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.

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.​


Wednesday, March 1, 2017

The emergency department can be an exciting yet sometimes violent place to work, often because of a patient presenting with excited delirium syndrome (ExDS), the most severe form of agitation. It is associated with the use of sympathomimetics such as methamphetamine, cocaine, and PCP.

Patients with ExDS present with sudden onset of aggressive and bizarre behavior. These patients generally demonstrate unexpected physical strength and hyperthermia. This disease process is extremely important for prehospital responders and emergency physicians to recognize because almost two-thirds of the patients with ExDS die at the scene or during transport. (West J Emerg Med 2011;12[1]:77.) Death is generally due to hyperthermia, rhabdomyolysis, or multiorgan failure. Several medications can be used to sedate these patients.

Ketamine

Intramuscular ketamine has become increasingly popular in the prehospital setting for chemical sedation of agitated patients due to its rapid onset of action and wide therapeutic window. The use of ketamine has been described to be safe and effective in the prehospital setting, and appears to have minimal side effects. (West J Emerg Med 2014;15[7]:736; Prehosp Emerg Care 2013;17[2]:274.)

The recommended dose is 4-5 mg/kg IM. IM ketamine has the most rapid onset of sedation (three minutes or less), and it acts as an analgesic. There appears to be a positive association between higher incidence of intubation and increasing doses of ketamine. (Am J Emerg Med 2015;33[1]:76.)

Olanzapine

This antipsychotic has been used for chemical sedation because it causes the least amount of QT prolongation of all of the antipsychotics, and it has not been reported to cause torsades de pointes. A recent randomized controlled trial demonstrated that only 65.8 percent of patients were sedated at 15 minutes, with that number increasing to only 80 percent at 30 minutes. Ten percent of patients in the olanzapine group also developed hypoxia. (Ann Emerg Med 2016 Oct 10. doi: 10.1016/j.annemergmed.2016.07.033.)​

The recommended dose is 10 mg IM or oral. It's important to remember that olanzapine fails to sedate a large portion of patients in a timely manner, and cases of concomitant use of benzodiazepines are associated with lower oxygen saturations. (J Emerg Med 2012;43[5]:790.)

Droperidol

Droperidol's use has declined due to a black box warning from the FDA stating that droperidol can cause significant QT prolongation and lead to torsades de pointes. (FDA. Dec. 6, 2001; http://bit.ly/2kDuFD4.) Several recent studies, however, have demonstrated a good safety profile for droperidol used in the ED. (Ann Emerg Med 2015;66[3]:230.) A position statement by the American Academy of Emergency Medicine in 2015 stated that doses of up to 10 mg IM appear to be as safe and efficacious as other medications used for sedation. (J Emerg Med 2015;49[1]:91.)

A double-blind prospective study demonstrated that midazolam (5 mg IM) with 10 mg IM droperidol led to more rapid sedation when compared with administering droperidol alone. (Ann Emerg Med 2016 Oct 10. doi: 10.1016/j.annemergmed.2016.07.033.) The recommended dose is 5-10 mg IM. Droperidol leads to rapid onset of sedation compared with Haldol or lorazepam. It can lead to torsades, though recent literature shows this does not occur with the doses generally used in the ED.

Haloperidol and Lorazepam

Haloperidol and lorazepam have been used singly and together for sedation. Their use together has been supported by double-blind studies demonstrating a more rapid onset of sedation than either medication alone. (Am J Emerg Med 1997;15[4]:335; Pharmacotherapy 1998;18[1]:57.) The combination treatment also results in a decrease in extrapyramidal symptoms with haloperidol alone.

The recommended dose is lorazepam 2 mg IM and haloperidol 5 mg IM. The medications lead to rapid onset of sedation when compared with either medication alone, but prolonged sedation delays medical evaluation. Haloperidol might also cause extrapyramidal symptoms and QT prolongation.

Midazolam

Several studies have demonstrated midazolam's efficacy when given IM singly or with other medications. A double-blind prospective study found that 5 mg of IM midazolam had a faster time to sedation than haloperidol or lorazepam alone, as well as a faster time to arousal. (Acad Emerg Med 2004;11[7]:744.) Recent prospective studies demonstrated that midazolam 5 mg IM in combination with droperidol 10 mg IM had a faster time to sedation than either droperidol or olanzapine alone. Fourteen percent of patients developed transient hypoxia (O2 saturation < 90%). (Ann Emerg Med 2016 Oct 10. doi: 10.1016/j.annemergmed.2016.07.033.)

The recommended dose is 5 mg IM. Midazolam has a rapid onset of sedation and a good safety profile with minimal adverse effects. It triggers, however, mild respiratory depression that responds well to supplemental oxygen.

Attacks on health care workers are among the highest in the emergency department, as reported in EMN. ("The Most Dangerous Workplace in America?" EMN 2017;39[2]:12; http://bit.ly/2kkZyw8.) Using chemical sedation to help restrain patients who are at high risk for hurting themselves or others is recommended.

tox cave ketamine.jpg


Thursday, December 1, 2016

A 26-year-old man presented to the emergency department with nausea, vomiting, and abdominal pain. He said he had had the pain, which he said encompassed his entire abdomen, for three days.

He had been unable to tolerate anything by mouth. His vitals on presentation included a heart rate of 115 bpm, blood pressure of 126/70 mm Hg, respiratory rate of 22 bpm, and pulse oximetry of 100% on room air.

Physical examination revealed dry mucus membranes, dry skin, tachycardia without murmurs, and clear lungs. Abdominal examination demonstrates hyperactive bowel sounds without pain on palpation or hepatosplenomegaly. The patient had no medical history except for this chronic abdominal pain and vomiting, for which he takes metoclopramide and ondansetron.

This was his fourth visit in six months for the same complaint, and all workups, including CT of the abdomen/pelvis and labs, were negative. He had also been evaluated by a GI doctor who performed an endoscopy, which was negative. The patient stated that nothing relieved his symptoms except for hot showers, so he took three to four of them daily.

What is the differential for cyclic vomiting?

  • Cyclic vomiting syndrome
  • Cannabinoid hyperemesis syndrome (CHS)
  • Infection
  • Hyperemesis gravidarum
  • Migraines
  • Metabolic disorders
  • Motility disorders
  • Psychogenic vomiting
  • Diabetic gastroparesis
  • Bulimia

What are the clinical features of CHS?

  • Long-term, regular cannabis use (essential)
  • Severe cyclic nausea and vomiting
  • Resolution with cannabis cessation
  • Relief of symptoms with hot showers/baths
  • Abdominal pain, epigastric or periumbilical

What is the pathophysiology of CHS?

The pathophysiology behind CHS is poorly understood. One hypothesis is that the disease is caused by the cannabinoid receptor type 1 (CB1). CB1 receptors are found in the brain and the GI tract. Delta-9-tetrahydrocannabinol is the main active metabolite of cannabis and exerts its psychotropic and antiemetic effects by binding to CB1 receptors in the brain. It also binds to CB1 receptors in the GI tract causing gastroparesis. With chronic use of cannabis, sensitization of the CB1 receptors in the brain may occur, leading to the pro-emetic CB1 effects in the gut and overriding the antiemetic CB1 effects in the brain.

What is the treatment for CHS?

The only definitive treatment is cessation of cannabinoid use. Supportive measures include electrolyte repletion, IV fluids for dehydration, and antiemetics. Case reports describe the successful use of topical capsaicin cream applied to the abdomen and haloperidol in cases where vomiting is refractory to common antiemetics.

What is thought to be the mechanism of action of capsaicin cream?

Topical capsaicin cream is hypothesized to stimulate the same receptors as hot showers for these patients. This has yet to be proven, and there is only anecdotal evidence for its use. The cream is a supplement, and it is very safe and relieves symptoms, aside from patient complaints of heat.​

The toxicology service was called, and  the patient admitted to drinking occasionally and smoking marijuana daily because it helped with his nausea. The patient was treated with IV Haldol and capsaicin cream, and his symptoms were resolved in the ED. He was counseled and advised to stop using marijuana. He was discharged with the rest of the capsaicin cream.​​



Tuesday, November 1, 2016

A 64-year old woman presented to the emergency department with nausea, vomiting, dry mouth, dry eyes, and difficulty keeping her eyes open. She admitted to eating mandarin oranges out of a can the night before, and at that time she thought they "tasted funny" but did not think much of it.

The next morning she noticed she was having trouble opening her eyes and that her mouth was dry. She looked inside the can of oranges and saw it was discolored.

Her presenting vital signs were unremarkable. The patient was alert and awake. She had ptosis bilaterally, with mydriatic pupils unresponsive to light. The patient had dry mucous membranes with no oropharyngeal erythema or exudates. Her heart rate and rhythm were regular without murmurs. Her lungs were clear to auscultation, and her abdominal exam demonstrated no tenderness, but she became nauseous with palpation. She was able to move all four extremities spontaneously, and her deep tendon reflexes were intact. Initial labs included a CBC, BMP, hepatic panel, lipase, VBG, UA, and CT of the head, all of which were unremarkable.

The Toxicologic Differential

  • Aminoglycoside
  • Anticholinergic
  • Buckthorn (Karwinskia humboldtiana)
  • Botulinum toxin
  • Carbon monoxide
  • Diphtheria
  • Elapid envenomation
  • N-hexane
  • Organophosphorus compounds
  • Paralytic shellfish poisoning
  • Tetrodotoxin
  • Thallium
  • Tick paralysis
  • Exogenous thyroid hormone in patients who develop thyrotoxic periodic paralysis

Scenarios of Botulism Exposure

  • Foodborne botulism occurs after ingestion of preformed toxin in food, including improperly canned foods. Botulism outbreaks in prison was associated with hooch or pruno (prison wine). The incubation period is around one day.
  • Infant botulism results from ingestion of Clostridium botulinum spores, which produce toxins in the infant's GI tract that are absorbed into the bloodstream. Many cases are associated with raw honey.
  • Adult colonization botulism is a disease where the predisposing factors to enteric colonization include history of GI surgery and inflammatory bowel disease.
  • Wound botulism occurs when wounds have been contaminated by spores which then proliferate to form the toxin. The incubation period is typically one to two weeks. This is common among IV drug abusers.
  • Iatrogenic botulism results from injection of Botox.
  • The toxin can be aerosolized and used as a weapon. A lethal dose is 1 ng/kg via inhalation.

Clinical Presentation of Botulism

Onset of symptoms generally occurs the day following ingestion. It generally begins with nausea and vomiting. Neurologic signs may lag by 12 hours and include:

  • Eyes
    • Diplopia (often with lateral rectus palsy)
    • Blurred vision
    • Mydriasis
    • Ptosis
  • Mouth
  • Dry mouth
  • Dysphagia
  • Dysarthria
  • Extremities
    • Descending symmetrical flaccid paralysis
    • Loss of deep tendon reflexes
  • Mental status and sensation remain intact

Workup for Suspected Botulism

Diagnosis is based on clinical symptoms and history of exposure. Confirmatory testing takes days, so initial treatment should not be delayed. Testing involves demonstrating the toxin in the serum, stool, gastric aspirate, wound, or implicated food. A mouse bioassay is used. Fecal and gastric samples are cultured anaerobically. Routine labs tests and imaging may be helpful to exclude other etiologies.

Treatment for Botulism

Airway protection is important because respiratory failure is the usual cause of death. Methods for monitoring the patient's respiratory status may include negative inspiratory force (NIF), end-tidal CO2, SPO2, gag reflex, vital capacity, and peak expiratory flow rate.

An equine-derived botulinum antitoxin is available for foodborne, wound, adult intestinal colonization, and iatrogenic botulism. Early administration is helpful to stop the progression of paralysis. BabyBIG (botulism immune globulin intravenous) is indicated for infant botulism.

The state health department should be contacted, which will arrange clinical consultation with the Centers for Disease Control and Prevention. The CDC will request release of the antitoxin if it is determined that there is botulism exposure. The antitoxin is not available in hospital pharmacies and must be shipped from designated centers throughout the United States.

Food-associated botulism was suspected based on the patient's presentation. Consultation with the CDC concluded that this patient was likely exposed to botulinum toxin and administration of antitoxin was recommended.

The patient was admitted to the ICU, and the following day she experienced some blurred vision and had a mild dysarthria but no further neurologic progression. Botulinum toxin was confirmed in the patient's stool and in the can of oranges. The patient was downgraded from the ICU two days later when it became apparent that her paralysis was not progressing.

References:

1. Arnon SS, et al. JAMA 2001;285(8):1059.

2. Zhang JC, Sun L, Nie QH. Clin Toxicol 2010;48(9):867.

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Photo Credit: Centers for Disease Control and Prevention




Monday, October 3, 2016

A 29-year-old man presented to the emergency department with numbness and tingling of his entire body for three weeks. He said the symptoms started when he entered a drug rehab facility for benzodiazepine and opiate abuse, and that the last time he used either drug was more than a month ago. His initial vitals demonstrated a heart rate of 106 bpm, blood pressure of 115/70 mm Hg, temperature of 98.6°F, respiratory rate of 14 bpm, and SPO2 of 99% on room air.

He is well nourished, alert, and oriented but anxious-appearing. His neurologic exam demonstrates no ataxia on ambulation with cranial nerves II-XII intact. His motor exam of upper and lower extremities is intact, and he has no evidence of dysdiadochokinesia. His patellar reflexes are 2+ bilaterally. He has slightly diminished sensation in all extremities. The rest of his physical examination is unremarkable. CBC, BMP and UA are within normal limits. A noncontrast head CT demonstrates no acute intracranial abnormalities.

The Toxicologic Differential

  • Arsenic
  • n-Hexane (in glue)
  • Nitrous oxide
  • Ciguatoxin
  • Thallium
  • Medications including pyridoxine, amiodarone, tacrolimus, vincristine, thalidomide, paclitaxel, and nucleoside reverse transcriptase inhibitors
  • Drug-induced electrolyte (potassium and magnesium) abnormalities
  • Drug intoxication leading to spinal cord or other physical trauma

The patient eventually admitted to abusing nitrous oxide for the past three weeks. He said he had been using an average of 50 cartridges a day. His reasoning was that he had become so anxious from withdrawing from benzodiazepines and opiates that this was the only available means of controlling his anxiety.

whip.jpg

Nitrous Oxide Abuse
Nitrous oxide can be obtained in small cartridges or large tanks. The easiest form to obtain and most commonly abused is the cartridge and cracker system. (Photo.)

The cartridges are intended to be used for whipped cream and may be available in cooking stores, but they are also found in head shops, where the "crackers" and balloons are also legal to buy. Nitrous oxide may also be found in large tanks similar to helium. Balloons are filled with nitrous oxide and the contents are inhaled to achieve a high.

balloon.jpg

Chronic exposure to nitrous oxide leads to the oxidation of the cobalt ion in cyanocobalamin (vitamin B12). This blocks the formation of methylcobalamin, a coenzyme necessary for the production of myelin sheaths.

The most common complaints are numbness and tingling of the distal extremities. Physical exam may reveal diminished sensation to light touch, proprioception, gait ataxia, Lhermitte's sign, hyperreflexia, and spasticity. Nitrous oxide also has hematologic effects causing megaloblastic anemia.

​Commonly Abused Inhalants
Solvents, glue, shoe polish, toluene, gasoline, lighter fluid, spray paint, and paint remover and thinner are also commonly abused. Their contents typically contain a mixture of hydrocarbons that may contain:

  • Toluene: Acute effects include ataxia, disorientation, headache, hallucinations, and seizures. Chronic effects include cerebellar dysfunction, neurocognitive impairment, and peripheral neuropathy.
  • Aliphatic nitrates (amyl nitrates): Side effects include methemoglobinemia, peripheral vasodilation, flushing, hypotension, headache, skin irritation, and allergic reactions.
  • Xylene: A disulfiram-like reaction
  • Halogenated hydrocarbons: CNS depression
  • N-hexane: Peripheral neuropathy

The patient was given a shot of vitamin B12 (1000 mcg) and L-methionine (1 g). He was advised to abstain from inhaling nitrous oxide and referred to the neurology clinic for follow-up. He never went to the clinic and was lost to follow-up.

References:
1. Lin CY, Guo WY, et al. "Neurotoxicity of Nitrous Oxide: Multimodal Evoked Potentials in an Abuser." Clin Toxicol 2007;45[1]:67.
2. Meyers LE, Judge BS. "Myeloneuropathy in a Dentist." Clin Toxicol 2008;46[10]:1095.