When Swole Takes its Toll

/ myemresidency

Author: Don Vongviphut, DO MBS, Emergency Medicine Resident, PGY-1
Faculty: Alexis Cates, DO, Medical Toxicology / Emergency Medicine Attending

The Case…

A 21 year old with no significant past medical history presents to the emergency department (ED) after ingesting an unknown substance that he ‘bought online’. He appears to be anxious and diaphoretic. Initial temperature was 36.5C taken rectally, but on repeat after about 3 hours in the waiting room is 38.9C taken orally. He’s tachycardic now at 125 bpm, RR 35 per minute, 190/60 mmHg.  He is noted to be increasingly agitated and perseverating over his medical crisis and being in the emergency department.  After speaking with a friend, you realize that the patient has been extremely concerned about his weight.  This raises your suspicion that the patient is actually experiencing an agitated delirium from acute intoxication of a very dangerous xenobiotic.

Learning Point 1: Weight Loss miracle

  • 2,4-Dinitrophenol is the culprit in this case; a substance that has quite the history of uses
  • Used in the manufacture of munitions in World War I
  • Used as a dye, wood preserver, herbicide, photo developer
  • Discovered in 1933 that it could lead to weight loss
  • Anecdotally prescribed to Russians in World War II for warmth
  • 1981, marketed as ‘Mitcal’ for weight loss 

Mechanism of Action

  • Oxidative phosphorylation uncoupler by interfering with final energy pathway of uptake of inorganic phosphate molecules into mitochondria
  • Picks up protons, diffuses across inner mitochondrial membrane, deprotonates, returns to pickup up more protons, messes pH gradient and electrochemical potential required for ATP generation
  • Also acts as ionophore, exporting protons needed for ATP
  • Only way to dissipate normally created proton gradient is via ATP synthase that phosphorylates ADP -> ATP
  • Electron transport from NADH to O2 can increase, but energy produced usually as ATP released thermogenically
  • Stimulates glycolysis, leading to increased lactic acid
  • Leads to accumulation of K+ and phosphate (as it is no longer absorbed into mitochondria)

Click to access tp64.pdf

Learning Point 2: 2,4-dinitrophenol’s characteristics 

•   Absorption – oral, inhalation, dermal

•   Distribution – Eyes, serum, liver/kidneys (not as significant)

•   Not significantly studied

•   Metabolism – rat: 60%kidney, 59%spleen, 47%fat, 29%heart, 16%muscle, 3%brain

•   Rabbit: 41%kidney, 3%heart

Not studied in humans; but inferences can be made

•   Elimination – Urine; metabolite as 2-amino-4-nitrophenol

Learning Point 3: Toxicity

  • Signs/Symptoms of acute toxicity
    • Hyperthermia
    • Tachycardia 
    • Shock / hypotension 
    • Changes in mental status, confusion, encephalopathy
    • Cardiac dysrhythmias, potentially leading to pulseless electrical activity 
  • Average time of death is somewhere around 14 hours following ingestion if untreated particularly with concern of untreated hyperthermia
  • Other possible manifestations of toxicity
    • Rhabdomyolysis
    • Convulsions
    • Coma
    • Gastroenteritis leading to anorexia and acute renal failure
    • Peripheral neuritis
    • Agranulocytosis and neutropenia
    • Cataract formation 

The case continued…

Upon realizing the toxic ingestion, you treated your patient with active cooling, benzodiazepines and intravenous crystalloid.  The patient is still tachycardic, but his body temperature has normalized to 37C and has remained stable. Labs are remarkable only for elevated creatinine kinase which is being treated with intravenous fluid resuscitation. Otherwise, the patient has no acute or worsening changes. He is admitted to the general medical floor with the toxicology service consulted.

Learning Point 4: Management

  • If asymptomatic: observe for at least 12 hours – trend temperature, cardiac monitoring
  • May consider activated charcoal if ingested recently enough and meets criteria without any contraindications
  • There is no current evidence for the use of whole bowel irrigation
  • External decontamination only if skin exposure
  • AVOID SALICYLATES to prevent worsening hyperthermia from uncoupling of oxidative phosphorylation 
  • Aggressive fluid resuscitation; cooled fluids for hyperthermiaBenzodiazepines for seizures and agitation; may also be beneficial in correcting hyperthermia through muscle relaxation
  • Dantrolene is likely not useful and has limited evidence
  • Benzodiazepines for seizures and agitation; may also be beneficial in correcting hyperthermia through muscle relaxation
  • Active external cooling (Arctic Sun, cooling blankets, etc)
  • Possible intubation for airway protection

The Case Concluded…

After active cooling, resuscitation and supportive care, the patient did well and recovered. He was able to be discharged home with strict instructions to avoid ingesting any further weight loss supplements.

References

Grundlingh, J., Dargan, P., El-Zanfaly, M. and Wood, D., 2022. 2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death.

Holborow, A., Purnell, R. and Wong, J., 2022. Beware the yellow slimming pill: fatal 2,4-dinitrophenol overdose.

Tcichemicals.com. 2022. 2,4-Dinitrophenol 51-28-5 | TCI AMERICA. [online] Available at: <https://www.tcichemicals.com/US/en/p/D0109&gt;

2,4-dinitrophenol. 2,4-Dinitrophenol – an overview | ScienceDirect Topics. https://www.sciencedirect.com/topics/neuroscience/2-4-dinitrophenol.&nbsp;

Epa.gov. 2022. [online] Available at: <https://www.epa.gov/sites/default/files/2016-09/documents/2-4-dinitrophenol.pdf>&nbsp;

Atsdr.cdc.gov. 2022. [online] Available at: <https://www.atsdr.cdc.gov/ToxProfiles/tp64.pdf>&nbsp;

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