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.

Wednesday, November 1, 2017

Part 1 in a Four-part Series

A 32-year-old man was taken to the ED by EMS after being found unresponsive in a subway station. His pupils were pinpoint, and he was breathing at fourth breaths per minute. He had a blood pressure of 94/63 mm Hg, pulse oximetry of 91% on room air, and a heart rate of 51 beats per minute. He was given 2 mg of intranasal Narcan by EMS and became more responsive, breathing at 14 breaths per minute with a blood pressure of 125/82 mm Hg, heart rate of 74 bpm, and 98% on room air. He admitted in the ED to using three bags of heroin.​

The opioid epidemic is a national public health crisis in the United States with more than 90 deaths a day due to drug overdose. (http://bit.ly/2zcfM1s.) That is more than the number of deaths per day from motor vehicle crashes. Nearly half of those overdose deaths are due to opioids. More than 64,000 people died in 2016 from overdose, a nearly 20 percent rise from 2015 and nearly quadruple the number of overdose deaths in 2000. (New York Times. June 5, 2017; http://nyti.ms/2whjiJw.)

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There are three main opioid receptors: the mu (mu1 and mu2), kappa, and delta. (National Institute on Drug Abuse. June 30, 2017; http://bit.ly/2zcApdS.) Respiratory depression is mu2-mediated. Euphoria is mediated by the mu-delta receptor agonism and subsequent dopamine release in the mesolimbic system. Kappa agonism can also produce analgesia, but it can also cause dysphoria.​

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The opioid toxidrome consists of miosis, bradycardia, hypotension, hypoventilation, decreased bowel sounds, and constipation. These do not all have to be present or can be present at varying degrees. They may also be only partially present, especially if there are other medications or drugs (legal or illicit) on board.

There are many types of opioids, with three main categories. Naturally occurring opioids include morphine and codeine; synthetic includes meperidine, fentanyl (acetyl-fentanyl, carfentanil, butyrfentanyl, and U47700), and methadone, semi-synthetic ones include hydrocodone, oxycodone, heroin, hydromorphone, Oxymorphone, and buprenorphine.

Another consideration is the potency of the drugs:

 

Medication

 

Route



Time to Effect

 

Duration



Routine Dosage Equivalent
Morphine sulfateIV5-10 min3-6 hours10 mg IV
IM15-30 min3-6 hours10 mg IM
PO30-60 min3-6 hours30-60 mg PO
OxycodonePO10-15 min4-6 hours10-20 mg PO
HydrocodonePO30-60 min4-6 hours15-30 mg PO
FentanylIVImmediate1-2 hours50 mcg IV
HydromorphonePO15-30 min4-6 hours7.5 mg
IV15 min4-6 hours1.5 mg
IM15 min4-6 hours1.5 mg
CodeinePO30-60 min4-6 hours200 mg
NalbuphineIM15 min3-6 hours10 mg

Routine dosage is equivalent to morphine 10 mg IM or IV. Table is adapted from http://bit.ly/2zcuzJN.​

Fentanyl and its analogues have been largely responsible for overdose deaths. They are significantly more potent than morphine.

Drug

​Number of Times More Potent Than Morphine

Fentanyl80
U4770012
Acetyl fentanyl15
Butyrfentanyl30
Carfentanil10000

The patient was monitored in the ED for four hours. He was awake, alert, and oriented with normal vital signs. He ambulated around the ED, and persistently asked to leave. He did not require any additional Narcan while in the ED​.


Monday, October 2, 2017

An 18-year-old woman presented for altered mental status. EMS reported that she was at a beach party when she became unresponsive. Friends said she may have been drinking alcohol, but denied other illicit drug use. Initial vital signs included a blood pressure of 117/69 mm Hg, heart rate of 110 bpm, respiratory rate of 11 bpm, SPO2 99% on room air, and a temperature of 98.9°F.

The patient was somnolent and reacted intermittently to physical stimuli on exam. She intermittently moved all four extremities. Her gag reflex was intact. Pupils were 4 mm bilaterally reactive without nystagmus. She had tachycardia, her lungs were clear, and her abdomen was soft and nontender. Pertinent labs findings included glucose of 98, serum ethanol of 200 mg/dL, and liver function tests within normal limits. Several hours later, her parents arrived in the ED. The patient was more awake and alert, and she reported that she had only drunk one glass of white wine.

The estimated serum level of alcohol in a 70-kg adult after drinking a four-ounce (120 mL) glass of wine containing 12 percent alcohol is 43 mg/dL; one shot (30 mL) of 40 percent alcohol (80 proof) is 27 mg/dL; and a10-ounce (300 mL) bottle of beer containing five percent alcohol is 43 mg/dL.

Calculating the Serum Ethanol Concentration

The estimated dose of alcohol should be calculated to determine the serum level. The concentration of alcohol may be found expressed in several terms: "% alcohol" by volume and historically as "proof." A hundred percent proof contains 50 percent alcohol by volume in the United States. A hundred percent proof in the United Kingdom contains 57 percent alcohol by volume.

Dose of alcohol (g) = volume ingested (mL) x concentration of drink (mL alcohol/100 mL) x specific gravity (0.8 g/mL)

 

Serum ethanol level (mg/dL)        =       dose (mg)             

                                                     0.6 L/kg x weight (kg) x 10

Acute Ethanol Effects on a Non-Tolerant Adult

with Different Serum Concentrations

BACEffects
0.01-0.05No loss of coordination, slight euphoria, loss of shyness
0.04-0.06Well-being feeling, relaxation, lower inhibitions, minor impairment of reasoning and memory, euphoria
0.07-0.09Slight impairment of balance, speech, vision, reaction time, and hearing. Euphoria. Reduced judgment and self-control. Impaired caution, reasoning, and memory.
0.10-0.125Significant impairment of motor coordination and loss of good judgment. Speech may be slurred; balance, vision, reaction time, and hearing will be impaired. Euphoria.
0.13-0.15Gross motor impairment and lack of physical control. Blurred vision and major loss of balance. Euphoria is reduced, and dysphoria is beginning to appear.
0.16-0.20Dysphoria (anxiety, restlessness) predominates; nausea may appear. The drinker has the appearance of a "sloppy drunk."
0.25Needs assistance in walking. Total mental confusion. Dysphoria with nausea and some vomiting.
0.30Loss of consciousness
0.40 and upOnset of coma, possible death due to respiratory depression/arrest.

Effects are dependent on individual use, chronicity, and tolerance, and other factors. Adapted from Medscape table. (http://bit.ly/2vM7J8S.)

Blood Ethanol Level and Serum Ethanol Level

Serum levels are typically used in hospital settings, while whole blood levels are used in forensic settings. Serum ethanol levels will be slightly higher than whole blood levels because of its higher water content. The estimated ratio of serum-to-whole blood ethanol concentrations is between 0.88 to 1.59.

Clearance Rate of Ethanol in an Adult?

The majority of ethanol consumed is eliminated by the liver. A small percentage is eliminated by the kidneys, sweat, and lungs. The rate is 10 to 15 mg/dL/hour in non-tolerant drinkers, and 20 to 40 mg/dL/hour in tolerant drinkers. The difference is explained by the additional pathway of metabolism with CYP2E1 in tolerant/chronic drinkers.

Factors that Modify Absorption, Metabolism, and Elimination of Ethanol

Absorption:

-Increases with factors that stimulate gastric emptying such as erythromycin, ranitidine, and gastric bypass surgery.

-Decreases with factors that slow gastric emptying, including food, aspirin, and narcotics.

Metabolism:

-Increases for chronic drinkers due to the activation of CYP450 enzymes.

-Decreases for patients with liver cirrhosis (decreased amounts of alcohol dehydrogenase).

Elimination:

-Decreases for individuals with aldehyde dehydrogenase deficiency.​

The patient was observed in the emergency department. Intravenous fluids were administered. She became more responsive, and returned to her neurologic baseline in five hours. The patient later admitted that she likely drank more than one glass of wine.

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Credit:

Rick/Creative Commons​


Friday, September 1, 2017

A 27-year-old man with an unknown past medical history presented with altered mental status. Bystanders found him on the sidewalk acting strangely, according to EMS. The patient was drowsy with incomprehensible speech on arrival. He was diaphoretic, tachycardic, and combative. No signs of trauma were noted. His heart rate was 130 bpm, blood pressure 169/90 mm Hg, respiratory rate 30 bpm, SPO2 98% on room air, and temperature 105.3°F. His blood glucose was 150. The patient continued to be minimally responsive.

Etiologies of Hyperthermia

  • Neuroleptic malignant syndrome
  • Serotonin syndrome
  • Anticholinergic syndrome
  • Sympathomimetic
  • Heat stroke
  • Baclofen withdrawal
  • Thyroid storm
  • Seizures
  • Other drugs: salicylates, 2,4-dinitrophenol
  • Malignant hyperthermia
  • Infection

Complications Associated with Hyperthermia

Hyperthermia is generally considered to be body temperatures greater than 104.0°F. Prolonged hyperthermia is associated with high morbidity and mortality. Complications include altered mental status, rhabdomyolysis, multisystem organ failure, DIC, and death. (Curr Opin Pediatr 2004;16[2]:211.)

Cooling Drug-Induced Hyperthermic Patients

You must stop the psychomotor agitation for patients with hyperthermia. (Am J Health Syst Pharm 2013;70[1]:34.) Treatment may include benzodiazepines and paralytics if agitation is still severe. Some causes of hyperthermia may have specific antidotes such as physostigmine for anticholinergic syndrome and dantrolene for malignant hyperthermia. (Am J Health Syst Pharm 2013;70[1]:34.)

Patients should be aggressively cooled while agitation is being controlled. The optimal cooling method, however, remains controversial. (Clin Toxicol [Phila] 2015;53[3]:181.) Ice-water submersion results in faster cooling in some studies, but is resource-intensive for preparation, monitoring, and attention to patient and staff safety compared with other techniques. This method requires a water-impermeable bed or tub, access to a large volume of ice, experienced staff, and control of patient agitation.

Other cooling methods include applying ice packs to the axilla and groin, evaporative cooling with water sprays or mists with fans, specialized cooling devices, cold intravenous fluids, gastric lavage with ice water, and bladder irrigation with fluids.

The goal should be to decrease the patient's temperature below 104°F within 30 minutes because studies have demonstrated that mortality approaches zero when hyperthermia is reversed in this time frame. Core temperature should be continuously monitored and aggressive cooling stopped at 101°F so hypothermia is not overshot. Be aware that patients can also develop rebound hyperthermia.

Medications Contraindicated in Drug-Induced Hyperthermia

Generally, antipsychotics should be avoided. Most of these patients are at high risk of developing seizures, and antipsychotics may lower the seizure threshold, worsening psychomotor agitation. (Am J Health Syst Pharm 2013;70[1]:34.) Certain causes of hyperthermia such as serotonin syndrome, neuroleptic malignant syndrome, and anticholinergic toxidromes also may be exacerbated by antipsychotics. (Eur J Clin Pharmacol 2007;63[6]:627.)​

A sympathomimetic toxidrome was suspected for our patient. He was rapidly intubated for his severely altered mental status and psychomotor agitation. He was submerged in ice water, and his core temperatures were recorded. Intravenous fluids and lorazepam were also administered. He was removed when his temperature decreased to 101°F. His core temperature continued to be monitored, and the patient was admitted to the ICU. He remained intubated for 24 hours, and was discharged from the hospital four days later with minimal sequelae.

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Credit

Lippincott Williams & Wilkins, 2007​


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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