Harrison, G.; Critchley, A.; Mayhew, C.; Thompson, J. Brit. J. Anaesth. 2003, 91, 797-799. (5) Takita, A.; Masui, K.; Kazama, T. Anesthesiology 2007, 106, 659-664. (6) Hornuss, C.; Wiepcke, D.; Praun, S.; Dolch, M.; Apfel, C.; Schelling, G. Anal. Bioanal. Chem. 2012, 21



403, 555-561. (7) Grossherr, M.; Varadarajan, B.; Dibbelt, L.; Schmucker, P.; Gehring, H.; Hengstenberg, A. Anal. Bioanal. Chem. 2011, 401, 2063-2067. (8) Hornuss, C.; Praun, S.; Villinger, J. Anesthesiology 2007, 106, 665-674. (9) Elizarov, A. Y.; Ershov, T. D.; Levshankov, A. I. Tech. Phys. 2011, 56, 1807-1810. (10) Elizarov, A. Y.; Ershov, T. D.; Kozlovskii, A. V.; Levshankov, A. I. J. Anal. Chem. 2011, 66, 1470-1473. (11) Boshier, P. R.; Cushnir, J. R.; Mistry, V.; Knaggs, A.; Spanel, P.; Smith, D.; Hanna, G. B. Analyst 2011, 136, 3233-3237. (12) Kamysek, S.; Fuchs, P.; Schwoebel, H.; Roesner, J. P.; Kischkel, S.; Wolter, K.; Loeseken, C.; Schubert, J. K.; Miekisch, W. Anal. Bioanal. Chem. 2011, 401, 2093-2102. (13) Grossherr, M.; Hengstenberg, A.; Meier, T.; Dibbelt, L.; Igl, B. W.; Ziegler, A.; Schmucker, P.; Gehring, H. Brit. J. Anaesth. 2009, 102, 608-613. (14) Miekisch, W.; Fuchs, P.; Kamysek, S.; Neumann, C.; Schubert, J. K. Clin. Chim. Acta 2008, 395, 32-37. (15) Grossherr, M.; Hengstenberg, A.; Meier, T.; Dibbelt, L.; Gerlach, K.; Gehring, H. Anesthesiology 2006, 104, 786-790. (16) Navas, M. J.; Jimenez, A. M.; Asuero, A. G. Clin. Chim. Acta 2012, 413, 1171-1178. (17) Dong, H.; Zhang, F. J.; Wang, F. Y.; Wang, Y. Y.; Guo, J.; Kanhar, G. M.; Chen, J.; Liu, J.; Zhou, C.; Yan, M.; Chen, X. J. Chromatogr. A 2017, 1506, 93-100. (18) Chouinard, C. D.; Wei, M. S.; Beekman, C. R.; Kemperman, R. H.; Yost, R. A. Clin. Chem. 2016, 62, 124-133. (19) Eiceman, G. A.; Shoff, D. B.; Harden, C. S.; Snyder, A. P. Anal. Chem. 1989, 61, 1093-1099. (20) Perl, T.; Carstens, E.; Hirn, A.; Quintel, M.; Vautz, W.; Nolte, J.; Junger, M. Brit. J. Anaesth. 2009, 103, 822-827. (21) Kunze, N.; Weigel, C.; Vautz, W.; Schwerdtfeger, K.; Junger, M.; Quintel, M.; Perl, T. J. Occup. Med. Toxicol. 2015, 10, 12. (22) Zhou, Q.; Hua, L.; Wang, C.; Li, E.; Li, H. J. Am. Soc. Mass Spectrom. 2014. (23) Cheng, S.; Dou, J.; Wang, W.; Chen, C.; Hua, L.; Zhou, Q.; Hou, K.; Li, J.; Li, H. Anal. Chem. 2013, 85, 319-326. (24) Cheng, S.; Wang, W.; Zhou, Q.; Chen, C.; Peng, L.; Hua, L.; Li, Y.; Hou, K.; Li, H. Anal. Chem. 2014, 86, 2687-2693. (25) Buchinger, H.; Kreuer, S.; Hellbrück, R.; Wolf, A.; Fink, T.; Volk, T.; Bödeker, B.; Maddula, S.; Baumbach, J. I. Int. J. Ion Mobil. Spec. 2013, 16, 185-190. (26) Kreuder, A. E.; Buchinger, H.; Kreuer, S.; Volk, T.; Maddula, S.; Baumbach, J. I. Int. J. Ion Mobil. Spec. 2011, 14, 167-175. (27) Zhou, Q.; Wang, W.; Cang, H.; Du, Y.; Han, F.; Chen, C.; Cheng, S.; Li, J.; Li, H. Talanta 2012, 98, 241-246. (28) Zhou, Q.; Li, E.; Wang, X.; Gong, Y.; Hua, L.; Wang, W.; Qu, T.; Li, J.; Liu, Y.; Wang, C.; Li, H. Anal. Methods 2014, 6, 698-703. (29) Zhou, Q.; Li, E.; Wang, Z.; Gong, Y.; Wang, C.; Guo, L.; Li, H. J. Breath Res. 2015, 9, 016002. (30) Nazarov, E. G.; Miller, R. A.; Eiceman, G. A.; Stone, J. A. Anal. Chem. 2006, 78, 4553-4563. (31) Bruhn, J.; Myles, P. S.; Sneyd, R.; Struys, M. M. Brit. J. Anaesth. 2006, 97, 85-94. (32) Ludbrook, G. L.; Visco, E.; Lam, A. M. Anesthesiology 2002, 97, 1363-1370.

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(33) Avidan, M. S.; Zhang, L.; Burnside, B. A.; Finkel, K. J.; Searleman, A. C.; Selvidge, J. A.; Saager, L.; Turner, M. S.; Rao, S.; Bottros, M.; Hantler, C.; Jacobsohn, E.; Evers, A. S. New Engl. J. Med. 2008, 358, 1097-1108.

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for TOC only

24


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Figure 1. Schematic diagram of the side-mounted VUV lamp based on acetone-assisted negative photoionization ion mobility spectrometer coupled with (a) the sampling process and (b) the injection process. 72x29mm (300 x 300 DPI)



Figure 2. The percentage of O2-(H2O)n in the unidirectional flow mode by the side-mounted VUV lamp based on acetone-assisted negative photoionization ion mobility spectrometer for (a) carrier gas and (b) drift gas flow rate. 68x26mm (300 x 300 DPI)


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Figure 3. With direct introduction (a) the ion mobility spectra of 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv, (b) the signal intensities of different concentration of sevoflurane from 10 to 237 ppbv only (blue square) and sevoflurane with 5 ppbv propofol (red circle), (c) the signal intensities of 5 ppbv propofol only (blue square) and 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv (red circle). 135x103mm (300 x 300 DPI)



Figure 4. The time-resolved profiles of 2 ppbv propofol and sevoflurane with the inner diameter of (a) 1 mm, (b) 3 mm, (c) 6 mm, and (d) the signal intensities of 2 ppbv propofol and the time resolution factor α between 2 ppbv propofol and sevoflurane with the inner diameter of sample loop from 1 mm to 6 mm. 126x90mm (300 x 300 DPI)


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Figure 5. The time-resolved profiles of 2 ppbv propofol and sevoflurane with the length of (a) 50 cm, (b) 150 cm, (c) 250 cm, and (d) the signal intensities of 2 ppbv propofol and the time resolution factor α between 2 ppbv propofol and sevoflurane with the length of sample loop from 25 cm to 250 cm. 129x94mm (300 x 300 DPI)



Figure 6. With time-resolved purge introduction (a) the signal intensities of 5 ppbv propofol only and 5 ppbv propofol with different concentration of sevoflurane from 10 to 237 ppbv, (b) five measurements of 2 ppbv propofol with sevoflurane. 68x26mm (300 x 300 DPI)


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Figure 7. (a) The time-resolved ion mobility spectra of the 10 s purge introduction, (b) the comparison between the 4th s ion mobility spectrum of the time-resolved purge introduction and the ion mobility spectrum of the direct introduction, and (c) the measured temporal profiles of exhaled propofol and sevoflurane, the BIS and the plasma propofol concentration set by TCI for a patient undergoing laparoscopic distal pancreatectomy combined with cholecystectomy. 156x138mm (300 x 300 DPI)



for TOC only 47x29mm (300 x 300 DPI)


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Online Monitoring of Intraoperative Exhaled Propofol by Acetone

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