Kassandra Luening and Neil Rybak
“In 2004, 643 bromethalin exposures were reported to 62 major poison
control centers across the United States . . . to our knowledge, a fatal
human poisoning has never been previously reported.”
The Case Report
• 21 year old male brought to emergency room after discovery with
“multiple open packages of rat poison”, self reportedly ate “8 packs”
• Symptoms: repetitive speech, labile emotions, diminished responsiveness
to direct questions, normal vital signs, one episode of emesis
• Treated with promethazine, thiamine, folic acid, and diphenhydramine
• “medically cleared” and sent to psychiatric hospital
• The last 2 days of 3 in psychiatric hospital, was “obtunded and catatonic”,
sent to hospital for further study
• Stable vital signs, no fever, anisocori pupils, unresponsive to verbal or
painful stimuli. Flaccid extremities
•
•
Intubated and placed on a ventilator
Developed distended bladder, and decreased rectal tone
• Declared brain dead 7 days after ingestion of “No Pest”
Overview
• Chemistry of MS SIM
• Quantification problems
• Lethal Dosage
• Process of determination of cause of death
• Alternate hypothesis for cause of death
Mass Spectrometry
Selected Ion Monitoring
• Allows for scanning of specific mass fragments, as
opposed to a full scan
• Faster than a full scan as only a section of the
spectrum is being scanned
•Less matrix interference
•The atomic mass units of the fragments of interest
must be known
• Demethylated form of
bromethalin found in brain
and liver samples
•Positive control resulted in
a peak
•Negative control resulted in
no peak
Problem:
Knowing that there is bromethalin in the tissues does not
necessarily indicate a lethal dosage, only that it was
there.
The Quantification Problem
“Because of a lack of analytical
standard, no attempt was
made to quantitate this
analyte.”1
The presence of bromethalin was shown, but not the quantity.
“accurate quantification of
bromethalin in tissues is limited
by the rapid photodegredation of
bromethalin in sample extracts” 2
Would quantification even be accurate?
Lethal Dosages
•The lethal dosage (LD 50) is the amount of a substance
that would kill a certain percent of a population
•Based on the ‘standard person’ concept and may not be
suitable to all sub-populations
Determining Lethal Dosage
•
•
Extrapolating from human cultures
Extrapolating from LD50 of other animals
Bromethalin Lethal Dosages
•Cat: 0.54 mg/kg1, 1.8 mg/kg2
•Dog: 4.7 mg/kg2
•Rabbit: 13 mg/kg2
•Guinea Pig: >1,000 mg/kg 2
•Case Study Patient: 0.33 mg/kg
• Not quantified experimentally
• Based on self report of the patient who had shown
diminished cognitive function, as well had a chronicled
history of strange behaviour
• unreliable source of information
“the ischemic neuronal changes seen on
microscopic examination are likely
related to his terminal diagnosis and do
not necessarily reflect bromethalin
toxicity”1
“the sensitivity of humans to
bromethalin has not been previously
studied, and the LD50 in people is
unknown”1
Determination of Cause of Death in
Case Study
1. History of exposure to potentially toxic dose
2. Clinical signs
3. Physiological indicators
• Histologic presence of white matter vacuolization
4. Detection of drug in the body
• Bromethalin found in brain and liver samples
•
It’s possible to use this same methodology to
identify barbiturates as a possible cause of
death
Barbiturates
• Central Nervous System depressants
• Resulting in mild sedation, to total anesthesia
• Possible side effects include; hypotensia, ataxia, mortality,
sedation (coma), areflexia, apnoea, hypotension, hypothermia
• Widely prescribed and frequently used for intentional self
poisoning4
•15th most common medication class associated with fatal
poisoning in the US 4
•“the collective experience (and comfort) of clinicians for
managing patients with severe barbiturate toxicity is fading” 4
1. History of Exposure to Toxic Dose
• A urine drug screen was positive for barbiturates
• Lethal dosage ranges from 30 µg/ml to 80 µg/ml
depending on which barbiturate 5
• Combined with other CNS depressants, toxicity can increase5
• Patient was treated with promethazine, and
phenhydramine; both are strong sedatives
2. Clinical Signs of Barbiturate Overdose
Barbiturate
•Changes
in Overdose
alertness, decreased interpersonal
Patientfunction,
symptoms
severe confusion,
areflexia, ataxia, pupil effects, decreased urine production, ventilation
Changes in alertness
Repetitive speech
required, possible complications such as pneumonia, coma, brain death,
Decreased interpersonal function
Diminished response to questions
mortality
Severe confusion
Labile emotions
Ataxia, areflexia
Flaccid extremities
Pupil effects
Aniscorcic pupils
• These signs were apparent in the case study patient
Ventilation required
Placed on ventilator
Possible complications- pneumonia
Acute bronchoalveolar pneumonia
Coma
Coma
•Possible
Patientbrain
exhibited;
repetitive
speech,
labile
motions,
death
Brain
death diminished response to
direct
questioning, aniscoric pupils, flaccid
extremities (ataxia), and was
mortality
Death
placed on a ventilator, coma, brain death, declared dead
3. Physiological Indicators
• Barbiturate overdose can lead to global ischemia, a complete stoppage of
blood flow to the brain
• EEG performed on patient a day before death indicated low amplitude voltage, which
is a non specific finding consistent with global ischemia and impending brain death
•Other possible explanations for white matter vacuolization
•Can be caused by PCP and ketamines
• Carbon tetrachloride exposure from cleaning agents can cause white
matter vacuolization 6
• It has been shown that bromethalin exposure at an anticipated lethal
dosage does not necessarily lead to death 7
4. Detection of Barbiturate in the Body
•An initial urine screening was positive for barbiturates
•No further testing was done
“The initial positive urine barbiturate screen
was never accounted for in the medical
records reviewed.”
Barbiturate Poisoning Diagnosis
• Urine screening show barbiturates
•Indicated a history of drug use
•Clinical signs of barbiturate overdose were seen
• Global ischemia, a result of barbiturate overdose was observed in
the patient
•MS SIM analysis was only done for expected demethylated
bromethalin, no follow up was done on the positive screening in the
urine analysis
Summary
The bromethalin found in the patient was
not quantified
•
•The LD50 of bromethalin in humans is not
known
•The method used to determine
bromethalin poisoning as cause of death
could also be used to determine barbiturate
poisoning as cause of death
Conclusion
It cannot be positively determined that
Bromothalin poisoning was the only
possible cause of death in this case study.
References
1.Pasquale-Style, M., Sochaski, M., Dorman, D., Krell, W., Shah, A., Schmidt, C., Fatal
Bromethalin Poisoning Journal of Forensic Science 2006 vol 51, pp. 1154 – 1157
2.Dorman, D., Simon, J., Harlin, K., Buck, W., Diagnosis of Bromethalin Toxicosis in the Dog J Vet
Diagn Invest 1990 pp 123 – 128
3.Cooks, R., Soltero-Rigau, E., Kruger, T., Identification of Barbiturates by Chemical Ionization
and Mass Analyzed Ion Kinetic Energy Spectrometry Analytical Chemistry 1977 vol 49 pp. 435 –
442
4.Roberts, D., Buckley, N., Enhanced Elimination in Acute Barbiturate Poisoning – A Systematic
Review Clinical Toxicology 2011 vol 49 pp. 2 – 12
5.American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD.
(2009), p. 2578
6.USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I.
Rockville, MD: Convention, Inc., 1997. (Plus Updates)., p. 505
7.Odabasi, M., Halogenated Volatile Organic Compounds from the Use of Chlorine – Bleach –
Containing Household Products Environmental Science and Technology 2008 vol 42 pp. 1445 –
1451
8.Dorman, D., Zachary, J., Buck, W., Neuropathological Findings of Bromethalin Toxicosis in the
Cat Veterinary Pathology Online 1992 vol 29 pp. 139 – 144
• “the sensitivity of humans to bromethalin
has not been previously studied and the LD 50
in people is unknown” 1
•“no attempt was made to quantitate this
analyte”1
•“the ischemic neuronal changes seen on
microscopic examination are likely related to
his terminal diagnosis and do not necessarily
reflect bromethalin toxicity” 1