Journal of Forensic and Legal Medicine 74 (2020) 101982

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Journal of Forensic and Legal Medicine

journal homepage: http://www.elsevier.com/locate/yjflm

Assessment of stress markers in restrained individuals following physical

stress with and without sham CED activation
Christian Sloane a, *, Deborah C. Mash b, Theodore C. Chan a, Fred Kolkhorst c, Tom Neuman a,
Edward M. Castillo a, Daniel Lasoff a, Gabriel Wardi a, d, Xiaobin Xie b, Gary M. Vilke a
a
Department of Emergency Medicine, University of California, San Diego, CA, USA
b
Department of Neurology, Molecular and Cellular Pharmacology, University of Miami, Miami, FL, USA
c
School of Exercise and Nutritional Sciences, San Diego State University San Diego, CA, USA
d
Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego, San Diego, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Law enforcement and pre-hospital care personnel often confront individuals who must be physically
Psychological stress restrained. Many are under the influence of illicit substances, and law enforcement officers may need to use a
ExDS controlled electrical device (CED) to gain control of the individual and they are often placed into the prone
Excited delirium syndrome
maximum restraint (PMR) position. These techniques have previously been evaluated for their physiologic ef­
Biomarkers
Copeptin
fects. The purpose of this study was to investigate the psychological effects of anticipating and experiencing a
sham CED activation in healthy human subjects who were exercised and restrained compared with no sham
activation by assessing the differences in a panel of several known biomarkers of stress.
Methods: We performed a randomized, crossover controlled human subject trial to study the stress associated
with exercise, physical exhaustion, and restraint with and without an added psychological stress simulating the
field use of a CED. Twenty five total subjects; each subject performed two different trials each consisting of a brief
period of intense exercise on a treadmill to exhaustion followed by placement in the PMR with and without
induced psychological stress. Blood samples were collected for analysis pre and post exercise, as well as 10 min
after completion of the exercise. A panel of hormones and stress markers were measured.
Results: We found no significant differences in any of the stress biomarkers measured between the two study
groups. A trend towards higher levels of copeptin was measured in the sham CED activation arm.
Conclusion: During a brief period of intense exercise followed by the psychological stress of anticipated CED
application, there did not appear to be statistically significant changes in the stress panel of biomarkers
measured, only a trend towards significance for higher copeptin levels in the patients exposed to the psycho­
logical stress.

1. Introduction could lead to adverse events.1–5 There are a number of well-established

Law enforcement and pre-hospital care personnel frequently
encounter violent, dangerous individuals who require physical restraint.
Many of these individuals are often under the influence of drugs and/or
alcohol, and law enforcement officers may need to use a conducted
energy device (CED), such as a TASER™, to gain control and then place
into the prone maximum restraint (PMR) position. Prior investigations
have evaluated the impact of such restraint techniques on ventilation
and metabolic function as these techniques have been reported to in­
crease psychological and physiologic stress on an individual, which
biochemical mediators of stress. Each of these stress responses are in­
tegrated with significant interaction between them. In states of extreme
agitation, such as the excited delirium syndrome (ExDS), there is the
propensity to be fatal with no clear biochemical pathway thus far
identified.6–8, One challenge to clinicians treating ExDS as well as in­
vestigators evaluating subjects after sudden in custody deaths, is the lack
of a diagnostic test to evaluate for and diagnose ExDS. The purpose of
this study was to determine the impact of the psychological stress of an
anticipated CED activation on healthy volunteers after vigorous exercise
and placement in the PMR position. We aimed to achieve this

* Corresponding author. UCSD Medical Center, Department of Emergency Medicine, 200 W. Arbor Dr., MC-8676, San Diego, CA, USA.
E-mail address: csloane@ucsd.edu (C. Sloane).

https://doi.org/10.1016/j.jflm.2020.101982
Received 12 July 2019; Received in revised form 23 January 2020; Accepted 16 May 2020
Available online 26 June 2020
1752-928X/© 2020 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.
C. Sloane et al.
specifically by analyzing the changes in a panel of human hormones and
biomarkers of stress. .
2. Methods
2.1. Research design
We performed a randomized, crossover controlled trial to study
stress associated with exercise, physical exhaustion, and restraint with
and without an induced psychological stress by simulating field settings
of CED activation in 25 human volunteer subjects. Each subject per­
formed two trials, each consisting of a brief period of intense exercise
followed by placement in the PMR, with the variable being an induced
psychological stress as described later. The PMR involves placing the
subject on the stomach in a prone position with wrists secured together
behind the back with a strap and the ankles drawn up near the wrists.
The wrists and ankles are secured together with a police restraining
fabric cuff following standard procedures of law enforcement (Fig. 1).
Each trial was conducted over approximately 90 min during a single
visit to the laboratory.
During the consenting process each subject was informed of the
study protocol, and that s/he would be receiving a 5 s TASER™ X26
activation in drive stun mode to the thigh during neither, one, or both of
the trials (they were not informed which it would be). We only per­
formed one trial with the emotional stress of anticipating a CED acti­
vation and one without. We felt that the ambiguity offered to the
subjects that they may also receive zero or two shocks was important so
that after the first trial they were not able to anticipate what the next
trial may be, and therefore bias our results. No actual contact between
subject and the activated CED was made during the implemented study
protocol and any physiologic response subsequently detected would be
from the stress and not an actual CED shock.
Once written consent was obtained, the subject had baseline blood
pressure (BP), heart rate (HR) and pulse oximetry (spO2) recorded for
monitoring purposes. An intravenous (IV) catheter was placed in stan­
dard sterile fashion in the subject’s arm or hand to facilitate blood
draws. Baseline blood samples were obtained. The subject then ran on a
treadmill at maximum exertion until exhaustion as defined by the sub­
jects themselves. Immediately following exercise, another blood sample
was obtained. The subject was then placed in the hobble restraint po­
sition and remained in this position for 10 min during which HR and
spO2 were monitored. Repeat vital signs and blood draw was obtained at
the end of 10 min. Study arms were identical to this point.
Participants were randomized into exercise and restraint (EX), or
exercise (study control), restraint and CED stress (EX þ STRESS) as their
first position prior to the start of the study using a randomization plan
Fig. 1. The prone maximum restraint position (PMR) used in the study.
2
Journal of Forensic and Legal Medicine 74 (2020) 101982
for two treatments/activities using balances permutations (randomiz
ation.com). Subjects served as their own control. All other aspects of
the study protocol were the same and can be found in Fig. 2.
For the (EX) arm of the study, no further intervention occurred
during the 10-min restraint period. For the (EX þ STRESS) arm, at 5 min
into the restraint position, subjects were informed that a CED activation
was to be deployed on the thigh. The CED was then brandished in front
of the subject, sparked up for a couple of seconds where the subject
could see the electricity arcing and then the subject was told that he or
she will be getting the 5-s activation. The CED was then pressed against
the skin, the operator announcing, “Clear, TASER! TASER!” and then
removed and the activation immediately given to open air, and not to
the subject thus providing the subject the emotional anxiety and stress of
an anticipated activation, but not the physical component of the pain.
After completing the first arm of the study the subjects were allowed
a 30-min period of rest before beginning the arm. Vitals were assessed to
confirm a return to baseline HR prior to starting the second arm. After it
was confirmed vital signs had normalized, a second identical exercise
period on the treadmill was performed, and the subjects followed the
alternate post-exercise protocol (EX or EX þ STRESS) to complete the
cross-over trial. Blood was sampled before exercise, after exercise, and
during the restraint period as previously described.
All venous blood samples were sent per protocol to the Biorepository
and Laboratory Data Site in Miami for ELISA immunoassays of the blood
biomarker panel. Quality control (QC) samples intra and inter-assay
variation was established by measuring each sample five times per
assay. Specificity is based on comparison of HPLC profiles of standard
curves, a blank sample and a plasma or serum sample with and without
spike in controls run in duplicate with each assay.
After both study trials were completed, the subjects were read the
following debriefing script to explain the rationale of the study. “As you
can see you did not receive an actual TASER shock. The purpose of this
study is to assess the effect of the stress and apprehension in anticipation
of receiving a TASER shock. This required that we mislead you about our
intentions to apply the TASER device to your thigh. We hope that you
can understand our need to lead you to believe that we actually intended
to apply the TASER to your body. Do you have any questions?” They
were also instructed not to disclose the study protocol to anyone until
study completion.
2.2. Selection criteria and participant screening
Subjects were recruited from a local university between 18 and 45
years of age. Prior to conducting the study, each participant completed
the Physical Activity Recall Questionnaire (PAR-Q: http://www.csep.ca/
CMFiles/publications/parq/par-q.pdf) to screen for cardiovascular
risks. Positive responses to questions from the PAR-Q eliminated the
individual from participation. Additional subject exclusion criteria
included pregnancy, recent illicit drug use or history of previous chronic
illicit drug use, current illness, chronic psychiatric medical diagnosis
requiring medical therapy, inability to be handcuffed behind the back,
inability to exert themselves on a running treadmill machine, or refusal
of consent. No exclusion was made on the basis of gender, race, ethnicity
or sexual preference. Subjects who completed the study received
financial compensation for their participation in the form of a $100
check budgeted from the grant sponsoring agency.
The primary outcome measures were a comparison of the levels of
the various biomarkers between the psychological stress and non-
psychological stress groups. Hormones and stress markers measured
included cortisol, copeptin, orexin A, dynorphin, oxytocin, neuropeptide
Y, dopamine, norepinephrine, and the cortisol-ACTH ratio. We selected
these particular hormones and biomarkers based on either prior
research or physiologic rationale and plausibility for a role of stress in
the pathogenesis of the ExDS.9–15 Standard sample acquisition, pro­
cessing, storage, shipping and evaluating were used for all samples.
Laboratory tests performed in Miami included Biospecimen Quality
C. Sloane et al. Journal of Forensic and Legal Medicine 74 (2020) 101982

Fig. 2. Two arms of study protocol. Subjects were randomized to have sham CED activation (STRESS) first followed by no sham activation or vice-versa as part of the
randomized cross-over controlled trial. Thirty minutes were allotted for recovery prior to second leg of study to allow subjects to recover.

Control Testing. Each assay for the biomarker panel utilized standard­ ANOVA and for differences based on position. Statistical significance
ized in-house testing procedures with standardized quality controls and was defined as p < 0.05. Variations in biomarker values in relation to
documented the results in associated quality records. This included tests age, gender, and time of day were tested using ANOVA (Bonferroni-
to assess and control biospecimen quality, such as confirmation of adjusted post hoc test).
biomarker integrity in blood, or biomarker expression or levels
compared to standard reference values and compared to the range of 3. Results
published literature values in adults for each biomarker.
3.1. Subject demographics
2.3. ELISA immunoassays
A total of 25 subjects were enrolled in the study. Age ranged between
Hormone and biomarker concentrations were measured in single 18 and 45 with an average age of 25.7 years (median 24). Additional
batches thawed from frozen (- 80 � C) supernatants of centrifuged serum demographic information is provided in Table 1. Each study participant
gel or plasma tubes and assayed according to manufacturers specifica­ completed both arms of the trial.
tions. Norepinephrine and dopamine were measured in plasma, A summary of results is listed in Table 2. There were no statistically
respectively using 3- CAT Plasma ELISA High Sensitive kits (Cat. # BA significant differences between the sham CED and control groups at
E 4600, Cat.# BA E 6300, Rocky Mountain Diagnostics, Inc, Colorado equivalent time periods during the study across the nine stress bio­
Springs, CO). Cortisol was measured using MS E 5000 Cortisol ELISA markers assayed in this study. However, there was a trend towards
kit (Rocky Mountain Diag. Inc). Sensitivity of the kit is 0.4 μg/dl and significance for serum levels of copeptin, in the sham CED group.
standard range is from 0.5 to 60 μg/dl. The specimen plate was read at
450 nm. The concentration of cortisol was calculated based on a stan­ 4. Discussion
dard curve and spiked in reference controls.
Detection and quantitation of Orexins A in plasma was measured Stress is defined as anything that disrupts homeostatic balance of the
using Human Orexin A ELISA Kit [(Cat. # MBS732167) MyBioscource,
LLC, San Diego, CA)]. Dynorphin and neuropeptide Y were measured in Table 1
plasma using human dynorphin, Dyn ELISA Kit (Cat. # MBS701322, Demographics for the laboratory study group.
MyBioscource, LLC) and human neuropeptide Y, NP-Y ELISA Kit (Cat. # (n ¼ 25)
MBS701240, MyBioscource, LLC). Detection range of the kits is 0.78–50
N (%)
pg/ml with a minimum detection of 0.2 pg/ml. Quantitation of con­
centration of copeptin in serum was measured using the human copeptin Age
18–24 13 52.0
ELISA Kit (Cat. # MBS703328, MyBioscource, LLC). Detection range of
25–34 10 40.0
this kit is 78.13–5000 pg/ml and sensitivity is less than 19.53 pg/ml. 35–44 2 8.0
ELISA results were obtained from analysis of the standard curves and Gender
samples on a BioTek ELX 800 microplate reader set to 450 nm and a Male 19 76.0
reference wavelength between 662 and 650 nm. Female 6 24.0
Race/Ethnicity
White or Caucasian 13 52.0
2.4. Data analysis and statistics Black or African American 1 4.0
Hispanic or Latino 4 16.0
Analysis of the data was conducted using SPSS statistical software Asian 7 28.0
Other 0 0.0
(SPSS, Inc., Chicago, IL). Data were analyzed using repeated-measures

3
C. Sloane et al.
Table 2
Time course for biomarker and hormone levels in blood plasma or serum at different times during the study protocol. Pre-EX ¼ pre-exercise, post-ex ¼ post-exercise,
STRESS ¼ sham CED activation. Mean values and range (parenthesis) are shown.
Compound measured Pre-EX (N ¼ 25) Post-Ex (N ¼ 25) Post-Res (N ¼ 25)
Cortisol (ng/ml) 70.47 (38–102.7) 73.97 (36–111.9) 75.64 (52–99)
Copeptin (ng/ml) 1.77 (1.40–2.15) 1.68 (1.21–2.16) 1.32 (0.99–1.64)
Orexin A (pg/ml) 20.95 (10–31.9) 22.08 20.34 (8.1–32.6)
(11.6–32.6)
Dynorphin (pg/ml) 3.20 (0–7.7) 2.82 (0.6–5.1) 2.55 (0.9–4.2
Oxytocin (pg/ml) 49.7 (37–61) 46.47 (35–58) 49 (39–59)
Neuropeptide Y (pg/ml) 102.32 (66–139) 83.75 (60–107) 65.70 (48–83)
Dopamine (ng/L) 15.55 (3.4–27.7) 17.58 (6.9–28.3) 17.67 (9–26.3)
Norepinephrine (ng/ 24.39 20.64 (7.9–33.4) 17.71 (8.2–27.2)
ml) (11.1–37.7)
Cortisol/ACTH ratio 1.76 (0–3.54) 1.89 (0.2–3.58) 1.12 (.28–1.96)
body.16 Stress induces changes in higher nervous system processes,
sleep, wakefulness, fear, autonomic function and activation of the HPA
axis.16 There are multiple influences on stress, including duration, type
of stimulus (physical vs. psychological), context of the encounter, age,
gender, and one’s genetic make-up. We completed a randomized
crossover control trial using a multi-biomarker panel based on several
parameters that each mirror different pathophysiologic aspects to assess
the impact of the psychological stress of anticipated CED application.
Furthermore, we attempted to validate biomarker identification and
technology transfer of analytical techniques and criteria to assist path­
ologic and forensic-medical diagnosis of ExDS. While we acknowledge
the subjects in this study were not in the ExDS state, we attempted to
place significant physical and exertional stress on subjects to mimic
certain aspects of this syndrome which could worsen outcomes.
Although individuals with ExDS are at high risk of death, not all cases
are fatal.6,17 The issues currently challenging clinicians treating ExDS
patients who are still alive as well as investigators evaluating subjects
after sudden in custody deaths include the lack of an easily obtainable
test or reliable diagnostic to evaluate for and diagnose ExDS.
Our primary finding is that in healthy volunteers, there was no sig­
nificant difference between a panel of nine different stress markers and
hormones after intense physical exertion and the anticipated psycho­
logical stress of CED application. To our knowledge, this is the first
investigation into the physiologic impact of the psychological stress
associated with CED application in a controlled environment by
assessing the response of biomarkers and hormones in healthy subjects.
Our results can be interpreted in multiple ways. First, since we investi­
gated psychological stress effects on hormone secretion in healthy vol­
unteers, it is likely that the CED activation was associated with marginal
stress responses in these healthy volunteers since they did not result in
significant biomarker elevation. Second, that certain biomarkers and
hormones are rapidly metabolized and may have such a short duration
of elevation that it is very challenging to capture biomarker changes in
blood quickly enough for meaningful interpretation. Vasopressin, for
instance, is rapidly metabolized and rapid elevations are cleared
quickly.9,18 Finally, that the duration of psychological stress and time
course for the study was insufficient to generate significant responses in
healthy volunteers. Self-rated stress component feelings were not
determined in the pre-/post-anticipation period, post-test period and
post-recovery in our study.
However, this study provides further information into possible
biochemical pathways that contribute to the ExDS. Currently, there are
no diagnostic tests that clinicians can use to reliably diagnose ExDS. The
condition of ExDS is associated with psychological, cardiac and thermal
stressors. Our findings suggest that the psychological stress of CED
application in healthy volunteers may not be a significant cause of
biomarker elevation. Additional studies are needed to determine the
underlying physiologic and hormonal response to the actual CED
application in the setting of significant agitation and PMR positioning.
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Journal of Forensic and Legal Medicine 74 (2020) 101982
Pre-EX þ STRESS(N ¼ 25) Post-Ex þ STRESS(N ¼ Post-Res þ STRESS(N ¼
25) 25)
109.41 (78.7–140) 104 (70.8–137) 88.21 (49.5–127)
0.91 (0.69–1.14) 1.36 (0.73–1.99) 1.74 (1.30–2.18)
24.63 (10.7–38.5) 24.42 (12.2–36.6) 16.23 (7.1–25.4)
4.86 (0.3–9.4) 3.61 (1.2–6.0) 3.62 (1.2–6.0)
52.86 (40–66) 51.08 (37–65) 51.59 (38–65)
68.65 (36–101) 68.19 (46–90) 79.23 (59–100)
19.58 (5.5–33.7) 19.42 (5.8–33.1) 15.61 (8.6–22.6)
24.06 (14.1–34.0) 21.03 (9.7–32.3 16.93 (9.6–24.3)
1.80 (0.58–3.02) 1.47 (0.55–2.39) 1.51 (0–3.03)
4.1. Biomarker selection and evaluation in the setting of ExDS
There are a multiple mediators of stress that modulate brain function
by acting in concert.16 Some of these mediators but not all are reliably
measured in blood, providing a basis for the select biomarker panel in
this study. For instance, one of the major hypothalamic stress hormones,
stimulated by different stressors is vasopressin (AVP).9,18 However,
measurement of circulating AVP levels is challenging because it is
released in a pulsatile pattern, it is unstable and it is rapidly cleared from
plasma. This rapid clearance may explain why we did not find any sig­
nificant difference between AVP levels. AVP derives from a larger pre­
cursor peptide (pre-provasopressin) along with copeptin, which is
released in an equimolar ratio to AVP.
Copeptin is more stable in the circulation and easy to reliably mea­
sure during conditions of psychological and thermal stress.18 Prior in­
vestigations into the impact of psychological stress have shown that
copeptin is significantly elevated at times measured after a period of
prolonged anticipation of stress.19 These results suggest that the stress
hormone copeptin might represent a sensitive alternative to adreno­
corticotrophic hormone or cortisol to measure individual perception of
psychological stress. While cortisol levels follow a circadian rhythm, no
consistent circadian rhythm has been reported for copeptin levels.20,21
Furthermore, copeptin has been shown to have a greater increase than
cortisol in response to major stress11,20,21 We observed a trend towards
increased release during the psychological stress associated with CED
application with copeptin (Fig. 3).
Since neither cortisol nor copeptin were significantly elevated above
baseline measures and, the levels reported in our study agree with the
normal range of values reported previously (19), we suggest that CED
deployments in the field may not significantly impact the normal range
of responses of stress hormones and other markers tested in this study.
We examined a panel of nine different stress biomarkers in our study,
one of the largest to date examined in a laboratory CED study conducted
in healthy volunteers. While our study suggests that copeptin may be a
useful biomarker to evaluate the impact of psychological stress in a
population of ExDS subjects, these patients are intrinsically at high risk
for hyperthermia and heart failure. In volunteers with maximum tem­
peratures above >38 � C, serum copeptin levels are significantly
increased,22 suggesting that this hormone is sensitive to thermal as well
as psychological stress. We suggest that measures of copeptin may prove
important for identifying cardiac stress and hyperthemia in ExDS
cases.19,22 Since copeptin has been shown to have a greater increase than
cortisol in response to major stress,11 this biomarker may be a more
reliable indicator of a contributing stress response in cases of ExDS.
4.2. Limitations
This study is based on a small sample size and larger numbers would
be needed to further support these results. Actual field conditions cannot
be completely duplicated due to safety concerns. Differences that may
C. Sloane et al. Journal of Forensic and Legal Medicine 74 (2020) 101982

Fig. 3. Box plots of summary data. Black line is median, red line is mean. (For interpretation of the references to colour in this figure legend, the reader is referred to
the Web version of this article.)

occur in the field include subject intoxication with psychostimulants or
sympathomimetics, the presence of psychiatric and other disease states,
underlying cardiac comorbidities such as coronary artery disease, and
inclusion of painful stimuli on the subject such as physical assault or the
deployment of CED. Additionally, we used fabric handcuffs instead of a
standard police handcuff. This allowed for an approximate 5-inch space
between the subjects’ wrists, instead of a more standard 4-inch space
allowed for by chain linked handcuffs. It is possible that this may have
allowed for a slightly greater chest expansion and thus decreasing the
effect of the cuffs. We believe this difference to be minimal. Also, our
subjects took several minutes to reach exhaustion. This could be longer
than a typical brief anaerobic burst of activity involved in a police
pursuit and restrain situation. Thus, the laboratory conditions used in
this study would closely approximate but never fully capture all vari­
ables associated with the field use of CED.
5. Conclusion
needed to further validate these results and in particular, investigate the
role of co-peptin in possible cases of ExDS.
Funding source
This study is part of a larger study funded by: “EXCITATION
Study: Unexplained In-Custody Deaths: Evaluating Biomarkers of Stress
and Agitation.” The National Institute of Justice, U.S. Department of
Justice, January 11, 2012 to 10/31/2014. USDOJ Federal Award #
2012-R2-CX-K006. Amount: $ 431,943.
Declaration of competing interest
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its outcom

CRediT authorship contribution statement

In this study, we examined the effects of a simulated psychological
stress on exercised and restrained individuals. We successfully measured
Christian Sloane: Data curation, Formal analysis, Writing - original
several common biomarkers of stress. We failed to note statistically
draft. Deborah C. Mash: Data curation, Formal analysis, Writing -
significant variations in the blood markers measured, but there was a
original draft. Theodore C. Chan: Data curation, Formal analysis,
trend towards significance in the levels of copeptin in the psycholog­
Writing - original draft. Fred Kolkhorst: Data curation, Formal analysis,
ically stressed group, which may suggest an increase in cardiovascular
Writing - original draft. Tom Neuman: Data curation, Formal analysis,
stress associated with the sham CED activation. Future studies are
Writing - original draft. Edward M. Castillo: Data curation, Formal

5
C. Sloane et al.
analysis, Writing - original draft. Daniel Lasoff: Data curation, Formal
analysis, Writing - original draft. Gabriel Wardi: Data curation, Formal
analysis, Writing - original draft. Xiaobin Xie: Data curation, Formal
analysis, Writing - original draft. Gary M. Vilke: Data curation, Formal
analysis, Writing - original draft.
Acknowledgment
The authors would like to thank Melina Andriano, MS, for her
assistance in the performance of the study.
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