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The Tox Cave by Gregory S. LaSala, MD; 
Rita G. McKeever, MD; & Jolene Yehl, MD

 

 

 


​The Tox Cave dissects 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 the authors' 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.​

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Monday, August 2, 2021

August 2021: Adulterant in Fentanyl Complicates OD

​A 38-year-old woman with opioid use disorder presented to the emergency department after an unintentional overdose. EMS said the patient was found with decreased respirations, and she was given 2 mg intranasal naloxone. She was awake, alert, and oriented x 3 in the emergency department.

She reported that she used one bundle of fentanyl/heroin a day intravenously and that she had recently been hospitalized for four weeks for a wound infection. She stated that she used her usual dosage of fentanyl/heroin on discharge, not realizing how much her tolerance had decreased.

She also said the fentanyl contained “tranq" (xylazine), and it made her feel like she was “dipping out" but was more sedating than the typical heroin high that she would get. Her vital signs were normal, and her physical exam revealed track marks in her arms, an old, well-healed wound to her left upper arm, and some sores in different stages of healing. Her rapid glucose was 114 mg/dL.

Symptoms

Xylazine is a nonnarcotic sedative used exclusively in veterinary medicine for analgesia and muscle relaxation, and it is now increasingly found as an adulterant in fentanyl. Xylazine was first reported as an adulterant in Puerto Rico in the early 2000s, and it is known as anestesia de caballo (horse anesthetic). Xylazine is not a scheduled medication.

Xylazine's chemical structure is similar to clonidine and phenothiazines, and it acts as a central alpha-2 agonist. Alpha-2 agonism decreases the release of norepinephrine and dopamine in the central nervous system, leading to its clinical effects.

The pharmacokinetics have not been reported in humans, but animal studies showed IV xylazine's onset of action is within 30 minutes. The reported duration of effects ranges from eight to 72 hours and depends on the route of administration.

The clinical presentation can include hypertension followed by hypotension, bradycardia, ventricular dysrhythmias, respiratory depression, CNS depression, and hyperglycemia. Combined with fentanyl, it may potentiate respiratory depression and coma.

Treatment

Treatment is primarily supportive. Naloxone is given for respiratory depression because fentanyl is almost always present. The xylazine, however, may make the naloxone less effective. Hypotension usually is responsive to IV fluids, but vasopressors may be necessary if it is refractory or persistent.

The patient was monitored in the emergency department for four hours without further sedation. Her vital signs remained normal during this time, and she required no further intervention. Medication-assisted treatment was discussed. The patient stated she had been on suboxone before and would like to restart treatment. She was given a referral to a suboxone program and a prescription for naloxone.


Tuesday, June 1, 2021

June 2021: Mounting Evidence Supports Ivermectin for COVID-19

​Ivermectin has been proposed as a treatment for COVID-19 based on in vitro studies. It is currently FDA-approved for treating parasites (intestinal strongyloidiasis and onchocerciasis) but not approved for COVID-19, though a large body of evidence supports its use in inpatients and outpatients. (Antiviral Res. 2020;178:104787; https://bit.ly/3bpeTrm.)

Mechanism of Action

Ivermectin is an antiparasitic agent that binds directly and has high affinity to the glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria. This causes the cell membrane to have increased permeability to chloride ions and leads to hyperpolarization of the cell, which then leads to the paralysis and eventual death of the parasite. It is also believed to act as a GABA agonist and to disrupt GABA-mediated neurotransmission.

Proposed Action against SARS-CoV-2

The in vitro studies demonstrated that ivermectin inhibits host importin alpha/beta-1 nuclear transport proteins. This transport system is used by the COVID-19 virus to suppress the host's antiviral response. (National Institutes of Health. April 21, 2021; https://bit.ly/3w98rwC.) Ivermectin may also inhibit the attachment of the SARS-CoV-2 spike protein to the cell membrane. (National Institutes of Health. April 21, 2021; https://bit.ly/3w98rwC.) It also inhibited SARS-CoV-2 replication in in vitro studies, and appears to have antiviral and anti-inflammatory properties.

Proposed Dosage for COVID-19

  • Post-COVID exposure prophylaxis: 0.2 mg/kg on days one and three.
  • Early disease: 0.2 mg/kg-0.4 mg/kg
  • Late disease: 0.4 mg/kg-0.6 mg/kg
  • To be given daily and continued for five days. (Front Line COVID-19 Critical Care Alliance. May 12, 2021; https://covid19criticalcare.com.)

Toxicity from Ivermectin

Ivermectin appears to be well tolerated in humans. Most of the side effects reported have been nausea, vomiting, abdominal pain, diarrhea, and pruritus. Stevens-Johnson syndrome has been rarely reported with its use.

Drug-Drug Interactions

Many drug-drug interactions occur with ivermectin, and it is important to review a patient's medication list prior to prescribing.

Treatment

Care is primarily supportive because evidence of toxicity is minimal.

Sixteen randomized controlled trials have been done, many of which demonstrated a statistically significant reduction in transmission, progression of disease, and mortality. (Front Line COVID-19 Critical Care Alliance. May 12, 2021; https://covid19criticalcare.com.) The methodology and extrapolation of results can be debated, but the risk with this medication appears to be minimal.​




Friday, April 30, 2021

May 2021: The Asphyxiants that Cause Pulmonary Toxicity

​The American Association of Poison Control Centers reported more than 37,000 exposures to gas, fumes, and vapors in 2019, and those were the most common exposures in pediatric deaths. Toxicity from gas, fume, and vapor exposures can be categorized by their mechanism: simple asphyxiants, pulmonary irritants, and systemic asphyxiants.

Simple Asphyxiation
Simple asphyxiants work by displacing oxygen from ambient air. Patients may be exposed to these chemicals by huffing. A 2010 survey reported that more than two million adolescents in the United States ages 12-17 reported using inhalants at least once, including noble gases (helium), nitrogen gas (nitrous oxide), and aliphatic hydrocarbons (methane, ethane, propane).

May tox cave balloon.JPG 

Gas is inhaled by discharging nitrous gas cartridges, often called whippets, into an object like a balloon or directly into the mouth. Credit: evemilla/iStockphoto.com

Simple Asphyxiant Symptoms
Symptoms are consistent with hypoxia and include tachypnea, lethargy, nausea and vomiting, seizures, and death. Patients who have been huffing may present with burns on the oral mucosa.

may tox cave lips.JPG 

This patient presented after huffing with swollen lips, bullae on the lateral margin of the mouth, and midline burns. (Courtesy Brandie LaSala, MD; Pediatr Dermatol. 2013;30[4]:e57; https://bit.ly/3ujAWqm.)

Treatment for Simple Asphyxiants
Treatment is the immediate removal from the exposure and supplemental oxygen. Assisting with respirations may be needed until a patient is awake enough to maintain his own respirations.

Pulmonary Irritants
Pulmonary irritants are water-soluble chemicals that combine with water in the mucosa to produce acid. This destroys the endothelial lining and causes an inflammatory response that leads to the destruction of the mucosal barrier of the respiratory tract. Examples include ammonia, chlorine, sulfur dioxide, phosgene, and chloramine, a combination of bleach and ammonia.

May bleach and amonia.png
Illustration: Sam Teng; [email protected]

Pulmonary Irritant Symptoms
Patients generally develop mucosal injury in the upper respiratory tract. They have nasal and oropharyngeal pain, drooling, edema, cough, and stridor, and can develop conjunctival irritation and lacrimation. Patients can also go on to develop acute respiratory distress syndrome. This can be immediate or delayed up to six hours after exposure.

may tox cave x-ray.jpg

Treatment for Pulmonary Irritants
Remove the patient from the exposure, and provide supportive care and oxygenation. Signs of upper airway dysfunction (stridor) require direct visualization of the larynx. If a patient develops ARDS and requires intubation, treating this similar to other etiologies of ARDS is reasonable: lower tidal volume 6 mL/kg, elevated PEEP, early neuromuscular blockade, and sometimes proning.

Nebulized albuterol can benefit patients with bronchospasm. Nebulized bicarbonate has shown some efficacy in chlorine gas exposure but is inconclusive for chloramine exposure, though it offers little harm and may be recommended. Steroids are controversial and have shown no proven benefit on mortality.

Systemic Asphyxiants
Systemic asphyxiants cause cellular hypoxia by interfering with oxygen transport or mitochondrial respiration. Examples include carbon monoxide, hydrogen cyanide, and hydrogen sulfide.

Treatments for Systemic Pulmonary Asphyxiants
The treatment would depend on the gas to which the patient was exposed. Initial treatment for all would be immediate removal from the exposure and supportive care with supplemental oxygen. Carbon monoxide exposures should be treated with supplemental oxygen and followed by hyperbaric oxygen if indicated. Hydrogen cyanide toxicity patients should receive supportive care and hydroxocobalamin if the patient is unstable. Hydrogen sulfide is considered a knock-down gas, and death from inhalation is rapid. No definitive treatments or antidotes show improvement.

Suggested Reading
2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report. Clin Toxicol (Phila). 2020;58(12):1360; https://bit.ly/3cRWgNC.

  • Cutaneous and Mucosal Blistering Secondary to “Huffing." Pediatr Dermatol. 2013;30(4):e57; https://bit.ly/3ujAWqm.
  • “Simple Asphyxiants and Pulmonary Irritants." Goldfrank's Toxicologic Emergencies, 11th Edition. 2019.




Thursday, April 1, 2021

April 2021: An Eye on the Problem

​A 3-year-old boy presented to the emergency department with lethargy. He was bradycardic and somnolent, responding only to physical stimuli. His vital signs were a temperature of 37°C, a heart rate of 50 bpm, a respiratory rate of 26 breaths per minute, a blood pressure of 92/41 mm Hg, and a pulse oximetry of 100% on room air.

When awoken, the child answered questions appropriately but then fell back asleep quickly. His pupils were pinpoint. There were no signs of trauma. A cardiac examination demonstrated bradycardia, and the remainder of the examination was unremarkable.
The child was given an IV fluid bolus and placed on a cardiac monitor. Labs were sent, including a CBC, BMP, LFTS, and urine drug screen. An ECG was done, remarkable only for bradycardia. A head CT was obtained, but all imaging and labs were unremarkable.

What ingestions are in the differential?
•    Clonidine
•    Beta blockers
•    Opioids
•    Benzodiazepines
•    Barbiturates
•    Psychotropics

A thorough medication history was obtained, which included all potential medications available to the child in the household. Those were acetaminophen, ibuprofen, tetrahydrozoline optic (Visine), sertraline, Adderall, and liquid nicotine. A comprehensive toxicology panel was performed, and returned positive for tetrahydrozoline.

What is the mechanism of action of tetrahydrozoline (THZ) hydrochloride?
THZ is the active ingredient in Visine ophthalmic drops. It is an imidazoline derivative, a family that also consists of oxymetazoline (i.e., Afrin nasal spray) and clonidine. When used as directed, THZ is a peripheral alpha-1 adrenergic agonist, resulting in local vasoconstriction and the therapeutic relief of conjunctival injection. Ingestion of this agent may result in significant alpha-2 adrenergic agonist, decreasing central nervous system sympathetic outflow.

What are signs and symptoms of tetrahydrozoline toxicity?
The toxicity of these medications is similar to clonidine. Symptoms typically occur within two hours of ingestion with complete resolution of symptoms in 24 hours. Symptoms consist of depressed mental status, bradycardia, hypotension, and miosis.

What is the treatment for THZ toxicity?
Treatment is focused on supportive care.
•    IV fluids and vasopressors for hypotension and bradycardia
•    Supplemental oxygen and endotracheal intubation for respiratory depression
•    Naloxone has been used in this setting with mixed results.

Disposition
The patient was admitted and continued on maintenance fluids throughout the night. He did not require further intervention. The child was awake and alert the following day, and his heart rate had returned to normal. The parents were interviewed separately, and it was determined this was an accidental ingestion. He was discharged hospital day three.

References:
1. Mitchell AA, Lovejoy FH, Goldman P. Drug ingestions associated with miosis in comatose children. J Pediatr. 1976;89(2):303.
2. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Saf. 2005;28(11):1029.
3. Gunn VL, Taha SH, Liebelt EL, Serwint JR. Toxicity of over-the-counter cough and cold medications. Pediatrics. 2001;108(3):E52.
4. Bamshad MJ, Wasserman GS. Pediatric clonidine intoxications. Vet Hum Toxicol. 1990;32(3):220.
5. Stillwell ME, Saady JJ. Use of tetrahydrozoline for chemical submission. Forensic Sci Int. 2012;221(1-3):e12.

Monday, March 1, 2021

March 2021: ​The Toxicity of Fire Smoke

A 54-year-old man was brought to the ED unresponsive by paramedics after his neighbors called 911 because they smelled smoke in his apartment. The patient was found unconscious in his living room, and a fire was burning in an adjoining room.
His initial vital signs were a blood pressure of 115/80 mm Hg, a heart rate of 120 bpm, a respiratory rate of 30 bpm, an SPO2 of 94% on a nonrebreather, and a temperature of 98.9° F. The patient was unresponsive to verbal and physical stimuli but had spontaneous respirations. His nose and mouth were filled with soot, his lungs had trace wheezes, and his skin appeared flushed.

What toxins should be considered in a patient with signs of smoke inhalation?
•    Carbon monoxide (CO): asphyxiant and chemical toxicity effects
•    Hydrogen cyanide (HCN): generated during burning of synthetic building and furnishing materials (polyurethane, melamine, nylon, etc.) and natural materials (wool, silk)
•    Irritant smoke products (nitrogen oxides, hydrogen chloride, hydrogen bromide)
•    Carbon dioxide: asphyxiant

What information can help determine toxic smoke exposure?
•    Was it an indoor or outdoor fire? Patients are unlikely to develop toxic levels of carbon monoxide unless they are in an enclosed structure. Hydrogen cyanide is generated from the burning of synthetic building material and therefore unlikely to be the cause of injury in an outdoor fire.
•    Was the patient found away from the room of origin? A patient who is found in the same room as the fire is more likely to develop thermal injury or asphyxia from smoke prior to developing toxicity from carbon monoxide or hydrogen cyanide. Patients must be exposed to fire smoke for a long time to develop toxic levels of carbon monoxide or hydrogen cyanide. Those patients found outside of the room of origin are unlikely to develop thermal injuries and therefore may be exposed to toxic smoke for a longer period of time.
•    Did the building have high ceilings? Irritant gases and carbon monoxide tend to rise with the heat and are less likely to cause injury in a room with high ceilings.

What are indications for antidotal therapy for suspected hydrogen cyanide toxicity?
Antidotal treatment for cyanide should be emergently considered. The preferred antidote is hydroxocobalamin (Cyanokit). Its mechanism involves combining with cyanide to form nontoxic vitamin B12, which is then renally excreted. A second-line treatment is sodium thiosulfate. Because there is not a readily available test result for cyanide, clinical indications for treating empirically are cardiac arrest, seizure, hypotension, and lactate >8 mmol/L in setting of altered mental status, signs of cardiotoxicity, or high suspicion for cyanide exposure.

Carbon Monoxide Treatment
When CO toxicity is suspected, the patient should be treated with 100% oxygen via a nonrebreather mask. Hyperbaric oxygen is also a therapeutic option for severe carbon monoxide poisoning.
    A venous or arterial blood carboxyhemoglobin level should be obtained. A pulse-CO oximeter alone should not be used to diagnose CO toxicity because of possible sensitivity and accuracy issues. This noninvasive device may have utility in mass screening. An ECG, continuous cardiac monitoring, and cardiac biomarkers should also be done to identify signs of CO-induced cardiotoxicity (ischemia and dysrhythmias).

What are the indications for hyperbaric oxygen treatment (HBO2) for significant carbon monoxide exposures?
Hyperbaric oxygen therapy quickly reduces the half-life of CO and may decrease neurocognitive sequelae (cognitive impairment, ataxia, parkinsonism, neuropathy, etc.) after severe CO exposure. This treatment may also help at a molecular level (reduces lipid peroxidation). The benefit over normobaric oxygen therapy is unclear. It may also be more beneficial if it can be initiated within six hours of presentation. According to current ACEP clinical policy, the use of hyperbaric oxygen is an option but is not mandated.

Indications to consider include:
•    Transient or prolonged loss of consciousness.
•    Abnormal neurologic signs: confusion, seizures, abnormal cerebellar function, and coma.
•    COHb >25%; in pregnancy, COHb level >15%.
•    Severe metabolic acidosis.
•    Cardiovascular dysfunction; cardiac interventions, however, should still be prioritized for ischemia.
The patient was intubated shortly after arrival for airway protection. His COHb level was 30%. He was treated empirically with hydroxocobalamin. He underwent hyperbaric oxygen therapy, and was then admitted to the ICU. The patient improved, and was extubated on day 2. He appeared to be neurologically intact. He was discharged on hospital day 3 and lost to follow-up.

References:
•    Giebułtowicz J, et al. Analysis of Fire Deaths in Poland and Influence of Smoke Toxicity. Forensic Sci Int. 2017;277:77.
•    Hamad E, et al. Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote? J Med Toxicol. 2016;12(2):192; http://bit.ly/3jmZRVT.
•    Wolf SJ, et al. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Acute Carbon Monoxide Poisoning. Ann Emerg Med. 2017;69(1):98.