The Tox Cave
The Tox Cave will dissect interesting ED cases from the perspective of a toxicologist, focusing on applying up-to-date management of the poisoned patient. The name Tox Cave was coined by a former toxicology fellow to describe our small office space, likening it to the Bat Cave. The Tox Cave is where Drexel toxicology fellows and attendings have gathered to discuss the nuances of toxicology over the years.

Tuesday, August 1, 2017

A 14-year-old boy with no past medical history was brought to the ED in some distress by his parents. One hour earlier while looking for his baseball glove in the garage he had felt a small pinprick just above his right ankle. The patient, however, became increasingly uncomfortable and began complaining of diffuse abdominal pain.

His initial vital signs were a temperature of 97°F, heart rate of 112 bpm, blood pressure of 151/91 mm Hg, and 98% pulse oximetry on room air. He appeared uncomfortable, was diaphoretic, and had a rigid abdomen. A small puncture wound with some mild erythema to the lateral right ankle was noted.

Poisonous Spiders in the United States

-The black widow (Latrodectus spider) is the most commonly reported spider envenomation in the United States, and is involved in more than 2,500 calls to poison control centers annually. (Perm J 2011;15[3]:76.) The 8-10 mm females are identified as being shiny and black with a ventral red hourglass on their belly. Males may be smaller with a white and gray marking and a less prominent hourglass. There are five Latrodectus spiders in the country, with Latrodectus mactans and variolus (predominantly in the southern and eastern states) being the two main ones.

-The brown recluse spider or the Fiddleback spider contains a violin-shaped marking on its cephalothorax. Bites are uncommon and likely overdiagnosed. When bites occur, a dermonecrotic lesion can develop over hours and progress over weeks. They are mainly found in the central Midwestern states in the United States.

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Black Widow Spiders' Toxicity

Latrodectus venom is one of the most potent poisons by volume. It contains five neurotoxins, the primary one affecting humans being alpha-latrotoxin. The venom acts at the neuromuscular junction by binding to glycoproteins and causing a large release of acetylcholine and norepinephrine at the presynaptic terminal, while simultaneously inhibiting the reuptake of choline.

The primary feature of envenomation is pain, particularly in the abdomen or back. (Ann Emerg Med 1992;21[7]:782.) Severe muscle cramping and pain are commonly seen in a waxing/waning-type picture. Neuromuscular symptoms include cramping, rigidity, priapism, ptosis, fasciculations, and tremors. Cardiopulmonary symptoms include hypertension and tachycardia. Other systemic symptoms include nausea, vomiting, and diaphoresis, which may be localized to the extremities that are bitten but also frequently on the forehead. Latrodectus facies may also occur, which presents with periorbital swelling, facial muscle spasms, lacrimation, and photophobia.

Diagnosis is aided with visual identification of the spider. The site of the spider bite may be unremarkable with a tiny punctum and slightly erythematous and indurated surrounding skin. No routine diagnostic lab testing is necessary, but workup of alternative diagnosis should be considered. Wound care includes tetanus prophylaxis. The primary component of management is pain control. Pain may be managed with cold packs, NSAIDs, opioids, and benzodiazepines. (Ann Emerg Med 2014;64[6]:620.) Use of IV calcium gluconate has been described, but studies show little benefit.

A Latrodectus antivenin exists in the United States, and is equine-derived. Adverse events include anaphylactoid reaction and serum sickness. One report in the literature describes a fatality due to an anaphylactoid reaction from the antivenin, and antivenin should only be administered in the most severe cases. (Dosing below.) The antivenin is a category C drug, and has safely been given in pregnancy. Patients should be monitored for at least six to eight hours, and follow-up seven to 12 days after the antivenin is given is important as serum sickness can occur within this time frame. Hospitalization may be considered for patients with moderate to severe symptoms and hypertension. Pain symptoms may last for days.

Dosing:

-Dilute one to two vials in 50-100 ml 5% dextrose and infuse over one hour.

-Patients may be pretreated with diphenhydramine and steroids to blunt any hypersensitivity reaction.

-Multiple allergies, asthma, or previous reactions to equine-based products should be considered a contraindication.

The patient in our case was treated symptomatically with Toradol and diazepam IV. He was monitored closely for six hours. His symptoms improved, and he did not require antivenin. A repeat examination of his abdomen was noted to be soft and nontender.​


Monday, July 3, 2017

A 35-year-old man with a history of asthma presented with an exposure after spraying his garage with an insecticide he bought at the hardware store. Shortly after spraying the insecticide, he noticed eye itchiness, tingling, pruritus over his arms and legs, and shortness of breath. His blood pressure was 130/85 mm Hg, heart rate 70 bpm, respiratory rate 14 bpm, temperature 98.7°F, and SpO2 96% on room air.

He was alert and anxious, his skin was warm with mild erythema, and he had urticaria over his forearms and ankles. His lung exam revealed diffuse wheezing bilaterally. His eyes were watery, and his pupils were 4 mm and reactive bilaterally. The remainder of his exam was unremarkable.

Potential Insecticides

-Carbamates and organophosphates may be found in products used in households, gardens, and farms. They are also found in powders, sprays, and shampoos targeting fleas and ticks in animals.

-Organochlorines including hexachlorocyclohexane (Lindane) are historically used in products such as DDT, chlordane, aldrin, and toxaphene that are now generally banned in most countries.

-Pyrethrins and pyrethroids include cypermethrin, imiprothrin, and tetramethrin that can be found in household Raid products. Permethrin is also in this class, and is used in Nix and Elimite to kill head lice and scabies.

-Boric acid is found in ant and roach killers.

-Pet-related products used as topical insecticides to kill fleas on cats and dogs include neonicotinoid imidacloprid (Advantage), GABA receptor antagonist fipronil (Frontline), GABA-releasing agents avermectin and ivermectin (Revolution), and selamectin (Revolution).

Toxicities of Insecticides

Carbamates and organophosphates inhibit acetylcholinesterase. Toxicity is manifested as muscarinic signs (SLUDGE, bradycardia, miosis) and nicotinic signs (muscle fasciculations, tremors, weakness).

Organochlorines are absorbed by the skin due to their lipophilic properties. They may cause CNS stimulation and seizures. Mechanisms of toxicity for the different classes of organochlorines include sodium channel opening and GABA antagonism.

Pyrethrins/pyrethroids are derived from chrysanthemums and typically have low toxicity in humans. Toxicity in insects is attributed to its sodium channel-opening properties. Pyrethrins may cause allergic reactions in humans. Pyrethroid type I "T" syndrome includes tremors, and a pyrethroid type II "CS" syndrome includes choreoathetosis, salivation, paresthesias, nausea, vomiting, diarrhea, pulmonary symptoms, and neuroexcitation. Additional toxicity from exposure to pyrethroid-containing products may be from other ingredients such as solvents and surfactants. Boric acid is associated with blue-green emesis and a "boiled lobster" rash.

Management of Pyrethrin/Pyrethroid Insecticide Exposure

Identification of ingredients can be found by looking at the available Safety Data Sheets (SDSs) or Material Safety Data Sheet (MSDS). Removal from the source of exposure and dermal decontamination should be initiated.

Patients with an anaphylactic should be treated like patients with any other anaphylactic reaction, using diphenhydramine, antihistamines, epinephrine, and intubation as required. Treat asthma exacerbations or wheezing with nebulized beta agonists and steroids. Decontaminate any areas that have been exposed to the insecticide using copious amounts of water. Vitamin E has been used to treat paresthesias anecdotally. Irrigate the eyes and do a fluorescein check to evaluate for any corneal involvement. Refer to an ophthalmologist for corneal injury.​

The patient had been using a pyrethroid-based insecticide. He was monitored and given Benadryl, prednisone, and nebulized albuterol. His skin and eyes were copiously irrigated. His eyes had no evidence of corneal injury on Wood's lamp examination, and improved after irrigation. He was monitored for six hours in the emergency department, and his symptoms resolved. He was discharged and advised to open the garage to allow any residual insecticide to dissipate.

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Thursday, June 1, 2017

The Syrian government recently used what is believed to be sarin on civilians, killing 80 people and injuring many more. (CNN. April 20, 2017; http://cnn.it/2oXX47G.) The use of a nerve agent was confirmed by the Turkish government after examining several bodies during autopsy.

Sarin was first developed by the Germans as a pesticide in 1938, and is one of the G-series nerve agents that includes tabun, soman, and cyclosarin. Sarin was also used in a terrorist attack in the Tokyo subway in 1995, killing 12 people. (TIME. March 20, 2015; http://ti.me/2oY3F1Y.) Sarin is an organophosphorus compound similar to what is found in older insecticides, but it is much more potent.

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Mechanism of Organophosphate (OP) Toxicity

Organophosphates inhibit cholinesterase, which results in the accumulation of acetylcholine and causes nicotinic and muscarinic effects. These receptors can be found in the autonomic nervous system, central nervous system, and neuromuscular junctions.

Signs and Symptoms of OP Toxicity

The classic symptoms are unresponsiveness, pinpoint pupils, muscle fasciculations, diaphoresis, emesis, diarrhea, salivation, and lacrimation. Seizures may occur. The most serious symptoms are bronchorrhea and bronchoconstriction, which were seen on videos taken during the attacks in Syria.

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Treatment for Acute OP Toxicity

Airway management is first and foremost the response, whether with simple airway maneuvers or intubation in severe cases. Many of these patients will have significant pulmonary edema and essentially drown in their own fluids. Treatment of organophosphates is unique compared with other insecticides such as carbamates in that these chemicals undergo a process called "aging." If the organophosphate is allowed to age, then the acetylcholinesterase can no longer be reactivated. To halt this process, pralidoxime chloride is used to regenerate the cholinesterase activity. This is concomitant with the use of atropine to dry respiratory secretions and clear airway sounds. Diazepam should also be administered for seizures.​

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Pralidoxime chloride should be given 2 g over 20 to 30 minutes and followed by infusion of 0.5-1 g/hr in normal saline. Continue the infusion until atropine has not been needed for 12-24 hours.

Atropine should be given 1-3 mg bolus depending on severity, with total doses of 10-20 mg within the first several hours. Administer double the original bolus dose if no improvement is seen after five minutes. Continue to reassess every five minutes and double the dose if there is no response. After the patient is stable, start an infusion to give about 10-20 percent of the total dose needed for improvement hourly.

Delayed Complications of OP Toxicity

Intermediate syndrome may occur 24 to 96 hours after acute OP poisoning. Patients may develop proximal muscle weakness, specifically affecting the neck flexors which may progress to respiratory failure that can persist for several weeks. To identify this syndrome, assess a conscious patient's neck strength by asking him to lift his head off the bed while you apply pressure to his forehead. Any signs of weakness show that the patient is at risk of developing this syndrome.

Organic phosphorus compound-induced delayed neuropathy may also occur. It is characterized by peripheral neuropathies that can occur days to weeks following acute exposures. Patients with this complication complain of vague distal muscle weakness and pain.​


Monday, May 1, 2017

Poison has been used for many purposes since humans have existed, often for assassination or assassination attempts. Some of those make the news, the most recent being the assassination of Kim Jong-nam, the half-brother of North Korean leader Kim Jong-un.

Authorities identified the nerve agent VX on his face, and video corroborated two women wiping a substance on his face before his collapse and death. VX is the most potent nerve agent, and was developed in the United States in the 1950s during the Cold War. It is an acetylcholinesterase inhibitor, and exerts its effects like organophosphate insecticides. Victims develop severe respiratory secretions, bronchospasm, muscle fasciculations, and seizures, and they can die from respiratory paralysis. The lethal dose is 30 mcg. A drop approximately the size of Abraham Lincoln's eye on a penny is enough to kill a human.

Alexander Litvinenko became the first known victim in November 2006 of polonium-210-induced acute radiation syndrome. Mr. Litvinenko, a former officer of the Russian Federal Security Service, had fled the country after accusing his superiors of ordering the assassination of Boris Berezovsky, a vocal critic of Vladimir Putin. He suddenly became ill with several days of diarrhea and vomiting, and his condition worsened for several weeks. His blood and urine samples were sent to the UK Atomic Weapons Establishment where polonium-210 was detected. It was determined that the Po-210 had been placed in his tea. The median lethal dose of polonium is 50 ng, and those poisoned experience four stages of the syndrome: prodromal stage (nausea, vomiting, diarrhea), latent stage; manifest illness (fever, anorexia, malaise, convulsions, coma); and recovery or death.

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Alexander Litvinenko before his death. (Photo by José Repetto.)

Viktor Yushchenko was a Ukrainian presidential candidate in 2004 when he became ill and developed severely pockmarked and scarred skin, which is termed chloracne, a typical effect of dioxin exposure. Doctors found a large amount of 2,3,7,8 tetrachlorodibenzodioxin (TCDD), a potent dioxin, in his bloodstream. TCDD is the same contaminate that was found in Agent Orange during the Vietnam War. Dioxins are the byproduct of the manufacturing process of chlorine herbicides. Despite the assassination attempt, he recovered and went on to win the presidency.

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Viktor Yushchenko after the assassination attempt. (Photo by Muumi.)

A botched assassination attempt on the life of Khaled Mashaal, a Palestinian political leader, occurred in 1997 when two Israeli operatives sprayed a substance into his ear. The operatives were captured, and King Hussein of Jordan threatened to hang them unless Israel gave them the antidote. Israel was also forced to free Palestinian prisoners to secure the return of their people. It is believed the substance was a fentanyl analog.

The 1978 assassination of Georgi Markov, a Bulgarian journalist who was an outspoken critic of the Bulgarian communist regime, was one of the most high profile of the Cold War. Mr. Markov was waiting for a bus at the Waterloo Bridge in London when he was stabbed in the thigh with a poisoned umbrella tip. He died four days later. After his death, it was discovered that the umbrella was used to inject a pinhead-sized dose of ricin into his thigh. Ricin is a naturally occurring poison found in castor beans. It inhibits protein synthesis likely by inhibiting the 60S ribosomal subunit. The symptoms of poisoning depend on the route of exposure and dose. If ingested, vomiting and diarrhea occur and become bloody. This is followed by dehydration and hypotension and eventually to multisystem organ failure. There is no known antidote.

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Device used inside umbrella to inject ricin into Georgi Markov. (Photo by D. O'Neil.)

Intentional poisonings represent a small fraction of all homicide deaths. Other notable poisons include arsenic, thallium, and cyanide. Homicides in which drugs were used also involved rocuronium, succinylcholine, digoxin, potassium chloride, and heroin.


Friday, March 31, 2017

A 22-year-old woman with no past medical history presented to the emergency department with palpitations. She reported that she had ingested a handful of caffeine tablets with a large glass of wine two hours earlier. She reported feeling "stressed out" and wanting to hurt herself. The patient was alert but appeared anxious on arrival at the ED.

Her blood pressure was 90/49 mm Hg, heart rate was 115 beats/min, respiratory rate was 20 breaths/min, and SPO2 was 100% on room air. An ECG showed sinus tachycardia at 120 beats/min with normal intervals. Shortly after arrival, her blood pressure dropped to 83/42 mm Hg, and she appeared drowsy.

Comparing Caffeinated Products

Type of Coffee                         Size                      Caffeine

Brewed                                    8 oz. (237 mL)        95-200 mg

Brewed, decaffeinated           8 oz. (237 mL)        2-12 mg

Brewed, single-serve              8 oz. (237 mL)        75-150 mg

Brewed, single-serve,             8 oz. (237 mL)        2-4 mg

  decaffeinated

Espresso, restaurant-style     1 oz. (30 mL)           47-75 mg

Espresso, restaurant-style     1 oz. (30 mL)          0-15 mg

  Decaffeinated

Instant                                    8 oz. (237 mL)        27-173 mg

Instant, decaffeinated            8 oz. (237 mL)        2-12 mg

Specialty drink (latte              8 oz. (237 mL)        63-175 mg

  or mocha)

Adapted from Journal of Food Science, 2010; Pediatrics, 2011; USDA National Nutrient Database for Standard Reference, Release 26; Journal of Analytical Toxicology, 2006; Starbucks, 2014; Food and Chemical Toxicology, 2014; Keurig, 2014.

Over-the-counter caffeine tablets are available as 100 mg and 200 mg doses. There are also powdered caffeine products that may contain up to 100 percent caffeine, and a teaspoon may be equal to drinking 25-28 cups of coffee. A single tablet of Fioricet contains 40 mg of caffeine.

Toxic Doses

Acute caffeine toxicity is dose-dependent. Plasma concentrations over30 mg/L are associated with symptoms of toxicity. Serum levels above 80 mg/L and doses around 150-200 mg/kg are associated with death.

Mechanisms of Caffeine Toxicity

Toxicity may affect multiple organ systems. Caffeine is nearly 100 percent bioavailable, and peak concentrations occur within 30-60 minutes following oral ingestion. Caffeine exerts its toxicity via adenosine antagonism and stimulating the release of catecholamines, and it is a phosphodiesterase inhibitor.

Gastrointestinal symptoms typically include nausea and vomiting. Sinus tachycardia is typically seen in caffeine-toxic patients. Tachydysrhythmias and hypotension may also occur in these patients. Hypokalemia seen in caffeine toxicity due to beta-adrenergic agonism causes the shift of potassium intracellularly. Pulmonary toxicity includes hyperventilation, respiratory alkalosis, and acute lung injury. Neurotoxicity may manifest as tremors, anxiety, agitation, delirium, and seizures. Patients may also be hyperthermic from increased metabolic activity and muscle hyperactivity.

Managing Caffeine Toxicity

Diagnostic testing may include an ECG, serum electrolytes, and creatinine kinase. Caffeine levels are likely not readily available in the acute setting. Most caffeine overdoses can be managed with supportive care, and cardiac monitoring should be initiated to evaluate for dysrhythmias and hypotension. Gastrointestinal decontamination with activated charcoal may be considered if administered early, but symptoms of vomiting and altered mental status as well as the risk of seizures may preclude its use.

There is no antidote for caffeine toxicity. Benzodiazepines may be administered for agitation and seizures. IV fluids should be administered for hypotension. Phenylephrine or norepinephrine should be considered. Beta1-selective beta antagonists such as esmolol may also be considered to treat refractory hypotension to target the beta-adrenergic mediated vasodilation and tachycardia. Hemodialysis may also be considered in patients who have ingested massive amounts of caffeine and have persistent signs of severe toxicity (seizures, dysrhythmias, hypotension) despite these measures.

The patient in this case received IV normal saline boluses, and her blood pressure improved. She was monitored in the emergency department and remained hemodynamically stable. Psychiatry was consulted and admitted her to their service.​