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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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Friday, April 30, 2021

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

​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

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.

Friday, January 29, 2021

A 43-year-old man with a history of bipolar disorder, hypertension, and asthma presented with altered mental status and a tremor. He reported increasing fatigue and hand tremors for one day. He said he and his family recently had food poisoning with vomiting and diarrhea for several days. Those symptoms had resolved. He continued to take all of his prescribed medications, which included lithium carbonate (Lithobid) 800 mg BID and amlodipine 10 mg daily.

His initial vital signs were a heart rate of 104 bpm, a blood pressure of 136/82 mm Hg, a respiratory rate of 16 bpm, an oxygen saturation of 99% on room air, and a temperature of 98.9°F. His neurologic exam was significant for somnolence and a fine tremor of his hands. He was mildly tachycardic. His lungs were clear. No other significant findings were noted.

His lab results were significant for a lithium level of 2.4 mEq/L, a creatinine of 1.7 mg/dL (his baseline creatinine was 0.84 mg/dL), and a WBC count of 15. TSH and other laboratory tests were otherwise unremarkable. His last dose of lithium was taken approximately 10 hours prior to his arrival in the ED.

Pharmacokinetics of Lithium
Peak concentrations of immediate-release lithium occur within one to two hours while sustained-release formulations may peak at four to five hours. Large ingestions of lithium carbonate can form concretions in the stomach and therefore delay symptoms by up to 48 hours after ingestion.

Lithium initially distributes in the intravascular space and undergoes uptake into the kidneys, thyroid, bone, and other organs and tissues. It slowly diffuses into the central nervous system, which results in a delay between peak blood levels and neurologic effects. Lithium does not undergo any metabolism, and it is eliminated exclusively by the kidneys, making it accumulate in conditions that affect the glomerular filtration rate such as dehydration and use of medications like thiazide diuretics, NSAIDs, ACE inhibitors, and ARBs.

Clinical Presentation
Acute ingestion presents similarly to ingestion of other metals. GI symptoms include nausea, vomiting, and diarrhea. Neurologic findings such as dizziness or somnolence may develop later because lithium takes up to 24 hours to distribute into the CNS. Patients undergoing chronic therapy who acutely ingested a large amount of lithium will develop neurologic and GI manifestations.

Generally, chronic toxicity is due to worsening renal function, such as in dehydration, and it manifests predominantly as neurologic symptoms. Patients may develop a tremor, fasciculations, clonus, dysarthria, nystagmus, and ataxia. Neurologic symptoms can progress from confusion to stupor to seizures.

Other Organs Affected

  • A known complication of chronic treatment with lithium is the development of nephrogenic diabetes insipidus, which may lead to dehydration and hypernatremia.
  • Acute renal failure can also occur.
  • Hypothyroidism or hyperthyroidism is possible. Lithium interferes with thyroid hormone synthesis and decreases the responsiveness of peripheral tissues to T3.
  • Lithium toxicity may also cause hyperparathyroidism and hypercalcemia.
  • Cardiac abnormalities such as SA node dysfunction, prolonged QT interval, and intraventricular conduction delays.
  • Be mindful that lithium toxicity can also lead to serotonin syndrome, especially in those on other serotonergic medications. 

A rare complication of lithium toxicity is syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). This condition involves persistent cerebellar or cognitive dysfunction after cessation of lithium.

tox cave feb.jpg

Management of Lithium Toxicity
Initial management should include cardiac monitoring through ECG and checking BMP, Ca, TSH, and serum lithium levels. Of note, the tube this is collected in is important because the green top tubes contain lithium heparin and can show a falsely elevated lithium level.

Therapeutic range of serum lithium is 0.6 to 1.0 mmol/L. Lithium levels should be used more as a marker of exposure and response to therapy rather than level of toxicity. In chronic and acute cases of toxicity, clinical presentation is more important.

Lithium does not bind to charcoal, and is not recommended. Whole bowel irrigation should be considered in extended-release preparations. Mainstay of treatment is restoration of intravascular volume and electrolyte repletion. IVF hydration is important because most cases of chronic toxicity are due to worsening renal function.

The patient was admitted for IVF hydration and received several liters of normal saline. His home lithium medication was discontinued. Repeat labs showed a decrease in his lithium level, with subsequent levels of 1.9 mEq/L and 1.0 mEq/L. His creatinine also improved to 0.94 mg/dL. The patient's tremor resolved, and he was back to his baseline mental status. He was discharged home after a two-day hospitalization, and was restarted on lithium at that time.

References

  • Clin J Am Soc Nephrol. 2015;10(5):875; https://bit.ly/39jF4gX.
  • Goldfrank's Toxicologic Emergencies, 11e. New York: McGraw-Hill Education; 2019.
  • Lancet. 2012;379(9817):721.

 

 

Monday, November 30, 2020

​A 16-year-old boy presented to an emergency department in rural Pennsylvania for nausea, vomiting, and diarrhea. He reported diffuse abdominal cramping that had started two hours earlier. Shortly prior to arrival, he had multiple episodes of nonbloody diarrhea and emesis. He had no significant past medical history, and was not currently taking any medications or supplements. Initially, the history he gave was limited due to a language barrier. His sister was also being evaluated for similar symptoms.

The boy's vital signs were a heart rate of 130 bpm, a blood pressure of 100/50 mm Hg, a respiratory rate of 26 bpm, an oxygen saturation of 100% on room air, and a temperature of 98.9°F. His abdomen was diffusely tender, he was tachycardic with no murmurs, and his lung sounds were clear. His neurologic exam was significant for drowsiness, but he had no focal deficits, clonus, or rigidity. His mucous membranes were dry, and his pupils were normal with no scleral icterus. Treatment was started with IV fluids and ondansetron.

His lab results were remarkable for a white blood cell count of 20, a lactic acid of 3.5 mg/dL, a potassium of 2.8 mmol/L, an anion gap of 14 mEq/L, an AST of 200 U/L, and an ALT of 350 IU/L. Abdominal imaging showed no acute findings.

The differential diagnosis included acetaminophen toxicity, supplement ingestion such as comfrey, germander, kava kava, or pennyroyal, acute ethanol poisoning, hydrocarbon ingestion or inhalation, and mushroom poisoning.

Identifying the Toxin
After the laboratory results were reviewed, further history was obtained from the patient. He said he and his sister had picked a variety of mushrooms in a forest. They had eaten them about nine hours before presentation, and they felt well until about two hours before ED arrival. He was unable to describe the mushrooms, but a family member at home texted him pictures of the leftover mushrooms. (Image.)

On reassessment, the patient still appeared ill. He required additional doses of antiemetics, and IV fluids were continued. He had good urine output.

 tox cave.jpg

 

The Toxin's Mechanism
The mushroom was identified as Amanita phalloides. It is responsible for the majority of deaths due to mushrooms worldwide. Its toxicity is caused by alpha-amatoxin, which is readily bioavailable when ingested. The mechanism for toxicity involves inactivating RNA polymerase II, which inhibits protein synthesis and leads to cell death. The target organs include the GI tract, hepatocytes in the liver, and kidneys due to their high rates of cell turnover.

Amanita phalloides
toxicity has four phases:

    • Phase I: Latency (six to 24 hours)
    • Phase II: Severe gastroenteritis symptoms with a delayed onset (six to 24 hours after ingestion). The delayed onset of GI symptoms may be helpful in distinguishing Amanita toxicity from other mushroom poisonings. GI symptoms may persist for 12-36 hours.
    • Phase III: Clinical remission (ongoing organ damage despite clinical improvement)
    • Phase IV: Worsening hepatic and renal toxicity (two to six days after ingestion).

Treatment
IV fluid hydration is important in the renal elimination of amatoxin. Fluid resuscitation begins with normal saline and then D5 0.45% normal saline at a maintenance rate. Patients should be closely monitored for liver and renal function, urine output, electrolytes, coagulation factors, and lactic acid. Electrolyte repletion and symptomatic treatment (pain medications and antiemetics) should also continue.

GI decontamination is unlikely to be beneficial because patients often present hours after the ingestion when symptoms occur. Multidose activated charcoal may be considered to interrupt further absorption due to the enterohepatic circulation of the amatoxin.

There is limited evidence of efficacy for a specific antidote for amatoxins.

  • N-acetylcysteine has hepatoprotective effects but no specific benefit as an antidote for amatoxin toxicity.
  • Silibinin, derived from milk thistle (Silybum marianum), works by inhibiting the reuptake of amatoxin by hepatocytes, resulting in amatoxin being available in the general circulation for renal elimination. It also has antioxidant effects.
  • Other proposed therapies include cimetidine (has a hepatoprotective effect) and IV octreotide (prevents gallbladder contraction and release of amatoxin-containing bile).

    Early consultation with a transplant center should be considered for patients who are at risk for developing liver failure.

    There are limited data supporting the use of extracorporeal treatments like hemodialysis, hemoperfusion, plasmapheresis, and molecular adsorbent recirculating system (MARS).

    Identifying the mushrooms is important but should not delay treatment if there is strong clinical suspicion for an Amanita ingestion. Your local poison control center can assist. Another resource is the North American Mycological Association, which is made up of volunteer identification consultants. (https://namyco.org/mushroom_poisoning_identifiers.php.)

    The patient was admitted to the hospital, where aggressive hydration was maintained. He developed oliguric renal failure and worsening signs of liver failure. He was transferred to a tertiary care center where he received a liver transplant.
     
    References:
    1. Mycetism: A Review of the Recent Literature. J Med Toxicol. 2014;10[2]:173; https://bit.ly/2Undc4w.
    2. Mushrooms. Goldfrank's Toxicologic Emergencies. 11th edition, McGraw Hill: New York; 2019.