The Journal of Emergency Medicine, Vol. • . No . • , pp. 1-9,20 11
Copyright e 20 11 Elsevier Inc.
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ELSEVIER

dOi: l0.1016/j.jemermed.201 1.02.017

~~~ Clinical

~

Reviews

EXCITED DELIRIUM SYNDROME (EXDS): DEFINING BASED ON
A REVIEW OF THE LITERATURE
Gary M . Vi Ike, MD: Mark L. DeBard , MD,t Theodore C . Chan, MD: Jeffrey D. Ho, MD,:j: Donald M . Dawes, MD,§ I
Christine Hal l, MD, MSC,, - Michael D. Curtis, MD,ttH Melissa Wysong Costello , MD,§§ Deborah C . Mash , PHD, II
Stewart R. Coffman, MD", Mary Jo McMullen, MD:** Jeffery C. Metzger, MD, ttt James R. Roberts, MD,:j::t::j:
Matthew D. Sztajnkrcer, MD, PHD,§§§ Sean O . Henderson, MD,I II Jason Adler, MD" "
Fabrice Czarnecki, MD, MA, MPH:*** Joseph Heck, DO,tttt and William P. Bozeman, MD:j::j::j::j:
'University of California at San Diego Medical Center, San Diego, California, tOhio State University College of Medicine , Columbus, Ohio,
:t:Hennepin Co. Medical CenterlUniversity of Minnesota, Minneapolis, Minnesota, §University of Louisville, Louisville, Kentucky, ILompoc Valley
Medical Center, Lompoc, California, ,University of British Columbia Victoria, British Columbia Canada, "University of Calgary, Calgary, Alberta
Canada, ttSt. Michael's Hospital, Stevens Point, Wisconsin, ++St. C lare's Hospital , Weston, Wisconsin , §§University of South Alabama,
Mobile, Alabama, IIUn iversity of Miami, Miami, Florida, ''JUniversity of Texas, SW Dallas, Lewisville, Texas, "'Northeastern Ohio University
College of Medicine, Akron, Ohio, tttUniversity of Texas, Southwestern Med ical Center, Dallas, Texas, +++Drexel University Col lege of
Medicine, Mercy Catholic Medical Center, Ph iladelphia, Pennsylvania, §§§Mayo School of Medicine, Rochester, Minnesota, Ill Keck School of
Medicine of the University of Southern California, Los Angeles , Californ ia, ,.,.,.University of Maryland, Baltimore, Maryland, .. ··St. Joseph
Medical Center, Towson, Maryland, ttttTouro University - Nevada, Henderson, Nevada, and ++++Wake Forest University,
Winston Salem , North Carolina
Reprint Address: Gary M. Vilke, "-'D , Department of Emergenc y Medicine, UC San Diego Medical Center, 200 West Arbor Drive,

Mail code #8676. San Diego. CA 92103

o

Abstract-Background: Patients present to police, Emergency Medical Services, and the emergency department with
aggressive behavior, altered sensorium, and a host of other
signs that may include hyperthermia, "superhuman" strength,
diaphoresis, and lack of willingness to yield to overwhelming
force. A certain percentage of these individuals wiD go on to expire from a sudden cardiac arrest and death, despite optimal
therapy. Traditionally, the forensic community would often
classify these as "Excited Delirium" deaths. Objectives: This
article will review selected examples of the literature on this
topic to determine if it is definable as a discrete medical entity,
has a recognizable history, epidemiology, clinical presentation, pathophysiology, and treatment recommendations. Discussion: Excited delirium syndrome is characterized by
delirium, agitation, acidosis, and hyperadrenergic autonomic
dysfunction, typically in the setting of acute-on-chronic drug
abuse or serious mental illness or a combination of both. Conclusions: Based upon available evidence, it is the consensus of
an American College of Emergency Physicians Task Force

that Excited Delirium Syndrome is a real syndrome with
uncertain, likely multiple, etiologies. © 2011 Elsevier Inc.

o

Keywords-excited delirium; in-custody death; sudden
death; TASER; restraint; agitated delirium

INTRODUCTION
The term "Excited Delirium" has bee n used to refer to
a subcategory of delirium that has primarily been described retrospectively in the forensic literature. It has
also been referred to as "Agitated Delirium" and is
closely associated with the "Sudden Death in Custody
Syndrome." Originall y, the concept of excited delirium
was described in the forensic literature and has been synonymous with death, but over time the term has made
its way into the emergency medicine, psychi atric, law
enforcement, prehospital , and medicolegal literature. It

RECEIVED: 26 February 2010; FINAL SUBMISSION RECEIVED: 31 Augu st 2010;
ACCEPTED: 20 February 2011

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G. M. Vilke et al.

has generally been used to describe patients displaying altered mental status with severe agitation and combative or
assaultive behavior that has eluded a unifying, prospective clinical definition. For the remainder of this article,
these kinds of cases will be referred to as the Excited Delirium Syndrome (ExDS).
The difficulty surrounding the clinical identification of
ExDS is that the spectrum of behaviors and signs overlap
with many other clinical disease processes. Treatment interventions targeting these alternate diagnoses (e.g., acute
hypoglycemia) may potentially alleviate the clinical presentation of the ExDS. Faced with the lack of a clear definition and cause, as well as the infrequency of events
such that individual practitioners are unlikely to encounter large numbers of cases. the decision to identify ExDS
as a syndrome instead of a unique disease has been delayed, somewhat similar to the decades-long controversy
over Sudden Infant Death Syndrome.
The problem is that a small percentage of patients with
ExDS progress to sudden cardiopulmonary arrest and
death. Although many of the current deaths from ExDS
are likely not preventable, there may be an unidentified
subset in whom death could be averted with an early directed therapeutic intervention. In fact, it is impossible
at present to know how many patients with this type of
clinical presentation have received a therapeutic intervention that halted a terminal progression, or whether this is
a spectrum of severity to a disease state that causes death
to only a few of its victims.
In response to increased reports and Jay media coverage of sudden deaths in severely agitated subjects, along
with lack of clarity and consistency among the medical
community regarding ExDS, the American College of
Emergency Physicians (ACEP) convened a Task Force
of experts in the field of excited delirium. Experts included emergency physicians published in the field, forensic pathologists researching in the field, and tactical
Emergency Medical Services (EMS) physicians. The expertise was extended to include researchers knowledgeable in Sudden Death in Custody Syndrome, positional
asphyxia, conducted energy devices, and tactical medicine, This Task Force was charged with reviewing the
body of literature available and coming to a consensus,
if possible, to define two major questions:
L Does the entity commonly referred to as "excited
delirium" exist as a separate disease?
And if it does,
2. Can it be better defined, identified, and treated?
In this article, the Task Force provides a review of the
history and epidemiology of ExDS along with a discussion of the potential pathophysiology, clinical and diagnostic characteristics, differential diagnoses, and
treatment. The goal is to determine if ExDS is a disease,

and if so, to educate those who have to provide care for
the victims, which would include medical and public organizations, including first responders, law enforcement,
physicians, and other health care providers,
METHODS
ACEP convened a consensus group of experts in the field
of ExDS who have conducted research on or are nationally recognized as having specific expertise in ExDS,
The group was selected by assessing all ACEP members
who have published significant writings beyond case reports in the areas of Sudden Death in Custody Syndrome,
positional asphyxia, conducted energy devices, and tactical medicine. These individuals were invited to participate and queried for other "experts" in the field and
those individuals were also invited. All but one of the invitees participated. The group met by teleconference
three times and communicated electronically, and subsequently met in person on two separate occasions: a 2-day
retreat dedicated to the review and drafting of a consensus
paper, and a second time to finalize the working document.
The medical literature was reviewed to include key
word and topic searches on excited delirium, agitated delirium, acute exhaustive mania, sudden in-custody death,
in-custody death syndrome, TASER (TASER International Inc" Scottsdale, AZ), electronic control devices,
conducted electrical weapons, positional restraint, restraint asphyxia, positional asphyxia, and less lethal
weapons. Additionally, other special reports, text books
and chapters, agency reports, and governmental reviews
were evaluated, The task force reviewed these materials
for appropriateness to the topic and the quality of the
work. Studies included for the final review were hmited
to randomized controlled trials, clinical trials, prospective
and retrospective cohort studies, and meta-analyses in human subjects, Case reports, case series, and general review articles were not included for the selection criteria
for formal rigorous review but were utilized for the compilation of the published signs and symptoms.
DISCUSSION
ExDS History
For more than ISO years, there have been case reports that
do not use the exact term "excited delirium," yet describe
a similar constellation of symptoms and features. These
cases discuss clinical behavior and outcomes that are
strikingly similar to the modern-day concept of ExDS
(1), These historical cases occurred primarily within institutions that housed mentally disturbed individuals in protective custody due to their violent and aggressive

·.
Excited Delirium Syndrome

behavior. At that time, there was lack of effective pharmacologic treatment available for these patients. The behavior seen in these cases has been called "Bell's Mania,"

named after Dr. Luther Bell, the primary psychiatrist at
the McLean Asylum for the Insane in Massachusetts.

Dr. Bell was the first to describe a clinical condition
that took the lives of over 75% of those suffering from
it. Based on the clinical features and outcomes of the institutionalized cases from the 18008, when compared to
the presently accepted criteria known to accompany

ExDS, it may well be the case that Bell's Mania is related
to the syndrome of ExDS that we witness today. The incidence of the problem behaviors and sudden death described in the 1800s seemed to decline drastically by
the mid-1950s (2) . This has been largely attributed to
the advent of modern antipsychotic pharmaceutical therapy used for these patients with severe behavior issues.

In the 1980s, there was a dramatic increase in the number of reported cases with behavior similar to an uncon-

3
cluding the International Classification of Disease, Ninth
Revision (ICD-9) do not recognize the exact term "excited delirium" or "excited delirium syndrome" (1 3).
The countering argument is that there are organized medical associations, including the National Association of
Medical Examiners and the American College of Emergency Physicians, that do rec.ognize ExDS as an entity.

Additionally, the ICD-9 does contain several codes that
can be and are used to describe the same entity as

ExDS (Table 1). This semantic issue does not indicate
that ExDS does not exist, but it does mean that this exact

and specific terminology may not yet be accepted within
some organizations or references.

Epidemiology
The exact incidence of ExDS is impossible to determine
as there is no current standardized case definition by

which to identify ExDS. In addition, because ExDS is dis-

trolled psychiatric emergency. Whereas some seemed to
be unchecked psychiatric disease, most of these cases
were found to be associated with the introduction and
abuse of cocaine in North America (3,4) . Since then,
this connection between ExDS and cocaine has

cussed mainly in the forensic literature, and is a diagnosis
of exclusion established on autopsy, there is little documentation about survivors, which have led some to believe the syndrome to be near-uniformly fatal. However,
some Task Force members have reported caring for mul-

continued (5). Additionally, ExDS has now been recog-

tiple patients with ExDS who have survived. A published
observational study suggests that the incidence of death

nized to occur in association with other illicit drugs of
abuse, particularly cocaine, methamphetamine, and

PCP, as well as with certain types of mental illness and
their associated treatment medications (6- 10).
Before the mid-1980s, there was no single unifying

among patients manifesting signs and symptoms that

may be consistent with ExDS is < 10% (14). An exact fig-

and Fishbain in a seminal article that coined the term "ex-

ure is difficult to ascertain because it is believed that repetitive exposure to triggering substances, such as
cocaine or mental health medications, leads to kindling
events in the brain that start the patient down the progressive path of ExDS, with each subsequent presentation be-

cited delirium" (11 ). The typical patient involves an acute

coming worse until death occurs (1 5,16). A review of the

term to describe the clinical pattern seen in these patients.

In 1985 a subset of cocaine deaths was described by Wetli

drug intoxication, often a history of mental illness (especially those conditions involving paranoia), a struggle
with law enforcement, physical or noxious chemical control measures that may include an electrical control de-

vice (ECD) application, sudden and unexpected death,
and an autopsy that fails to reveal a definite cause of death

literature reveals common characteristics among patients

identified post-mortem as suffering from ExDS. More
than 95% of all published fatal cases involve men at
a mean age of 36 years (17- 24). These subjects are
hyper-aggressive with bizarre behavior, and are typically
impervious to pain, combative, hyperthetmic, and tachy-

from trauma or natural disease.
As a consequence of the circumstances surrounding

cardic. There is typically a struggle with law enforcement

the death and the lack of a definitive cause on autopsy,
there has been continued debate about the validity of

Table 1. ICD-9 Codes that Describe the Same Entity as
ExDS

the term "excited delirium." This debate continues today.
There are those who believe it to be a convenient term
used to excuse and exonerate law enforcement personnel
when someone dies while in their custody. It has been ar-

ticulated by some that ExDS is a term or concept that has
been "manufactured" as a law enforcement conspiracy or

cover-up for brutality (12).
This argument mainly centers on the fact that most organized medical associations, like the American Medical
Association, and medical coding reference materials in-

• 296.00S Manic Excitement
•
•
•
•

293.11 Delirium of Mixed Origin
292.81 Q Delirium, drug induced
292.81 R Delirium, induced by drug
307.9AD Agitation

• 780.09E Delirium
• 799 .2AM Psychomotor Excitement
• 799.2V Psychomotor Agitation
• 799 .2X Abnormal Ex.citement
ICD = International Classification of Diseases; ExDS
Delirium Syndrome.

= Excited

4

that involves physical, noxious chemical, or ECD use followed by a period of quiescence and sudden death. The
majority of cases involve stimulant abuse, most commonly
cocaine, although methamphetamine, PCP, and LSD have
also been described (25,26). As more attention is drawn to
ExDS as a recognized entity, it is likely that other drugs of
abuse may be identified as also etiologic.
Persons with psychiatric illnesses comprise the other
cohort of ExDS cases and deaths. The literature on
ExDS frequently cites abrupt cessation of psychotherapeutic medications as a cause (27). This raises the question of whether the behavioral changes seen in this
context represent withdrawal syndromes characteristic
of the medications involved, central nervous system adaptations to medications, or recrudescence of underlying
disease. Health care providers should be aware that medication noncompliance in psychiatric patients is a potential
cause for ExDS. Less commonly, persons with new-onset
psychiatric disease, particularly with manic or psychotic
features, will present with ExDS (1 4). In most cases, the
underlying psychiatric disease will be untreated at the
time of presentation, but in some cases the psychiatric illness may be partially treated or mistreated.
Over a 2-year period, the presence or absence of 10
potential clinical features of ExDS was recorded by Canadian police for cases seen in over 1 million policepublic interactions (28). The features of ExDS looked
for included pain tolerance, tachypnea, sweating, agitation, tactile hyperthermia, non-compliance with police,
lack of tiring, unusual strength, inappropriately clothed,
and mirror or glass attraction (which has been referred
to in the forensic literature as a possible commonality
in ExDS deaths). Of the 698 encounters involving use
offorce, 24 (3.4%) probable ExDS cases were identified
based upon the presence of perceived abnormal behavior
and at least six of the 10 potential clinical criteria for
ExDS. Eighteen (2.7%) of the cohort manifested seven
or more features, including tactile hyperthermia.

Pathophysiology
The actual pathophysiology of patients who have been
previously identified with signs and symptoms of ExDS
is complex and poorly understood. The fundamental
manifestation is delirium. As described above, there are
several different potential underlying associations or
causes, including stimulant drug abuse, psychiatric disease, psychiatric drug withdrawal, and metabolic disorders. Unknown mechanisms lead from these conditions
to the overt ExDS state. Specific manifestations vary
among different cases. We do not fully understand why
some cases progress to death and some do not.
Although our knowledge about the etiology and pathophysiology ofExDS is limited, basic science and clinical

G. M. Vilke et al.

studies have provided some insight. Stimulant drug use,
especially cocaine, is associated with ExDS (17,192 1,24,29). Post-mortem toxicological analysis of fatal
cocaine-associated ExDS patients demonstrates cocaine
concentrations similar to those found in recreational
drug users and less than those noted in acute cocaine ·
"overdose" deaths, suggesting a different mechanism of
death. Although some individuals have had alcohol in
their system at the time of death, many cases are not associated with alcohol ingestion, intoxication, or known
dependency.
Subsequent anatomic and molecular characterization
of this group of fatal ExDS patients has focused primarily
on postmortem brain examination findings . Results demonstrate a characteristic loss of the dopamine transporter
in the striatum of chronic cocaine abusers who die in police custody from apparent ExDS. This suggests that one
potential pathway for the development of ExDS is excessive dopamine stimulation in the striatum, but the significance of this in the larger context of ExDS unrelated to
chronic cocaine abuse remains unknown (30 ,31) .
Making a central dopamine hypothesis more appealing is the fact that hypothalamic dopamine receptors
are responsible for thermoregulation. Disturbances of dopamine neurotransmission may help explain the profound
hyperthermia noted in many ExDS patients (18). Postmortem studies in these patients have demonstrated elevated levels of heat shock proteins. The central dopamine
hypothesis also provides a link to psychiatric etiologies of
ExDS, such as schizophrenia.
Although the specific precipitants of fatal ExDS remain unclear, epidemiologic and clinical reports provide
some clues to the underlying pathophysiology. When
available, cardiac rhythm analysis demonstrates bradyasystole or pulseless electrical activity; ventricular dysrhythmias are rare, occurring in only a single patient in
one study (1 9). The majority of lethal ExDS patients
die during or shortly after a violent struggle. Severe aci dosis seems to play a prominent role in lethal ExDSassociated cardiovascular collapse (32).

Clinical Characteristics
Because ExDS resulting in death does not currently have
a known specific etiology or a consistent single anatomic
feature, it can only be described by its epidemiology,
commonly described clinical presentation, and usual
course. The minimum features for ExDS to be considered
include the presence of both delirium and an excited or
agitated state. As described in the Diagnostic and Statistical Manual of Mental Disorders, the features of delirium are constant and defined by a disturbance of
consciousness (reduced clarity of the awareness of the environment) with reduced ability to focus, sustain, or shift

Excited Delirium Syndrome
attention (33). The perceptual di sturbance develops over
a short period of time (usually hours to days) , may fluctuate during the course of a day, and is not accounted for by
underlying dementia.
Due to varied underlying medi cal conditions that may
generate ExDS, there is also variation in the specific
symptom cluster. As in any disorder that affects mental
status, there is no ass umption that each subject's presentation will have the same clinical presentation; however,
all patients with ExDS present deliriou s with evidence
of psychomotor and physiologic excitation. Lacking either of these findings eliminates ExDS as a diagnosis.
Historically in ExDS, there is typically a component of illi ci t drug use or psychi atric illness, partic ul arl y schi zophrenia. Clinical findings in subjects who die with
a post-mortem di agnosis of E xDS typically have many
or most of the features listed in Table 2.

Differential Diagnosis
Almost any drug. toxin , extraneous substance, psychiatric
or medical condition, or biochemical or physiologic alteration in th e body can cause acute changes in behavior or
me ntal status. The general public, law enforcement,
EMS, and eve n highly trained medical personnel will
not be able to readily di scern the cause of an acute behavioral disturbance, or differentiate a specific organic di sease from ExDS based solely on observation.
Several specific entities that cause altered mental status and may mimic ExDS deserve specific mention. Diabetic hypoglycemic reactions have been associated wi th
o utbursts of violent behavior and an appearance of intoxication. Heat stroke may manifest as tactile hyperthermia,
rhabdomyolysis, and delirium, and may be associated
with neuroleptic use and mental illness. T hyrotoxicosis
may manifest a sim i1 ar clinical presentation, especiall y
during episodes of thyroid storm. Serotonin syndrome
and neurol eptic malignant syndrome (NMS) may share
so me clinical characteristics with ExDS. However, they
usually do not share the aggressive violent behavior manifested by patients with ExDS.
Psychiatric issues may mimic ExDS, Some patients
experi ence behavioral disturban ces directly due to psychotropic drug withdrawal or noncomphance. Substance
abuse is also very common in psyc hi atri c patients. Many
psych iatric condition s the mselves, includi.ng acute paranoid schi zophrenia, bipolar disorder, and even emotional
rage from acute stressful social circumstances, may
mimic an ExDS-like state.
Sudden unexpected death is the hallmark of fatal
ExDS. The differential diagnosis for sudden death includes ischemic or drug-induced sudden cardiac death,
stress, or Takotsubo cardiomyopathy, inherited or acquired long QT syndrome, Brugada sy ndrome, and less

5
Table 2. ExOS Features by Literature Review

en = 18)
No.
Articles

Features in history
Male gender
Mean age ,.....30s
Sudden onset
History of mental illness
History of psychostimulant abuse
Features evident at scene
Call for disturbance/psychomotor agitation/
excitation
Violenticombative/belligerentlassault call
Not responding to authorities/verbal commands
PsychosisJdelusional/paranoid/feariul
Yelling/shouting/guttural sounds
Disrobing/inappropriate clothing
Violence toward/destruction of inanimate objects
Walking/running in traffic
Subject obese
Features evident on contact
Significant resistance to physical restraint
Superhuman strength
ImpelVious to pain
Continued struggle despite restraint
Profuse sweating/clammy skin
Features with clinical assessment
Tachypnea
Tachycard ia
Hyperthermia
Hypertension
Ac idosis
Rhabdomyolysis
Features of death
Period of tranqu ility/"giving up"
Sudden collapse after restraint
Respiratory arrest described
Cardiac rhythm brady-asystole or PEA
Aggressive resuscitation unsuccessful
Features on autopsy
Drug screen positive for psychostimulants
Drug levels lower than anticipated
No anatomic correlate for death
Dopamine transporter dysregulation

16
16
4
8
11
18
11
1
13
7
5
7
3
5
11
8
3
7
3
1
7
12
3
3
5
4
12
5
4
5
9
3
6
2

ExDS = Excited Delirium Syndrome; PEA = Pulseless electrical
activity.
This table lists the features of ExDS based on a review of the medicalliterature including 18 articles. The table is divided to indicate
features based on the medical history of the subject, features that
are observed in the company of the subject, featUres that are evident upon physical contact, features that are evident only with
clinical assessment li ke vital signs, features that are described if
the subject dies, and finally, features that are described on autopsy.

common entities such as Cannon's " voodoo" death, lethal catatonia, and sudden unexplained death in epilepsy
(SUDEP).

Treatment and Protocols
In the absence of clearly stated case definitions and prospective clinical studies, treatment of Ex DS remains
largely speculative and individually styled, directed towards supportive care and reversal of obvious clinical

..
6

and laboratory abnormalities. The specific circumstances
under which medical interventions will provide benefit
are currently unclear. Nonetheless, there are current medical approaches that have consensus support. Most authorities, including the Task Force, posit the beneficial
use of aggressive chemical sedation as first-line intervention, though the specific medications may vary based on
individual practice. Restraint will often be necessary for
safety of the staff as well as the patient, but should be
done in conjunction with aggressive chemical sedation.
As with any critically ill patient, treatment should proceed concurrently with evaluation for precipitating
causes or additional pathology.
In subjects who do not respond to verbal calming and
de-escalation techniques, control measures are a prerequisite for medical assessment and intervention. When necessary, this should be accomplished as rapidly and safely
as possible. There are well-documented cases of ExDS
deaths with minimal restraint such as handcuffs without
ECD or maximal "hogtie" restraint use. The use of multiple personnel with training in safe physical control measures is prudent.
Recent research indicates that physical struggle is
a much greater contributor to catecholamine surge and
metabolic acidosis than other causes of exertion or noxious stimuli (34). Because these parameters are thought
to contribute to poor outcomes in ExDS, the specific
physical control methods employed should optimally
minimize the time spent struggling, while safely achieving physical control.
After adequate physical control is achieved, medical
assessment and treatment should be immediately initiated. Indeed, because cardiopulmonary arrest might occur suddenly, EMS should ideally be present and
prepared to resuscitate before definitive law enforcement
officer control measures are initiated, when possible. Although the need for control measures may initially take
precedence, initial assessment should include vital signs,
cardiac monitoring, intravenous (i.v.) access, glucose
measurement, pulse oximetry and supplemental oxygen,
and careful physical examination. Several Task Force
members who have cared for witnessed ExDS sudden
death patients have experienced unsuccessful resuscitations even when the cardiopulmonary arrest occurs in
the setting of a well-staffed and well-equipped hospital
emergency department (ED). This implies that some patients who develop ExDS and go into cardiac arrest will
not be resuscitated, and that the cardiac arrest in these individuals is a terminal event despite optimal management.

Agitation. Agitation, hyperthermia, and acidosis are all
major components of ExDS that should be managed
with standard medical interventions. The approach to

G. M. Vilke et al.

each of these components is described below. For the
treatment of agitation, the Lv. route is preferred if available; however, intramuscular or intranasal transmucosal
administration of sedative agents may be needed initially
to facilitate i.v. placement. Commonly used agents
include benzodiazepines (midazolam, lorazepam, diazepam), anti psychotics (haloperidol, droperidol, ziprasidone, olanzapine), and the dissociative agent ketamine
(35-37) . The Food and Drug Administration has issued
"black box" warnings regarding potential serious
adverse effects (QT prolongation and torsades de
pointes) with the use of haloperidol and droperidol.
Clinicians should use their best clinical judgment
regarding the risk/benefit ratio on a case-by-case basis.
The actual effective dose of all suggested medications is
unknown. Because these agents have respiratory and cardiovascular effects, continuous monitoring of both heart
and lungs should be performed as soon as feasible whenever parenteral sedation is administered.

Hyperthennia. Empiric treatment for hyperthermia may
be initiated based on qualitative assessment (Le., tactile
hyperthermia) when needed, though core temperature
measurement is preferred when available and practical
(38). Basic cooling methods include removal of clothing
and placement in a cool environment. Active external
cooling may be initiated, with misting of water on exposed skin, providing air flow to enhance evaporative
cooling, and placement of ice packs at the neck, axillae,
and groin. Rapid cooling by infusion of cold saline i.v.
has been shown to be effective in a number of other settings and can also be used. Care must be taken to avoid
treatment "overshoot" leading to hypothermia.
Once the patient is stabilized in the ED or hospital setting, additional measures may be considered. In refractory or severe cases, immersion in cool water can
rapidly reduce core body temperature, though this will
present difficulty with monitoring and treatment. A variety of external and internal temperature control devices
are now available and may also be considered, If NMS
or malignant hyperthermia is suspected, dantrolene may
be indicated.
Acidosis. Metabolic acidosis and hypovolemia are
thought to be common in ExDS (32). If suspected based
on the clinical situation or physical examination, fluid resuscitation with intravenous fluids is prudent. In severe
cases, sodium bicarbonate may be used either empirically
or based on laboratory results revealing significant acidosis. Controversy exists regarding empiric use of sodium
bicarbonate; the efficacy of supplemental sodium bicarbonate is unknown, and has not been supported as routine
therapy for the metabolic acidosis of cardiac arrest.
Hyperventilation is the body's normal compensatory

Excited Delirium Syndrome

mechanism fo r correcting acidosis. Control measures that
might in terfere wi th ventilation should be avoided. In
some cases, patients have been treated with muscle paralyti c agents in the hope of preventing furthe r metaboli c
acidosis from movement when chemical sedation has
proven to be insufficient. Mechanical hyperventilation
is also deemed useful.

Rhabdomyolysis and Hyperkalemia. Other components
of ExDS may include rhabdomyolysis and hyperkalemia.
Rhabdomyolysis is initially managed by fluid administration and urine alkalinization with sodium bicarbonate.
These interventi ons may have already been initiated empirically for other components of ExDS before laboratory results allow confirmation of rhabdomyolysis.
Hyperkalemia may also be treated with standard interventions.

7

serum toxicology, thyroid functions, and blood and (if
fatal) anatomic brain speci mens for genetic, heat shock
proteins, and neurochemical analyses. Creating such
a regi stry would also allow the scientific community to
begin the process of identifying common characteristics
on a large scale as well as comparing therapies. Without
including suspected cases and survivors, no meaningful
conclusions can be reached that would allow the development of case definitions, etiologies. and treatments.
Studies should address the role of law enforceme nt
control techniques and devices in the death of subjects
with ExDS . Finally, research is needed to establish field
protocols and techniq ues that allow police, EMS, and
hospital personnel to interact with these agi tated, aggressive patients in a manner safe for both the patients and the
providers.
CONCLUSION

Future Directions
The primary issues surrounding identifying and studying
ExDS and subseq uent therapeutic interventions are the
lack of well-defined, consistent epidemiological case definition and overlap with other established diseases. In
those cases where a death occurs while in custody, there
is the additional difficulty of separating any potential contribution of control measures from the underlying pathology. For example, was death due to police ac ti ons or from
ExDS, or from interplay of all these factors? F urthermore, there is no clear proof of the most effective control
measures or therapy for the extreme ly agitated and delirious patient. Sedative or di ssoci ative agents such as benzodiazepines, major tranquilizers, and ketamine are
suggested and used regularly, but there is no evidence
yet to prove that these will result in a lower morbidity
or mortality.
Future research should focus on several areas. Animal
models should be developed to begin to better understand
the pathophysiology of ExDS. In hum ans, a consistent
case definition should be developed and applied in a large
epidemiologic prospective study or from a nationa l or international database of suspected cases, including tho se
who survive. At a mol ecul ar level, and based upon
post-mortem cocai ne-associated ExDS brain ti ssue, there
may be a genetic basis for susceptibility to ExDS.
Development of a national orphan case report registry
is recommended. This registry would be important in beginning to define the course of ExDS, and might eventually provide for earlier recognition of individuals at ri sk.
For these purposes, thorough documentation of the pati ent 's signs and symptoms alon g with appropriate testi ng
should occur in suspected cases, incl uding the presence of
sweating or muscle ri gidity, temperature, pulse, respiratory rate, blood pressure, venous blood gases, urine and

Based upon available evidence, it is the consensus of the
Task Force that ExDS is a real syndrome with uncertain,
likely multiple, etiologies. It is characterized by delirium,
agitation. acidosis, and hyperadrenergic autonomi c dysfunction, typically in the setting of acu te-an-chronic
drug abuse or serious mental illness.
Research suggests the pathophysiology may include
geneti c susceptibility and chronic stimulant-induced abnormalities of dopamine transporter pathways, along
with elevation of heat shock proteins in fatal cases. There
are insufficient data at this time to determine whether fatal ExDS is preventable, or whether there is a point of no
return after which the patient wi ll die regardl ess of advanced life support interventions.
The risk of death is like ly increased with physiologic
stress. Attempts to minimi ze suc h stress are needed in
the management of these patients. Ideally, any necessary
law enforcement con trol measures should be combined
with immediate sedative medical intervention to attempt
to reduce the ri sk of death.
For diagnostic and research purposes, thorough assessment and documentati on of a suspected ExDS patient 's
signs and symptoms, along with appropri ate testing,
should occur. Doing so would play an important role in
creating a large database of cases for study and scientific
investigation.
The ante-mortem di agnosis in the prehospital or ED
setting depends upon clinkal characteristics and the
excl usion of alternative di sease processes. It is our consensus opinion that rapid and appropriate control measures, and immedi ate adm inistration of supportive care
and sedation, such as Lv. benzodiazepines or ketamine,
intramuscular ketamine. or intranasal midazo lam, may
be lifesaving by preventing deterioration into sudden
death.

••
G. M. Vilke et al.

8

REFERENCES
I. Bell L. On a ronn of disease resembling some advanced stages of
mania and fever, bUI so contradistinguished from any ordinary observed or described combination of symptoms as to render it probable that it may be overlooked and hitherto unrecorded malady. A m
J Insanity 1849;6:97-127.
2. Di Maio TG , Di Maio VJM. Excited delirium syndrome cause of
death and prevention. 15t edo. Boca Raton, Fl.: Taylor & Francis
Group; 2006: 1-60.

3. Fishbain DA, WetJi CY. Cocaine intoxication, delirium and death in
a body packer. Ann Emerg Med 1981; I 0:531 -2.
4. Wetli Cv. Fatal cocaine intoxication. Am J Forensic Med Patho l
1987;8;1-2.
5. Ruttenber AJ , Lawler-Heavner J, Yin M, Wetli CV, Hearn WL,
Mash DC. Fatal excited delirium following cocaine use: e pidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci 1997;42:25-31.
6. Stratton SJ, Rogers C, Srickett K, Gruzinski G. Factors associated
with sudden death of individuals requiring restraint for excited delirium. Am J Emerg Med 200 1;19: 187-91 .
7. Ross DL. Factors associated with exc ited delirium deaths in police
custody. Mod Pathol 1998; 11: 1127-37.
8. Gran t JR, Southall PE, Mealey J, Scott SR, Fowler DR. Excited delirium deaths in custody past and present. Am J Forensic Med Pathol
2009;30; 1- 5.
9. Detweiler MS , Mehra A, Rowell T, Kim KY, Bader G. Delirious
mania and malignant catatonia: a repon of 3 cases and review. Psychiatr Q 2009;80:23-40.
10. Karch SB. Cardiac arrest in cocaine users. Am J Emerg Moo 1996;
14;79-81.
II. Wetli CV, Fishbain DA . Cocaine-induced psychosis and sudden
death in recreational cocaine users. J Forensic Sci 1985;30:873-80.
12. Sullivan L. Death by excited delirium: diagnosis or coverup? National Public Radio, All Things Considered, February 26, 2007.
Available at: http://www.npr.org!templateslstory/story.php?story
Id=7608386. Accessed July 1,2009.
13. Buck CJ. The international classification of diseases, 9th revision.
In: Mental disorders. Philadelphia: Elsevier Health Sciences; 2009:
290-319.
14. Barnell JH, Werners U, Seeher SM, et al. Substance use in a
population-based clinic sample of people with first-episode psychosis. Br J Psychiatry 2007;190:515-20.
IS. Mash DC. Bi ochemical brain markers in excited delirium deaths.
In: Kroll MW, Ho JD, eds. TASER conducted electrical weapons:
physiology, pathology, and law. New York: Springer; 2009 :
365-77.
16. Karch SB. Karch's pathology of drug abuse. 4th edn . Boca Raton,
FL Taylor & Francis Group CRC Press; 2009:45-65.
[7. All am S, Noble JS. Cocaine-excited delirium and severe acidosis.
Anesthesia 2001 ;56:385-6.
18. Bunai Y, Akaza K, Jiang WX, Nagai A. Fatal hyperthermia associated with excited delirium during an arrest. Leg Med (Tokyo) 2008;
10;306-9.
19. Escobedo LG , Ruttenbe r AJ, Agocs MM, Anda RF, Wetli CV.
Emerging patterns of cocaine use and the epidemic of cocaine over-

dose deaths in Dade County, Florida. Arch Pathol Lab Med 1991;
11 5;900-5.
20. Gruszecki AC, McGwin G, Robinson A, Davis GG. Unexplained
sudden death and the likelihood of drug abuse. J Forensic Sci
2005 ;50; 1-4.
2 1. Ruttenber AJ, McAnally HB , Wetli Cv. Cocaine-associated rhabdomyolysis and excited delirium: different stages of the same syndrome. Am J Forensic Med PathoI1999;20:120-7.
22 . Ruttenber AJ, Sweeney PA, Mendlein JM, Wetli Cv. Preliminary
findings of an epidemiologic study of cocaine-related deaths, Dade
County, Florida, 1978-85. NIDA Res Monogr 1991 ; 110:95-112.
23. Stephens BG , Jentzen JM , Karch S, Wetli CV. Mash DC. National
Association of Medical Examiners position paper on the certifica~
tion of cocaine-related deaths. Am J Forens ic Med Pathol 2004;
25;11 -3 .
24. Ho JD, Heegaard WG, Dawes DM, et al. Unexpected arrest-related
deaths in America: 12 months of open sou rce surveillance. West J
Emerg Med 2009;10:68-73.
25. Karch SB, Wetli Cv. Agitated delirium versus positional asphyx ia.
Ann Emerg Med 1995;26:760-1.
26. Karch SB, Stephens BG. Drug abusers who die during arrest or in
custody. J R Soc Med 1999;92 : 110-3.
27. Morrison A, Sadler D. Death of a psychiatric patient during physical
restraint. Med Sci Law 200 1;41 :46-50.
28. Hall C, Butler C, Kader A, et al. Police use of force, injuries and
death: prospective evaluation of outcomes for all police use of
force/restraint including conducted energy weapons in a large
Canadian city. Acad Emerg Med 2009;16:SI98-9.
29. Mirchandani HG, Rorke LB, Sekula-Perlman A, Hood IC. Cocaineinduced agitated delirium, fo rceful struggle, and minor head injury :
a further definition of sudden death during restraint. Am J Forensic
Med Pathol 1994;15:95-9 .
30. Mash DC, Duque L, Pablo J, et al. Brain biomarkers for identifying
exc ited delirium as a cause of sudden death . Forensic Sci Int 2009;
190;0 13-9.
31. Mash DC, Pablo J, Ouyang Q, et al. Dopami ne transport fu nction is
elevated in cocaine users. J Neurochem 2002;8 1:292-300.
32. Hick JL, Smith SW, Lynch MT. Metabolic acidosis in restraintassociated cardiac arrest: a case series. Acad Emerg Med 1999;6:
239-43.
33. American Psychiatric Association. Diagnostic and statistical manual of menIal disorders. 4th edition, text revision. Washington,
DC: American Psychiatric Association; 2000.
34. Ho J, Dawes D, Ryan P, et al. Catecholamines in simulated arrest
scenarios. Australasian College of Emergency Medicine Win!er
Symposium; June 25, 2009.
35. Hick JL, Ho JD. Ketamine chemical restrain! to facilitate rescue of
a combative "jumper". Prehosp Emerg Care 2005;9:85-9.
36. Roberts JR, Geeting GK. Intramuscular ketamine for the rapid Iranquilization of the uncontrollable, violent, and dangerous adult patient. J Trauma 200 I ;51 : 1008- 10.
37. Robens JR. Rapid tranquilization of violently agitated patients.
Emerg Med News 2007;29: 15-8.
38. Bouchama A, Dehbi M, Chaves~Carballo E. Cooling and hemodynamic manage ment in heatstroke: practical recomme ndations. Cril
Care 2007; II :R54.

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Excited Delirium Syndrome

ARTICLE SUMMARY
1. Why is this topic important?
Excited Delirium Syndrome (ExDS) is seen all across
the country in emergency departments, but is not always
recognized as a syndrome with significant mortality.
2. What does this review attempt to show?
To better define ExDS as a discrete medical entity, the
history, epidemiology, clinical presentation, pathophysiology, and treatment recommendations.
3. What are the key findings?
ExDS is characterized by delirium, agitation, acidosis,
and hyperadrenergic autonomic dysfunction, typically in
the setting of acute-on-chronic drug abuse or serious mental illness. Based upon available evidence, it is the consensus of the Task Force that ExDS is a real syndrome with
uncertain, likely multiple, etiologies.
4. How is patient care impacted?
Treatment options are described and with increased
awareness and knowledge, patient care can be improved.

9