Transcript hyperthermia - Calgary Emergency Medicine

Moritz Haager
PGY-2, Emergency Medicine
February 13, 2003
Isn’t ecstasy safe?
“I read this article about ecstasy being
safer than aspirin….I now take 2-3 in the
course of an evening…”
Anon MDMA user from Parrott & Lasky. 1998. Psychopharmacology 139: 261-268
What makes MDMA
dangerous?
Several variables

Factors related to the user
Susceptibility, Polydrug use, dose

Factors related to the drug
Purity, MDMA content, intrinsic toxicity

Factors related to the environment
Rave venues, access to water
Objectives
Epidemiology:
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What is rave culture, and how is it relevant?
What is the impact internationally? Locally?
Pharmacology:

What are the characteristics of club drugs?
Toxicology:

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What are the acute effects? Long-term
effects?
Are there any therapies we need to know
about?
Rave Culture
All-night dance parties in non-traditional
venues popularized in Europe in mid
1980’s
PLUR philosophy
Various genres of non-commercial
electronic music
Alternative fashions
Low EtOH use, but high prevalence of
designer drug use to achieve
“synesthesia”
Street Sense Trivia
What is
synesthesia?
A: the desired
drug-induced
state where
colors are
“heard” and
sound is “seen”,
hence the use
of glowsticks
Designer Drugs
Made by combining the desired properties
of two drugs into one new one

Fentanyl analogues
China white (α-methyl fentanyl)
New heroin (MPPP)

Hallucinogenic amphetamines
ring-substituted amphetamines
Blend of mescaline-like and amphetamine-like
effects
Drugs used at Raves
Cannabis
MDMA (ecstasy)
MDEA (eve)
MDA
Methamphetamine
PMA
Ketamine
GHB (gammahydroxybutyrate)
Cocaine
LSD
PCP (phencyclidine)
Others
The Dawn of Ecstasy
6000
5000
4000
MDMA
GHB
Ketamine
3000
2000
1000
0
1994 1995 1996 1997 1998 1999 2000 2001
DAWN statistics of the number of ED mentions of MDMA & GHB
Global Trends
Use of club drugs is increasing
MDMA use amongst students in the US :
Grade 8
Grade 10
Grade 12
1996
3.4%
5.6%
6.1%
2001
5.2%
8.0%
11.7%
By 1997 the UK had 53 deaths due to acute
MDMA toxicity
Worldwide >87 ecstasy related deaths reported
Canadian Data
Minimal data sources
Estimates for ecstasy use in school age children
are 3% & 5% for girls & boys
Prevalence of MDMA use increased from 0.6%
in 1993 to 4.4% in 1999 among Ontario
adolescents
2.4% of university students report prior MDMA
use
14 deaths between 1998 – 2000 in Ontario
At least 3 fatalities in Vancouver area
The Calgary Scene
Increasing
prevalence of
ecstasy
Drugs seen:
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Cannabis
Crack cocaine
Powder cocaine
MDA
MDMA
LSD
Ketamine
Opiates
Clandestine labs in
Vancouver and USA
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53 labs raided in
western Canada b/w
’91-’99
60% produced MDA
15% produced MDMA
Calgary data:
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90% of “E” contains no
MDMA at all
Usually MDA or
ketamine + PCP
Street Purity & Doses
Tremendous variation in content & dose

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70-fold variation in MDMA content b/w
brands
7-fold variation in MDMA content in same
brand
Virtually none contained solely MDMA
Ephedrine, ketamine, tylenol, caffeine
common
Sherlock et al. J Accid Emerg Med 1999. 16: 194-97
Pharmaceutical Grade Ecstasy
Lab
Chemical composition of
“ecstasy” tablets in Vancouver:
53% MDMA
17% MDA
15% ephedrine
12% Nethamphetamine
10% caffeine
5% PCP
4% ketamine
3% cocaine
3% dextromethorphan
3% codeine
2% amphetamine
Rintoul & MacKillican. 2001. Designer Drugs and Raves.
RCMP Drug Awareness Service
Hallucinogenic Amphetamines
Phenethylamines:

derived from amphetamine +
methamphetamine
Chemically & biologically similar to
epinephrine, dopamine, & serotonin
Chemical Structures
MDMA
(Ecstasy, E, XTC, Adam, Hug Drug, Love Drug, Clarity E-bombs)
3, 4-methylenedioxy-methamphetamine
Ring-substituted form of
methamphetamine



methylenedioxy group addition makes it
structurally similar to mescaline and conveys
hallucinogenic properties
new class of compounds: “enactogens”
chemically & biologically similar to MDA,
MDEA
MDMA
1912: 1st synthesized by Merck as
appetite suppressant but never marketed
1970’s: Thought to be beneficial in
psychotherapy due to its ability to break
down barriers and improve communication
1976: Classified as schedule III under
CDSA in Canada
1985: Classified as schedule 1 drug by
DEA
CDSA Schedule III
It is illegal to posses, produce, import or
export MDMA
Possession is a criminal offence
punishable for up to 3 years jail, $1000.00
fine or both.
Trafficking carries jail sentence up to 10
years
Legal for medical or scientific purposes
MDMA
Taken PO, but can be used IV, PN, PR
Comes as tabs with logos, or capsules
Typical dose is 50-150 mg but varies
widely
Onset within 20-40 min
Duration 3-8 hours
60% stimulant, 40% hallucinogen
Price is $20-40 Cdn per hit
MDMA: Mechanism of Action
Indirect Sympathomimetic:



Increases serotonin, noradrenaline, and dopamine
Serotonin & dopamine  mental effects
Noradrenaline  physical effects
Increases release, and blocks serotonin
reuptake by binding SERT
Direct agonism at 5-HT2, 5-HT1, and D2
receptors
Serotonin release can be blocked by SSRI’s
 attenuates drug effects
Also blocks MAO
MDMA Metabolism
MDMA
N-demethylation
MDA
CYP2D6 Demethylation
glutathione
DHMA
Toxic metabolites
CYP2D6
Demethylation
O-methylation
DHA
HMMA
N-demethylation
O-methylation
HMA
MDMA Pharmacokinetics
Rapid absorption via GI tract
Tmax is reached within 2 hours
T1/2 ~8-9 hrs
Metabolism appears to be non-linear; higher
doses cause disproportionately greater
increases in plasma levels
Elimination is via hepatic metabolism and direct
renal excretion
Tolerance develops rapidly polydrug use
Mas et al. 1999. J Pharm Exp Ther. 290: 136-45
Street Sense Trivia
Why do ravers suck
on lollipops or
pacifiers?
 To alleviate
bruxism which is
jaw clenching and
teeth grinding
associated with
MDMA use and
which can cause
significant dental
damage
MDMA Acute Effects
3 stages:
1. Initial disorientation
2. Tingling and spasmodic jerking
3. Happy sociability
Euphoria, inc’d energy, confidence & insight
Empathy, tolerance, & closeness towards
others
Sexual arousal, heightened sensory perception
Tachycardia, bruxism, trismus, mydriasis,
anorexia, nausea, ataxia, psychomotor
agitation
Acute CVS Effects
2 Double-blind RCT’s:
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Avg HR increased by 28-30 bpm
Systolic BP increased by 25-44 mm Hg
Diastolic BP increased by 7-25 mm Hg
CO increased by 2 L/min
No measurable inotropicity
Lester et al. 2000. Ann Int Med. 133: 969-973
Mas et al. 1999. J Pharm Exp Ther. 290: 136-45
Street Sense Trivia
What’s
“hammerheading”?
A: Combining
ecstasy and viagra
(also known as
“sextasy”), called
so for the resultant
H/A and priapism
MDMA: Aphrodisiac or OCP?
Retrospective study of 20 male and 15 female
users:
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all had mod-profound increase in sexual desire
most felt enhanced sensuality
90% M / 93% F had mod-profound satisfaction
80% M / 40% F had delayed orgasm
40% M reported erectile difficulty
80% F had improved lubrication
Zemishlany et al. 2001. Eur Psych. 16: 127-30
MDMA Subacute Effects
“Crash” phenomenon

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
Less pronounced than parent amphetamines
Occurs 24-48 hrs post-ingestion
Myalgias, fatigue, depression, irritability,
concentration deficits, memory deficits,
headache, akisthesia
MDMA Serious Adverse Effects
Appears to be NO relationship between dose,
serum levels, and severity of reactions
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CVS: increased BP & HR -- CVA’s, ICH
Endocrine: increases prolactin, cortisol, & ADH 
hyponatremia, hypoglycemia
CNS: hyperthermia, neurotoxicity
GI: hepatoxicity
MSK: rhabdomyolysis
GU: ARF
Psychiatric: acute psychosis, panic reactions,
depression, cognitive deficits
Street Sense Trivia:
What’s a “Vicks hit”?
A: inhaling Vicks
VapoRub, or applying
it and having
someone blow on it
while on ecstasy.
Done for the amplified
sensation of cooling
experienced on “E”.
Hyperpyrexia
Likely combined direct drug (class) effect
and environment in which drug is used
Most dangerous toxic pattern
Felt to precipitate further injury cascade:
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Rhabdomyolysis
ARF
Hepatotoxicity
DIC
Hyperpyrexia: Possible
Mechanisms
Postulated serotonin effect in hypothalamus
Loss of thermoregulation

MDMA-treated rats are both hypo- and
hyperpyrexic depending on ambient temp
Malberg & Seiden. 1998. J Neurosci. 18:5086-5094
Cutaneous Vasoconstriction

Rabbits exposed to MDMA exhibit
sympathetically-mediated vasoconstriction
Pedersen & Blessing. 2001. J Neurosci. 21: 8648-8654
Dopamine D1 agonism

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Hyperthermia is not attenuated by 5-HT uptake
inhibitors or 5-HT receptor antagonists in rats
D1 (but not D2) antagonism dec’s hyperthermia
Mechan et al. 2002. Br J Pharm 135: 170-180
Hyperpyrexia: Possible
Mechanisms
Increased adrenergic drive

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Increased metabolism
Muscle hyperactivity
Environment

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Crowded & hot rave venues
Vigorous physical activity
Is there a link to serotonin syndrome?
MH? NMS?
MDMA & Malignant Hyperthermia
Both appear to be idiosyncratic effects
MDMA toxicity case reports similar to MH
Dantrolene used “successfully” in several
MDMA elevates myoplasmic Ca2+ in vitro,
and potentiates halothane- and caffeineinduced muscle contracture
Denborough and Hopkinson. 1997. MJA. 16:165-166
Serotonin Syndrome vs. NMS
Differentiation important b/c different
therapies – using wrong drug may be fatal
At least 12 case reports of pts presenting
with MDMA –related hyperpyrexia that fit
diagnostic criteria for Serotonin syndrome
Several have overlapping clinical features
Symptom
Serotonin Syndrome Malignant
Hyperthermia
Neuroleptic
Malignant Syndrome
Onset
hrs
minutes
3-9 days
Fever
++
+++
++
Rigidity
+
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+++
Rhabdomyolysis
++
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++
Myoglobinuria
+
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++
Tachycardia
+
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++
BP changes
+
++
+
Hypercarbia
+
+++
++
Behaviour changes
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+
++
Altered LOC
+++
+
+++
Leukocytosis
+++
-
+
Clonus
+++
-
-
Shivering
+++
-
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Tremor
+++
-
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Hyper-reflexia
+++
-
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Hyperpyrexia: Treatment
Hyperthermia from ANY cause  MOF
Peak temp & duration appear correlated
with mortality & morbidity in MDMA
Dar & McBrien. Int Care Med 1996. 22: 995-96
Approach essentially as per heat stroke:
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General cooling measures
Consider more specific interventions
Hyperpyrexia: Treatment
General Measures:
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Ice packs to groin, axillae, neck
Makka Body Cooling technique
Iced peritoneal lavage
Cold humidified O2 & IV fluids
Cardiopulmonary bypass
Hyperpyrexia: Treatment
Specific treatment: Serotonin Antagonists
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Cyproheptadine & methysergide shown to
block SS in animal studies
No human studies looking at serotonin
antagonists in MDMA-induced hyperthermia
Needs further evaluation
Hyperpyrexia: Treatment
Specific Treatments: Dantrolene
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Evidence for Dantrolene in MDMA anecdotal
Dec’d mortality in MH from 70-80% to <10%
Used “successfully” in multiple MDMA cases
Inhibits Ca2+ release for sarcoplasmic
reticulum
1-2.5 mg/kg up to 20 mg/kg max
If successful start infusion of 10 mg/kg/24h
Hyperpyrexia: Treatment
BDZ’s / Neuromuscular blockade:
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Decrease agitation
Decrease neuromuscular activity &
metabolism
Non-depolarizing agents preferred
Evidence is anecdotal only
Hyperpyrexia: Treatment
Relatively contraindicated:

Bromocriptine
dopamine agonist  worsens NMS

Succinylcholine
Risk of malignant hyperthermia
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Haloperidol
Risk of NMS + anticholinergic effects
Hepatotoxicity
Exact mechanism unknown
Idiosyncratic reaction
Usually mild hepatitis-like, but can be
severe with liver failure requiring
transplant
Over 70 fatalities described after
developing MDMA-induced hepatitis b/w
’90 -’98
Hepatotoxicity: Mechanism
Postulated mechanisms:
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indirect hyperthermic and direct toxic
effects of reactive metabolites
Metabolites react with, and deplete,
glutathione  oxidative damage
Toxic effects of unknown contaminants
Immune-mediated damage
May have metabolic predispositon
related to CYP2D6 sub-types
Hepatotoxicity: Classification
Very early onset:

Liver injury with hyperthermia
Delayed onset:
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Acute liver failure in absence of hyperthermia
Late onset:

Hepatitis in absence of other detectable
causes other than MDMA exposure
Ellis et al. 1996. Gut. 38: 454
Hepatotoxicity: Treatment
Conservative vs.
transplant
Indications for liver
transplant:

Core temp > 41oC
and:
Acidosis
Renal failure
Grade III
encephalopathy
Coagulopathy w/ INR
>7+

Normal temp and:
Malaise, GI sx
Hyperbilirubinemia
Rising AST / ALT
Worsening
coagulopathy
Worsening
encephalopathy
Prognosis: 10-50%
survival
De Carlis et al. 2001. Transpl Proceed 33: 2743-44
Cardiovascular Toxicity
Related to noradrenaline and dopamine
release
Manifests as tachycardia, HTN, & arrythmias
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Intracranial hemorrhage
Cerebral infarct
Arrythmias
Retinal hemorrhages
CHF & pulmonary edema
High rate of underlying structural abnormalities
McEvoy et al. 1998. Lancet. 351: 1029
CNS Toxicity
Hyponatremia
Develop seizures, cerebral edema,
tentorial herniation, and/or respiratory
arrest
Females appear to be at increased risk

?estrogen effect
Hyponatremia: Mechanism
Profuse sweating & free water intake 
dilutional hyponatremia
ADH release  SIADH
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8 volunteers given 47.5 mg MDMA or placebo
Serum ADH increased in relation to MDMA
levels w/o concomitant increase in cortisol
Henry et al. 1998. Lancet. 351: 1784
Hyponatremia: Treatment
NS infusion
Fluid restriction <1 L/day
IV mannitol or lasix if cerebral edema
?hypertonic saline
Education regarding rehydration at raves
Acute Renal Failure
Mechanisms:
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Rhabdomyolysis
DIC  microvascular obstruction
Direct toxic effect
Report of CRF due to MDMA-induced necrotizing
angiitis
Bingham et al. 1998. Nephrol Dial Transplant. 13:
2654-2655
Street Sense Trivia
What is “hooping”?
A: using MDMA in suppository form.
Neurotoxicity
Most controversial research topic
FDA refusal to investigate medicinal uses
of MDMA based on potential neurotoxicity
Overall good animal data supporting a
detrimental effect on serotonergic system
Human studies more limited and
hampered by methodological
weaknessess
No clear evidence, but “highly suggestive”
What’s the big deal with 5-HT?
Implicated functions of serotonin:

Regulation of:
Mood
Aggression
Impulsivity
Sexual activity
Appetite
Sleep
Body temperature
Circadian / seasonal rhythms
Neurotoxicity
Mechanism not elucidated
Hypothesized to result from chemical cell
damage 2o to sudden massive serotonin
release and intracellular depletion
Excessive dopamine may also contribute
via free radical formation 2o to
deamination
Neurotoxicity
2 arms of research:
1. Biologic
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Animal studies
Imaging studies
Autopsy data
2. Psychological / Psychiatric
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Cognitive / memory testing
Surveillance for mood and other disorders
Neurotoxicity
Animal data:
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Multitude of studies showing neurotoxic effect
Concept of interspecies dosing:
Smaller animals require proportionately larger doses
to achieve toxic effects
E.g. 5 mg/kg in squirrel = 1.4 mg/kg in humans
Typical recreational human doses fall within toxic
doses in animals corrected for interspecies dosing

One report describes enduring serotonergic
toxicity with a single dose in baboons
Neurotoxicity: Animal Data
Biphasic response to single dose:
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Acute 5-HT depletion 3-6 hrs post-ingestion
Recovery by 24 hrs
2o 5-HT depletion 1 week post-ingestion
Long-term neurotoxicity:
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See morphologic neuronal changes consistent w/
injury
Either large single or moderate repetitive doses
Lowest neurotoxic dose in primates 5 mg/kg bid x 4
days
Only primates appear to have persistent
damage
Neurotoxicity
Human data
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MDMA users have decreased levels of
serotonin & its metabolites (HIAA) in CSF
Blunted neuroendocrine responses to
serotonin agonists
PET & SPECT studies using selective ligands
document decreased serotonin transporter
levels & altered glucose metabolism
EEG patterns similar to aging & dementia
Human Neuroimaging Studies
Most direct data supporting neurotoxicity
Semple et al. 1999. Br J Psych. 175: 63-69
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10 male MDMA users & 10 controls matched for
age, education, and other drug use
Neuropsych testing & SPECT imaging
Showed dec’d SERT binding in MDMA users
Showed correlation b/d life-time dose and trend
towards dec’d verbal and spatial memory
scores
Neurotoxicity
Psychological / Psychiatric Data:
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Memory impairment
Cognitive impairment
Increased impulsivity
Anxiety symptoms & panic attacks
Psychosis
Depression / suicidality
Flashbacks
Parkinsonism
Overall data suggests minimal sequelae in light
users, but plausible morbidity w/ heavy use
Street Sense Trivia
What is “preloading”?
A: ingesting prozac,
or various other
nutritional
supplements prior to
ecstasy use in a bid
to prevent its
neurotoxic effects
Are SSRI’s Neuroprotective?
Based on pre-clinical data, SSRI’s appear to block
MDMA-induced serotonin release
Contradictory reports regarding impact on
subjective experience when pre-loaded
DBRCT of 16 volunteers treated w/ MDMA &
citalopram found reduced (but prolonged)
subjective effects, as well as decreased CVS
effects.
Liechti et al. 2000. Neuropsychopharmacology. 22: 513-21
MDMA inhibits MAO-A & MAO-B in vitro, to a
lesser extent than prozac  ?breakdown >
synthesis
Efthimia et al. 1994. Neuropsychopharmacology. 10: 231-38
What About Dopamine?
DBRCT of 14 volunteers found that pretreating w/ haldol decreased the
pleasurable subjective effects of MDMA
Liechti & Vollenweider. 2000. Eur Neuropsychopharmacology 10:
289-295
Dopaminergic toxicity not previoulsy noted
More recent study of squirrel monkeys
and baboons found significant
dopaminergic toxicity when MDMA doses
are stacked
Ricaurte et al. 2002. Science. 297: 2260-2263
Dopaminergic Toxicity
Numerous markers of serotenergic toxicity
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Dec’d tissue 5-HT, 5-HIAA, and SERT
Direct demonstration of axonal degeneration
Numerous markers of dopaminergic toxicity
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Dec’d tissue DA, DOPAC, & DAT
Direct demonstration of axonal degeneration
No change in noradrenergic neurons
Inc’d sensitivity to AMPT  motor dysfuxn
Ricaurte et al. 2002. Science. 297: 2260-2263
Neurotoxicity
Methodological problems w/ human studies:
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Differences may have been pre-existant, co-incidental,
or predispose to MDMA use
Retrospective & un-blinded
Difficult to match controls / some studies don’t at all
Confounding effects of other illicit drug use
Small sample sizes
Self-referral (unknown bias)
Questionable drug histories / purity of drugs
Numerous psychological tests in different studies
Bottom line:

Can’t prove causality
Lab Testing
MDMA & amphetamines detectable for
24-48 hrs post-ingestion (effects may
outlast detectable serum levels)
Immunoassay
Drugwipe sweat testing kit
Gas chromatography - Mass
spectometry
Approach:

Screen with urine DOA test  confirmatory
testing if positive
Street Sense Trivia
Where does the expression “rolling on E” come
from?

A: a reference to the irregular eye movements
associated with ecstasy intoxication
Conclusion
Use of designer amphetamines is growing
rapidly
These drugs are not benign, and their
long-term toxicity is yet to be established
Treatment is primarily supportive, with
particular attention to cooling, hydration, &
electrolyte balance
Monitor for complications