the heat is on(and on) - necf€¦ · the heat is on(and on) cornelis kramers internist...
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The heat is on (and on)
Cornelis KramersCornelis Kramers
Internist clinical pharmacologist
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(potentiële) belangenverstrengeling Geen
Voor bijeenkomst mogelijk relevante relaties met bedrijven
Bedrijfsnamen
Sponsoring of onderzoeksgeld Honorarium of andere (financiële)
Disclosure belangen spreker
Honorarium of andere (financiële) vergoeding
Aandeelhouder Andere relatie, namelijk …
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Hyperthermia
Always a challengeSometimes life threatening
Expect the unexpected!
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Case 1
Woman , 54 years old2013: severe intoxication quetiapine
Arrival: 11 AM.Arrival: 11 AM.
8 AM: 120 x 20 mg paroxetine, Half a liter of brandy
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Physical examination
150 kg
RR 150/110; Heart rate 115 bpm
Temp 38,9
Agitated,
Trembling
Hyperreflexia
CK: 467 U/l
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Conclusion: serotonergic syndrome
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Tests
Lumbar puncture: normal
Urine culture: E Coli
TSH normal
CT brain: no abnormalitiesCT brain: no abnormalities
Blood and other cultures: all negative
Lab: ANA/ds DNA neg. Anti MPO en PR3 neg.
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Treatment
Active charcoal
Midazolam,
Paracetamol
Antibiotics (ceftriaxone)
Intubation (propofol) because of ARDS
Cooling (but not very long and aggressive)
Day 5-12: Cyproheptadine
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Clinical course
Antibiotic therapy not succesful.
Temperature stays elevated
Develops severe rhabdomyolysis
• Maximum CK 17.000 day 22• Maximum CK 17.000 day 22
• Returns to normal day 30
Paroxetine levels therapeutic at days 13
Paroxetine levels undetectable from day 23
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Course
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Course
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0
200
400
600
800
1000
1200
1400
1600
1800
2000
paroxetine levels (ug/l)
0
1 2 3 5 6 7 8 9 10 11 13 15 17 23
Half life 24 hours
Saturating kinetics
Inhibits own metabolizing route (CYP2D6)
This patient 150 kg!
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Paroxetine therapeutic very low
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Clinical course
Many complications
Day 87 the patient dies
Respiratory insufficient
Still hyperthermia
No rhabdomyolysis anymore
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Summary
Fatal paroxetine intoxication
Prolonged paroxetine exposure (2-3 weeks)
Long term rhabdomyolysis (5-6 weeks)Long term rhabdomyolysis (5-6 weeks)
Persistent hyperthermia (13 weeks)
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Woman, 20 years
Possible 2,4-dinitrophenol (DNP) – intoxication
Eating disorder, used many diet- and energyproducts (e.g. Meridia, Guarana).
Case 2
products (e.g. Meridia, Guarana).
Medication: Diazepam en Fluoxetine
Admits using DNP on a daily base
Increased dose because of upcoming birthday and wish to lose more weight.
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Complaints: dyspnoea, nausea, perspiration, muscle aches in arms and legs
Primary survey
A: Airway free
B: Breathing 40/min, sat 99% without oxygen, B: Breathing 40/min, sat 99% without oxygen,
C: Pulse 140bpm (ECG: ST), RR 170/70mmHg,
D: Max EMV, normoglycaemia
E: Temperature rapidly rising (in 30 minutesT37.4°C to 38.5°C), painful extremities ontouching
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Lab on arrival:
ABG: pH 7.49 / pO2 11.8kPa / pCO2 3.8kPa / bic 20.9mmol/L / BE-1.1
ASAT 463U/L, ALAT 136U/L, LDH 1925U/L
CK 18170U/L
Tox-screen:
Diazepam, Paracetamol en Fluoxetine: therapeutic
Cannabis: positive
Amphetamine / Barbiturate/ Cocaine / Methadone / Opiates / TCA: negative
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DNP
1933: Introduction for weight reduction
1938: FDA ban because of side effects
Until 2001 hardly severe intoxications, Until 2001 hardly severe intoxications,
increased abuse because of internet sales
2003: Again FDA ban
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http://news.sky.com/story/1477691/interpol-warns-over-potentially-deadly-diet-pills
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A. Young people with eating disordresB. BodybuildersC. People working in agriculture industry
Who are at risk?
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Mechanism of action
Uncouples oxidative phosphorylation in mitochondria
Cell switches to burning of fat
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Toxic dose
1-3 mg/kg toxic within a few hours
Median time to death: 14 hours
One single dose of 1-3 g fatal in adults,
3 g fatal if taken in a period of 5 days
Inhalation or dermal exposure systemically toxic
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Kinetics
• Absorption: fast
• Vd: ?
• Protein binding: probably high (?)
• Elimination: excretion via kidney, no accumulation
• Half life: estimated 5-14 days
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Differential
• Intoxication drugs of abuse (cocaine, amphetamin)
• Intoxication with other diet products
• Thyreotoxic crise• Thyreotoxic crise
• Sepsis
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Therapy
General
• Start agressive treament directly
• Beware of difficult intubation because of musclehypertonicity
Absorption reduction
• Active charcoal
• Gastric lavage ??
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Therapy
Symptoms
• Cool the patient!
• In agitated patients: benzodiazepines
• Dantrolene possibly useful• Dantrolene possibly useful
• Intravenous glucose
• If seizures: diazepam iv
• No Haloperidol
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In summary
The heat goes on (and on)
In neuroleptic malignant syndrome
This paroxetine intoxication?This paroxetine intoxication?
DNP