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ACEP Now: Vol 39 – No 12 – December 2020

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.