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2 4 - 0 9 - 2 0 0 5 Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a "dietary supplement"
Hsiao AL, Santucci KA, Seo-Mayer P, Mariappan MR, Hodsdon ME, Banasiak KJ, Baum CR.
CASE PRESENTATION A 17-yr-old female presented to the Pediatric Emergency Department (PED) after ingestion of an unknown substance. The patient reported that she ingested 12–15 'diet pills' in a suicide attempt just over 4 h prior to arrival. She denied any other ingestion, but recalled vomiting three to four times and observed yellow granules in the emesis. After she became diaphoretic and jittery she contacted her mother who immediately called emergency medical services. During preparation for transfer to the emergency department, the paramedics retrieved a clear plastic Ziploc bag, labeled '60 DNP' in black marker, containing 27 unmarked clear capsules filled with yellow powder. Upon arrival to the emergency department, the patient's vital signs included a tympanic temperature of 37.1 C, heart rate of 150 beats/min, respiratory rate of 42 breaths per minute, and blood pressure of 142/48mm Hg. Her oxygen saturation was 98% in room air and Glasgow Coma Scale was 15. Her estimated weight was 75 kg. She was flushed and diaphoretic. There were no signs of trauma. She was agitated and unable to find a comfortable position on the stretcher. Her pupils were reactive bilaterally and extra-ocular movements intact. She had mild erythema of the oropharynx, but no evidence of caustic injury. Her neck was supple. Cardiac examination was notable for tachycardia and a regular rhythm. Her lungs were clear to auscultation bilaterally. The words Don't Cut Me Open' were written across her abdomen in lipstick. Her abdomen was soft and nontender. Initial laboratory results included complete blood count, electrolytes, calcium, magnesium, hepatic transaminases, and amylase/lipase. All laboratory values were within established laboratory normal ranges except for a white cell count of 15,100 cells/mm3 and serum glucose of 181 mg/dL. A plasma toxicology screen was negative for alcohols (ethanol, methanol, isopropyl), tricyclic antidepressants, acetaminophen, salicylates, and barbiturates. Methemoglobin was measured at 0.7%, within normal limits. An electrocardiogram revealed sinus tachycardia at 150 beats/min, abnormal ventricular depolarization (but without ventricular ectopy), and a QTc of 500–569. A chest radiograph revealed a normal mediastinum, without any signs of pulmonary edema or infiltrate. The patient's mother informed the staff that her daughter had a history of depression, for which she had been prescribed bupropion. The child was under the care of a local university health service and had previously been under the care of a psychiatrist. She was unaware that her daughter had purchased any diet medication. MANAGEMENT Based on the child's presenting symptoms and physical examination, it was suspected that 'DNP' was likely an abbreviation for dinitrophenol, a dietary weight loss supplement. Intravenous access was established in both antecubital fossae, and multiple normal saline boluses totaling 4.9 L were administered. She was given 1 g/kg of activated charcoal by mouth that she vomited approximately 1 h later. A Foley catheter was placed, revealing orange-colored urine, and a sample was sent for analysis. Over the next few hours, the patient became febrile to 39.7C. Measures to lower her body temperature including tepid water compresses, increasing the flow rate of the room air conditioning, and administration of acetaminophen and ibuprofen lowered her body temperature only to 39.2C. A cooling blanket was obtained and placed on the patient. She was given dextrose 5% normal saline (D5NS) at twice the maintenance fluid rate based on weight to replace insensible fluid loss from fever. She became increasingly agitated and then incoherent and combative, and began to complain of severe leg cramps. She begged repeatedly for water. Multiple doses of lorazepam were given intravenously to control her agitation. The patient was then transferred to the pediatric intensive care unit (PICU). On arrival in the PICU, her rectal temperature was 40.0C, heart rate was 144 bpm, and respiratory rate 48 bpm. She remained combative and was unable to follow simple commands. Oxygen was administered at 3 L/min via nasal cannula, and intravenous hydration with D5NS was continued. Tepid soaks were applied to her skin and she was placed under electrical fans to enhance evaporative cooling. During the hour following admission to the PICU, the patient's body temperature rose 4C and she had a diminution in mental status, responding minimally to painful stimuli. Because of the uncontrolled fever, options for management were discussed with the hospital toxicologist, who consulted with colleagues at the Connecticut State Poison Control Center. The recommendations were to start either a continuous barbiturate or a benzodiazepine infusion in an attempt to lower the patient's basal metabolic rate. The patient was endotracheally intubated for airway protection following administration of midazolam and vecuronium. Approximately 5 min after intubation, the patient developed ventricular tachycardia, which progressed rapidly to asystole. She was given multiple doses of 1:10,000 epinephrine, atropine, calcium chloride, and bicarbonate. Defibrillation and transvenous cardiac pacing were also attempted. A bedside electrolyte test (iSTAT, East Windsor, NJ) revealed a serum sodium concentration of 160 mEq/L and potassium concentration greater than 9 mEq/L. Despite these resuscitative efforts over the course of 1 h, the patient did not have return of spontaneous heart rate or blood pressure. She was pronounced dead 5 h and 46 min after her arrival in the ED and approximately 10 h after her ingestion of the DNP. POSTMORTEM EVALUATION Autopsy by the State Chief Medical Examiner revealed yellow staining of the patient's skin and internal organs, and evidence of profound pulmonary edema. Of note, the liver was noted to have a widespread 'dendritic pattern of pale spots consistent with ischemic necrosis.' Blood analyzed by the medical examiner revealed the presence of dinitrophenol, bupropion, and caffeine (amounts not quantified) as well as small amounts of ibuprofen and acetaminophen. No other toxins were noted in her blood or tissue samples. The DNP capsules and samples of her blood were also sent to the Yale University Department of Laboratory Medicine for analysis. Two of the authors (MRM, MEH) were able to quantify the amount of DNP in her blood and in a sample capsule using ultraviolet-visible spectrophotometry based on previously described methods. The absorbance of a capsule sample at 360 nm was compared with standards prepared from commercially available DNP (SIGMA, St. Louis, MO) dissolved in 10 N NaOH, and serially diluted to final concentration of 0, 5, 10, 20 mg/mL using a Lambda 900 ultraviolet-visible spectrophotometer (Perkin-Elmer, Boston, MA). Twenty-three milligrams of the capsule contents were dissolved in 10 N NaOH and serially diluted to concentrations of 2.6, 5.3, 11, 21, and 42 mg/mL. The concentration of DNP in the samples was determined from a plot of concentration vs. absorbance generated from the DNP standards (Beer's law). From these measurements, the net content of DNP in the capsule was calculated to be 192 mg, close to 200 mg, as indicated on the otherwise plain capsule cover. The nature of any filler material, if present, was unknown. In order to accurately determine the concentration of DNP in the patient's serum, the standards were prepared in 10 N NaOH dissolved in pooled serum (Scantibodies Laboratory, Santee, CA) because serum per se has a nonspecific absorbance spectrum between 200 nm–600 nm. Absorbance measurements for samples and standards were obtained also at 360 nm. The calculated concentration of DNP in the patient's serum was 315 mg/mL. DISCUSSION The case described in this report, the third reported pediatric fatality, underscores 1) the profound risks associated with the use of DNP and other 'supplements' to promote weight loss and 2) the growing popularity and ease of access of DNP and weight loss supplements to the general public. Dinitrophenol toxic effects are directly linked to the uncoupling of oxidative phosphorylation in the mitochrondia. Energy is released from oxidation as heat, rather than in the high-energy phosphate bonds of adenosine triphosphate. This 'uncontrolled thermogenesis' leads to hyperthermia and systemic responses to elevated body temperature, including tachypnea, tachycardia, and diaphoresis. Patients may also experience headache, emesis, and seizures. Hepatic and renal failure likely result from direct tissue injury secondary to hyperthermia and cardiovascular compromise. Coma and death may ensue but reported deaths from DNP are rare, especially in children. Symptoms of chronic DNP exposure are similar to those of acute ingestion, but weakness, weight loss, and night sweats may also occur. Local exposure may cause irritation of the skin, eyes, and upper respiratory tract. DNP’s high potential for toxicity stems from its narrow 'therapeutic index.' Studies have shown that acute administration of only 20–50 mg/kg is lethal in humans, while at the same time DNP is easily accumulated in the body owing to its long half-life of 5–14 days. Proponents of DNP routinely advise users to take 5–8 mg/kg daily, despite the long half-life. It is alarming that despite its recognized danger and ban by the U.S. Food and Drug Administration (FDA), it is still widely recommended on the Internet for weight loss at doses only onethird that which is potentially lethal. Another concerning fact is that the ambient temperature at which DNP is administered may have a profound effect on its toxicity. Experiments on mice revealed the LD50 dropped from 35 mg/kg at room temperature to less than 5 mg/kg when the environmental temperature rose above 39C. This is an especially sobering fact if DNP becomes popular with athletes who use increased ambient temperatures for rapid weight loss, such as wrestlers. There is a report of a death by a wrestler using dinitrophenol, but no details are given [Vet Hum Toxicol. 1986 Dec;28(6):574-5.]. By our patient's report, she was calculated to have ingested a total DNP dose of approximately 33 mg/kg, presumably at room temperature. Management of DNP toxicity is limited as there is no specific antidote, and its wide volume of distribution and primarily intracellular mechanisms of action do not make it amenable to therapies such as dialysis or hemoperfusion. Therefore, the mainstays of therapy for DNP poisoning remain supportive. The basic principles of management include 1) control of fever with antipyretics and other measures to enhance body heat loss, 2) maintenance of airway for respiratory compromise, 3) restoration and support of peripheral perfusion including replacement of insensible fluid losses from fever and diaphoresis, and 4) treatment of complications (seizures, hypotension, and methemoglobinemia). Salicylates and anticholinergic agents may worsen hyperthermia, while sedation and paralysis ineffectively mitigates heat generated on a cellular level. There exists very little literature on how to successfully control the hyperthermic complications in DNP poisoning. It is certainly possible that more aggressive means of cooling, such as peritoneal dialysis, continuous veno-venous hemofiltration, and cardiopulmonary bypass might be helpful; however, the most aggressive method of cooling documented only include ice baths and cooling blankets. Another potential treatment strategy is to reduce the metabolic rate of a patient, as was attempted in this case, as a means of attempting to lower her temperature. The use of DNP for weight loss is representative of a growing trend in the United States. Approximately 2–4% of Americans use diet pills and an additional 7–10% ingest nutritional supplements to promote weight loss. However, the potential for misuse and abuse is great because most weight loss agents, including DNP, are sold without prescription or are prescribed for unlabeled indications despite FDA regulations and restrictions. DNP was first used as a component of the explosive trinitrotoluene (TNT) and is currently used as an agricultural insecticide and as a component of fabric and food dyes, such as Saffron Substitute1 and Martius Yellow. Dinitrophenol was first used as a diet agent in the 1930s during clinical studies by Cutting et al., whom demonstrated that DNP was able to induce significant weight loss, leading to its use as a diet aid. Its popularity stemmed from the fact that people were able to lose weight without exercise or limiting caloric intake; even today that remains the holy grail of diet agents. By 1934, an estimated 100,000 patients had been prescribed 1,200,000 capsules of DNP. Severe side effects and deaths attributable to DNP were soon recognized; many case reports were published in JAMA. Unfortunately, authorities were powerless to ban the sale of DNP until 1938, when the new Food, Drug, and Cosmetic Act was passed. Today, 70 yrs later, the popularity of DNP as weight loss aid is apparently on the rise again, if the numerous DNP websites advertising DNP are any reflection. Entering 'DNP' on any number of popular search engines reveals dozen of links to web pages extolling the weight loss benefits of DNP. One such web site selling dinitrophenol even purports that Hitler used DNP in concentration camps to keep prisoners warm, as a testimony to its potency. The parents of the patient in this report discovered an empty mail-order envelope sent from a business that sells DNP, among other weight loss agents, in their daughter's room. An order could be placed, apparently without proof of age, by leaving a message on a telephone answering machine. Such easy accessibility of DNP to minors such as our patient, especially with the advent and aid of the Internet, is alarming. Children are likely especially vulnerable to Internet-based marketing, which often is unregulated and aggressive; minors may lack the maturity and cognitive abilities to fully consider the claims of such marketing. FOLLOW-UP The mail-order package in which the DNP was shipped led authorities to two individuals. Both were ultimately arrested and prosecuted for 'conspiracy to introduce into interstate commerce a drug that is misbranded with the intent to defraud or mislead.' In this case, DNP met the definition of a drug by federal statutes: 18 USC 371, 21 USC 331, and 333 as it was sold as a weight loss aid and packaged for use by individuals. The two suspects have since pled guilty and are awaiting sentencing (personal communication, Special Agent Thomas E Dougherty, U.S. Food and Drug Administration Office of Criminal Investigations). |
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[Definitie:] "An ergogenic aid is any substance or phenomenon that enhances performance."
(Wilmore and Costill) 
