YAJEM-57182; No of Pages 5
American Journal of Emergency Medicine xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine
journal homepage: www.elsevier.com/locate/ajem

Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an
unstable patient
Chi-Wei Lee, MD, PhD a,b, Yu-Ying Chao, PhD c, Jentaie Shiea, PhD d,e, Jheng-Heng Shen, MD b,
Hei-Hwa Lee, MS f, Bai-Hsiun Chen, MD f,g,⁎
a

Institute of Medical Science and Technology, National Sun Yat-Sen University, Taiwan
Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
d
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan
e
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
f
Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
g
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
b
c

a r t i c l e

i n f o

Article history:
Received 26 August 2017
Received in revised form 7 December 2017
Accepted 19 December 2017
Available online xxxx
Keywords:
Multiple drugs overdose
Thermal desorption-electrospray ionizationmass spectrometry
Toxicological identification technique

a b s t r a c t
A 25-year-old man suffered from consciousness change was sent to our emergency department by friends who
reported that they were not sure what had happened to him. Physical examination revealed bilateral pupils dilatation, lethargy, slurred speech, and ataxia. Computer-aided tomographic scan of the brain revealed no definite
evidence of intracranial lesions. Routine laboratory tests revealed total physiological turmoil. Despite immediate
commencement of aggressive treatment, the patient's condition deteriorated long before the traditional drug
screen provided an answer for the identities of the multiple drugs overdose. It ended up with the need for
cardiopulmonary resuscitation, but in vain. At the end of the tragic event, under the suggestion of a colleague,
a portion of the patient's urine specimen was sent to our university esoteric laboratory for rapid analysis by
means of a newly-developed thermal desorption-electrospray ionization-mass spectrometry. Ketamine, 3,4methylenedioxymethamphetamine, and 3,4-methylenedioxyamphetamine were identified in the urine sample
within 30 s. Conventional toxicological testing techniques like gas chromatography–mass spectrometry or liquid
chromatography-mass spectrometry are currently used for identifying abused drugs. One concern is their timeconsuming sample pretreatment which leads to relatively low efficiency in terms of turnaround time for revealing the identity of the consumed drugs particularly when the patients are severely overdosed. We learned a lesson from this case that a more efficient toxicological identification technique is essential to expedite the process
of emergency care when the patients are so heavily overdosed that they are under critical life-threatening
conditions.
© 2017 Published by Elsevier Inc.

1. Introduction
Psychoactive drugs cause intoxication through various mechanisms
that require different therapeutic strategies [1,2]. Identification of
abused drugs is currently based on the history of exposure, clinical
signs and symptoms, and laboratory tests. Unfortunately, it is difficult
to identify rapidly drugs taken by severely overdosed patients at the
early stages of emergency care, because such patients usually suffer
Abbreviations: GC–MS, Gas chromatography-mass spectrometry; LC-MS/MS, Liquid
chromatography tandem mass spectrometry; TD-ESI-MS, Thermal desorption-electrospray
ionization-mass spectrometry; MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4methylenedioxyamphetamine; TD-ESI, Thermal desorption-electrospray ionization.
⁎ Corresponding author at: Department of Laboratory Medicine, Kaohsiung Medical
University Hospital, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan.
E-mail address: d670014@kmu.edu.tw (B.-H. Chen).

from mentality changes and fail to report precisely the type of
intoxicants consumed. Not all signs and symptoms of psychoactive
drug overdoses are present in every patient; the drugs have multiple
pharmacologic functions and affect the brain in different ways [3]. Severely intoxication mandates rapid identification of the offending
agents that guides the emergency physician to appropriate management and prescription of antidotes. Traditionally, abused drugs present
in urine or blood are identified and quantified by gas chromatography–
mass spectrometry (GC–MS) and/or liquid chromatography tandem
mass spectrometry (LC-MS/MS) [4,5]. Although both techniques are
sensitive and reliable, tedious and time-consuming sample pretreatment like solvent extraction, filtration, concentration, fractionation,
and derivatization are needed. These conventional methods require
hours for drug identification rendering delay in data-reporting. Although immunoassay techniques have also been introduced to identify

https://doi.org/10.1016/j.ajem.2017.12.042
0735-6757/© 2017 Published by Elsevier Inc.

Please cite this article as: Lee C-W, et al, Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient,
American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.12.042

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C.-W. Lee et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

Please cite this article as: Lee C-W, et al, Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient,
American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.12.042

C.-W. Lee et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

3

Fig. 2. Thermal desorption-electrospray-mass spectrometric signals of ketamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyamphetamine in the patient's urine
sample. TIC: total ion chromatogram. Data acquisition was attained within 30 s.

psychoactive drugs in saliva, the narrow specificity of determination
due to the variable cross-reactivity of the drugs with antibodies remains
their biggest limitation [4].
The aim of this case-report is to arouse attention to the current lack
of rapid point-of-care in vitro diagnostic technology for identifying various kinds of abused drugs in the patients. Hopefully, this may initiate
further research and development of innovative techniques (like TDESI-MS in our study) that work as alternative options besides “guessing”
for early detection of abused drugs during overdosing emergency.

2. Case report
A 25-year-old man presented to the emergency department with
slurred speech and drowsiness. His blood pressure was 98/60 mm Hg,
pulse rate 120 beats/min, respiratory rate 20 breaths per minute and
body temperature 40.1 degree Celsius. Physical examination revealed
bilateral pupils dilatation and ataxia. Immediate aggressive treatment
was given. Initial laboratory evaluation revealed serum sodium
133 mmol/L, potassium 5.8 mmol/L, chloride 92 mmol/L, bicarbonate

Fig. 1. Liquid chromatography-mass spectrometric signals of ketamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyamphetamine in the patient's urine sample were
obtained only after time-consuming pretreatment.

Please cite this article as: Lee C-W, et al, Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient,
American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.12.042

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C.-W. Lee et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

23 mmol/L, glucose 43 mg/dL, creatinine 1.61 mg/dL, blood urea nitrogen 32.7 mg/dL, and ammonia 304 μg/dL. Chest X-ray revealed mild pulmonary congestion. Computer-aided tomographic scan of brain
revealed no definite evidence of intracranial lesion. Meanwhile, there
was a prolonged pending for the laboratory results of traditional toxicology screen for drugs. Unfortunately, the patient's condition deteriorated
long before the traditional drug screen and confirmation by LC-MS/MS
which provides an answer of the drugs identity.[Fig. 1] Cardiopulmonary resuscitation was done but in vain. Soon after the tragic event,
the patient's urine specimen was sent to the laboratory of the Research
Center for Environmental Medicine in the Kaohsiung Medical University
for rapid analysis by using the thermal desorption-electrospray
ionization-mass spectrometry (TD-ESI-MS). The results were obtained
within 30 s - the presence of 3,4-methylenedioxymethamphetamine
(MDMA), 3,4-methylenedioxyamphetamine (MDA), and ketamine
(Fig. 2). LC-MS/MS data: MDMA: 422 ng/mL, ketamine 3985 ng/mL,
mephedrine: 3040 ng/mL matched the above TD-ESI-MS results. TDESI-MS technique was set up in a similar manner as described in previous publications [6,7]. A metallic sampling probe (60 mm long, 2.5 mm
in diameter) was dipped into the urine sample, and was then inserted
promptly into the thermal desorption-electrospray ionization (TD-ESI)
source transferring the analyte to the mass spectrometer for rapid identification. A TD-ESI source comprised of a metallic sampling probe, a
thermal desorption unit, and an electrospray ionization volume. It is
coupled to a triple quadrupole mass spectrometer (Agilent 6410B,
Santa Clara, CA, USA) for analyses. Once mass spectra of the abused
drugs were obtained by TD-ESI-MS, the data (such as m/z values of precursor and product ions of analytes) were matched with those in the
MassHunter Veterinary Drug Triggered MRM Database and Library
(Agilent Technologies) for identifying the compound. This had indeed
shortened the turnaround time of the offending drugs identification to
a significant extent, and the technique was expected to speed up the entire process of rescue and might have ended up with a different prognosis if it had been done for this case before it became too late.
3. Discussion
We learned from this case a lesson that a more efficient toxicological
identification technique is essential to expedite the process of emergency care when the patients are so heavily overdosed that under such lifethreatening conditions, because they fail to provide relevant information about the offending agents due to mentality change, which can result in a delayed diagnosis or misdiagnosis and mortality if specific
adequate treatment is not administered in a timely manner. LC-MS/
MS or GC–MS were commonly used for determination of various abused
drugs in biological matrixes. However, traditional GC–MS analysis required a derivatization process to increase the volatility of many polar
analytes and the derivatization step is costly, time-consuming, and susceptible to errors [8-12]. A head-to-head comparison between traditional LC-MS/MS and the state-of-the-art TD-ESI-MS in Table 1 reveals
the fact that ambient mass spectrometry is surpassing conventional
mass spectrometric techniques in terms of cost, speed and userfriendliness. Drug abuse screening has been used with immunoassay
methods for the purpose of cost-effectiveness and rapid reporting.
However, this may no longer be the optimal solution due to insufficient
analyte numbers [13,14]. In one of our latest studies, the high efficiency
of using TD-ESI-MS for drug characterization was demonstrated
through a typical analysis taking no N30 s [15]. The time required for
each analytical process includes: (1) using a metallic probe for sampling
(b5 s), (2) thermal desorption of analytes on the probe in the TD-ESI
source (b10 s), (3) electrospray ionization and mass spectrometric detection of the desorbed analytes (b10 s), and (4) removing residual
sample on the probe by burning it away with a high-temperature
flame (b 5 s). The cause of hyperthermia in this case is most likely be
the action of MDMA. This case-report represents the application of an
unprecedented method in rapid identification of the abused drugs

Table 1
Head-to-head comparison between TD-ESI-MS and LC-MS/MS for analyzing psychoactive
drugs.

Set up cost of
instruments
(US$)
Sum payable
per
specimen
(US$)
Turnaround
time
Demand of
technical
personnel

TD-ESI-MS

LC-MS/MS

0.133 million

0.33–0.5 million

5

16–50

Within 1 min

At least 1 h

Even the nurses in the
emergency department are able
to perform it under simple
instructions [15].
1000

Well-trained technicians are
required to perform the
pretreatment and analytical
procedure.
4000

Cost of
maintenance
(US$ per
month)
Accessibility
Developed by the Department of Commercially available
Chemistry, National Sun Yat-sen
University, Taiwan. It is currently under aggressive promotion
and considerable growth of its
accessibility is anticipated in the
near future.

including new psychoactive substances consumed by intoxicated patients at the emergency room. Furthermore, this might even play the
role of a very promising initiative in revolutionizing the present “helpless” attitude towards poison identification at the early stage of management, because in most conventional textbooks of emergency
medicine there is an obsolete dogma “If poisoning is probable, treat
the patient immediately. Do not wait for laboratory confirmation.”
which unfortunately reflects the fact that current methods of laboratory
confirmation are not timely enough to provide an early, rapid and precise identification of the poisons for saving lives. However, it is evident
to all that treating an intoxicated patient with full knowledge of the
exact identity of the contaminating poison is certainly a preferred option to mere guess-work bases on indirect clues, and this is the most important mission behind this particular case-report to introduce to the
medical community that there are in fact innovative cutting-edge technologies that can actually improve the present condition.

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Please cite this article as: Lee C-W, et al, Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient,
American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.12.042