The Case

A 22-year-old male arrived in the emergency department at 12:36 a.m., accompanied by his mother. His chief complaint was palpitations and sweating for three hours. He told the triage nurse he was taking “DNP, the fat-burning pill.” He had been taking the medication for two weeks and reported taking a “double dose” that evening. Later, he noted palpitations and excessive sweating. Triage vital signs included a pulse of 152, blood pressure of 134/77, oxygen saturation of 99 percent, and temperature of 37.1°C (98.7°F). His weight was 104.8 kg. An ECG showed sinus tachycardia. The patient was put in a treatment room at 12:58 a.m. Initial physical examination was remarkable for an otherwise healthy young man who was diaphoretic and tachycardic and appeared moderately agitated. Laboratory studies, IV fluids, urine toxicology, and a portable chest X-ray were ordered after examination. IV lorazepam was given for agitation. The heart rate did not change despite IV fluids and lorazepam. It was noted by his nurse that it was difficult to keep the cardiac monitor leads on because of profuse sweating.

The patient’s nurse learned that he took 1,000 mg of 2,4-Dinitrophenol (DNP) at about 9 p.m. A rapid review of literature done by the physician revealed deaths from hyperthermia from DNP due to decoupling of oxidative phosphorylation. The search also revealed that a typical dose is 200–400 mg. At 2:58 a.m., the physician asked for consultation with poison control and a recheck of temperature, which was 39.4°C (103.0°F). Topical cooling measures with ice packs were started immediately, and IV acetaminophen was ordered.

The physician was connected to the toxicologist at the Rocky Mountain Poison and Drug Center and asked if dantrolene and/or beta blockers would be useful. The toxicologist reported that, theoretically, acetaminophen and dantrolene would not help and suggested that paralysis with cooling measures might be necessary. While the physician was on the phone with the toxicologist, the patient deteriorated and was moved to a resuscitation room.

The patient was now having violent rigors and sweating profusely. The emergency department team prepared for rapid sequence intubation (RSI). The patient was given 2 mg of midazolam followed by 10 mg of vecuronium. There was a brief moment of muscle relaxation insufficient for intubation, followed by the patient’s jaw becoming clenched in a closed position. At 3:20 a.m., shortly after vecuronium administration, the patient became asystolic. Chest compressions were started. Asystole had no impact on muscle rigidity. IV placement was confirmed, and an additional 10 mg of vecuronium was given but had no paralytic effect on the patient, who now had whole-body rigidity. The emergency department physician was able to perform nasal intubation blindly with a 6.5 French endotracheal tube, confirmed by breath sounds and capnometer.

The staff hoped the patient would regain a cardiac rhythm by decreasing the core temperature. Aggressive cooling measures were used, including ice and ice water on all exposed skin, ice packs around the neck, IV saline in buckets of ice water, and a cooling blanket. Fans were not available. Despite these cooling measures, at 3:40 a.m., the rectal temperature had increased to 42.1°C (107.8°F). Asystole persisted, and advanced cardiovascular life support measures were continued. Rectal temperatures continued to rise, and at 3:49 a.m. while still covered with ice, the temperature was 42.3°C (108.2°F).

The patient remained in asystole during the entire resuscitation. Near the end of the attempted resuscitation, there was pink frothy fluid coming from the endotracheal tube. At 4:13 a.m., resuscitation efforts were stopped, and the patient was pronounced dead. A postmortem rectal temperature was 42.9°C (109.3°F). The core temperature had continued to rise for almost an hour during attempted resuscitation despite being covered with ice and ice water and infused with IV iced saline.

The Honolulu Police Department and the coroner were contacted. A family member was sent home to retrieve any available medications and returned with a bag, which included caffeine, propranolol, ephedrine with guaifenesin, and n-acetylcysteine (used for weight loss) but no DNP.¹ Family members were not aware of where the patient obtained the drug. The next day the state Department of Health was contacted, which then contacted the US Food and Drug Administration (FDA).

Discussion

Chris Whissen and Shutterstocl.com

DNP is a compound that was first described during World War I. It was initially manufactured to make explosives and has also been used in manufacturing sulfur black dye, pesticides, wood preservatives, and photographic developing chemicals.^2,3 The lethality of DNP was first reported in 1918 after numerous deaths of factory workers in the United States and France were linked to DNP exposure.⁴ DNP was studied at Stanford in the 1930s, during which time it was prescribed for weight loss.⁵ More side effects were identified, including cataracts, liver failure, and agranulocytosis. It was determined to be unfit for human consumption and was banned by the FDA in 1938.⁶

To understand the impact of DNP on heat production, we review the biochemistry of cellular respiration. Glycolysis is a biochemical process that results in the conversion of glucose into two ATP molecules, two NADH molecules, and two pyruvate molecules. The Krebs cycle follows and produces two more ATP, six NADH and H+ molecules, two FADH2 molecules, and the CO2 that we exhale. The final phase is oxidative phosphorylation, where the majority of energy is produced; 34 more ATP are created from ADP. With normal oxidative phosphorylation, ATP synthase converts ADP to ATP by adding an inorganic phosphate molecule. DNP interferes with this process by preventing phosphorous uptake into the mitochondria. DNP also allows hydrogen ions to leak across the mitochondrial membrane, thus bypassing ATP synthase.³ The potential energy that is normally stored during ATP production is released as heat, causing hyperthermia and calorie consumption through further carbohydrate and fat breakdown as cells attempt to create more ATP. This is the characteristic that made it a popular weight loss drug in the 1930s and what continues to make it prevalent today.

DNP causes release of calcium stores from mitochondria and prevents re-uptake; this free intracellular calcium in muscle cells causes unopposed muscle contraction and hyperthermia. The continuous release of calcium following death may also contribute to the rise in body temperature even after cardiopulmonary arrest.³

DNP toxicity most commonly presents as hyperthermia, tachycardia, tachypnea, and diaphoresis.^3,6,7 There have been numerous case reports of overdoses on this drug, with rare survivors but no known survivors of cardiac arrest.⁶ The drug has a narrow therapeutic window for its “desired effects,” and even slight deviations in dosing have been fatal. Case reports document generalized muscular rigidity, making intubation and mechanical ventilation difficult.⁷ 

DNP is typically sold illegally on the internet. Common names include DNP, Dinosan, Dnoc, Solfo Black, Nitrophen, Aldifen, and Chemox. Websites that sell DNP illegally offer advice on its use; a Google search of “buy DNP” yields pages of results. A typical recommended starting dose is 200 mg per day, and if tolerated, it can be increased to 400 mg daily. Some websites warn users about hyperthermia and recommend exercising in air-conditioned environments, lowering the dose for temperatures over 38.9°C (102°F), taking a cold bath, and ensuring adequate hydration.⁸ A vivid description from a patient who took DNP and became hyperthermic can be found on Wikipedia.⁹

Use of the drug for weight loss is making a resurgence. There has been an increasing number of articles describing overdoses resulting in deaths of young body builders and athletes.^6,10 In May 2016, Adam Alden of Bakersfield, California, pled guilty to introducing an unapproved drug into interstate commerce after a customer who purchased DNP via the internet died of DNP ingestion.¹¹ In 2018, a seller of DNP was convicted of manslaughter in the United Kingdom after selling and marketing DNP as a “fat burner” for human use. A March 2020 retrial confirmed the conviction and a seven-year sentence.^12,13

A review of the medical literature shows there are no established recommendations for care. Early aggressive management is often recommended, including cooling, fluid resuscitation, early intubation, and admission to an ICU. Acetaminophen theoretically does not help lower the temperature. Dantrolene has been discussed in case reports as a potential treatment, but its use remains controversial.^14,15 In a case where dantrolene was reported to have been successful in reducing temperature (in addition to cooling measures being applied), the patient had a temperature of 40.0°C. In a case where dantrolene was unsuccessful, the patient’s temperature was 41.5°C.¹⁴ The authors of the latter case state success using dantrolene is biochemically implausible.

Paralysis with intubation should be considered early; however, paralysis may not be possible due to the mechanism of action. DNP affects muscle contraction at the cellular level, whereas paralytic agents impact the neuromuscular junction. Rigidity causing difficult intubations has been reported in numerous case reports. In this patient, blind nasal tracheal intubation was possible and potentially was facilitated by paralysis of the vocal cords in an open position. A surgical airway should also be considered.

Aggressive cooling is likely the best hope for survival. From the authors’ perspective, the impact of DNP at the cellular level is likely to become irreversible at some point where no amount of cooling or pharmacological intervention will result in survival—a “point of no return.” The decoupling of oxidative phosphorylation and the conversion of glucose into heat increase the body temperature, which likely accelerates the rate of reaction, resulting in more heat production, similar to an explosion. Stopping the process before it reaches the point of no return is essential. The question to be answered is how to determine that point of no return. The authors suggest that a core temperature above 38.3°C (101°F) should prompt aggressive treatment, including intubation and aggressive cooling.

Conclusion

DNP is a diet drug that has been banned by the FDA. It has a very narrow therapeutic window, which has resulted in accidental death by hyperthermia of a number of patients, including the young man described in this article. Reversing the hyperthermic effect of DNP is difficult and may be impossible after a certain temperature has been reached. Airway control is compromised by muscle contraction at the cellular level. Death from taking this drug is tragic; those who cared for this patient felt this was a horrific way to die. Efforts to stop distribution of the drug are taking place in some countries and should be increased worldwide.

Dr. Jessa Baker is a fourth-year resident at the University of California, Los Angeles Department of Emergency Medicine.

Dr. Mark Baker is an emergency medicine physician with the Pali Momi Medical Center Department of Emergency Medicine in Aiea, Hawaii.

References

1. Busch S. N-Acetylcysteine for weight loss. Livestrong website. Accessed Oct. 22, 2020.
2. Hamilton A. Industrial poisoning in making coal-tar dyes and dye intermediates. Bulletin of the United States Bureau of Labor Statistics, No. 280. Washington, DC: US Government Printing Office; 1921.
3. Grundlingh J, Dargan PI, El-Zanfaly M, et al. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011;7(3):205-212.
4. Provisional peer reviewed toxicity values for 2,4-dinitrophenol (CASRN 51-28-5). United States Environmental Protection Agency website. Accessed Oct. 22, 2020.
5. Tainter ML, Cutting WC, Stockton AB. Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. Am J Public Health Nations Health. 1934;24(10):1045-1053.
6. Holborow A, Purnell RM, Wong JF. Beware the yellow slimming pill: fatal 2,4-dinitrophenol overdose. BMJ Case Rep. 2016;2016:bcr2016214689.
7. Toxicological profile for dinitrophenols, draft for public comment: chapter 2. health effects. Centers for Disease Control and Prevention website. Accessed Oct. 22, 2020.
8. DNP Guide #2. DNP (Dinitrophenol) Ressource website. Accessed Oct. 22, 2020.
9. Talk:2,4-Diniotrophenol. Wikipedia website. Accessed Oct. 22, 2020.
10. Haynes G. The killer weight loss drug DNP is still claiming young lives. Vice website. Accessed Oct. 22, 2020.
11. FDA targets unlawful internet sales of illegal prescription medicines during International Operation Pangea IX. US Food & Drug Administration website. Accessed Oct. 22, 2020.
12. Barraclough R, Menzies G. Dinitrophenol (‘DNP’) and the death of Eloise Parry. Six Pump Court Chambers website. Accessed Oct. 22, 2020.
13. Eloise Parry death: diet pill seller jailed after retrial. BBC News website. Accessed Oct. 22, 2020.
14. Kopec KT, Kim T, Mowry J, et al. Role of dantrolene in dinitrophenol (DNP) overdose: a continuing question? Am J Emerg Med. 2019;37(6):1216.e1-1216.e2.
15. Van Schoor J, Khanderia E, Thorniley A. Dantrolene is not the answer to 2,4-dinitrophenol poisoning: more heated debate. BMJ Case Rep. 2018;11(1):e225323.