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, July 2, 2018

A 24-year-old man presented with uncontrollable epistaxis. He said he had been bleeding "a ton" from his nose continuously for four hours. He denied recent trauma, and explained that this epistaxis was sudden onset. He had no past medical history, and denied previous episodes of excessive bleeding. An examination demonstrated no signs of trauma and was unremarkable aside from the epistaxis. His nostrils revealed no obvious bleeding vessels for cauterization. His social history was remarkable for occasional drinking, marijuana use, and recent use of synthetic marijuana.

His vital signs were a heart rate of 85 bpm, blood pressure of 135/80 mmHg, temperature of 98°F, and pulse oximetry of 100% on room air. Blood work revealed a hemoglobin of 13, hematocrit of 39, platelet of 250, PT of 35, INR of 8, and a PTT of 140.

Reports have recently been recounted of synthetic cannabinoids adulterated with brodifacoum, a long-acting vitamin K antagonist normally used in rat poison. More than 160 people presented to a U.S. health care facility between March and April 2018 with unexplained bleeding. Four fatalities were reported, all in Illinois. Lab testing confirmed the presence of brodifacoum in 18 people. Users described bleeding from their eyes and ears as well as heavy menstrual periods, frequent and severe nose bleeds, and gum bleeding.​

This outbreak appears to be from an unintentional adulteration of synthetic marijuana, but some reports have users intentionally smoking marijuana with brodifacoum for a greater high and to potentiate the effects of the illicit drug. The first report in the literature was a 17-year-old boy who presented to the ED with mucosal and skin bleeding, and was found to have a prolonged PT. (Arch Pathol Lab Med 1997;121[1]:67.) Another case reported a 37-year-old-man who smoked crack cocaine mixed with brodifacoum and presented with a severe coagulopathy. (N Engl J Med 2001;345[9]:700.)

 d-CON.png

Brodifacoum is a vitamin K antagonist similar to Coumadin but much longer acting. It is categorized as a superwarfarin, first introduced in 1975 for warfarin-resistant rodents.

                   Coumadin   Brodifacoum

Half-life        20-60 hrs      20-130 days

LD50                 3 mg/kg        0.27 mg/kg

Brodifacoum causes anticoagulation by inhibiting the action of vitamin K 2,3-epoxide reductase in the vitamin K cycle. The deficiency in active vitamin K leads to functionally inactive vitamin K-dependent coagulation factors II, VII, IX, IX, X, and proteins C and S. Acute symptoms are all associated with bleeding, and include hemoptysis, hematuria, GI bleeding, retroperitoneal hemorrhage, intracranial hemorrhage, and epistaxis.

Treating brodifacoum toxicity is similar to Coumadin reversal; vitamin K and PCC administration are the mainstays of treatment. Brodifacoum is more complicated because of the prolonged half-life and prolonged period of anticoagulation. Brodifacoum poisoning patients must first be divided into two groups to decide which treatment to give.

Unintentional Ingestions

These are generally children who present to the ED after accidentally eating a pellet of rat poisoning. These patients are generally just curious and exploring their environment; they tend to put a pellet in their mouth. They should be examined for active bleeding, and can be discharged home if there is none. Performing coagulation studies is unnecessary because the effects on the PT/INR from superwarfarins are delayed. These children should follow up with their doctors, but do not need laboratory testing unless they develop bleeding. Those patients who have active bleeding on presentation should have lab studies consisting of CBC, BMP, PT/INR, PTT, and type and screen.

Anticoagulation is reversed using PCC or oral vitamin K. Patients can be discharged if bleeding is controlled, but they need close follow-up for INR checks and repeat dosing of vitamin K until PT/INR levels normalize for several days without treatment.

Intentional Ingestions

These patients should be admitted and serial PT/INRs obtained because brodifacoum can cause delayed coagulopathy. PCC along with IV vitamin K should be administered for life-threatening bleeding. These patients should be given oral vitamin K starting at 50 mg three to four times a day for the first two days after bleeding is controlled. Oral vitamin K is continued for weeks, even months, until the INR normalizes even when bleeding has resolved.

The patient in our case was given PCC and vitamin K 10 mg IV. Nasal packing was placed, and his bleeding eventually stopped. He was admitted for observation, and given vitamin K 50 mg orally every six hours. His bleeding stopped on day two, but his INR remained elevated at 6. Brodifacoum levels were obtained and found to be 42 ng/ml. He was discharged home on hospital day three, and prescribed vitamin K 50 mg oral twice a day. He was also given strong bleeding precautions and advised to avoid any physical injury. He continued this treatment for several weeks until his INR levels normalized.

Suggested Readings:

1. Outbreak Alert: Potential Life-Threatening Vitamin K-Dependent Antagonist Coagulopathy Associated with Synthetic Cannabinoids Use. Centers for Disease Control and Prevention, April 5, 2018; http://bit.ly/2JIxOAH.

2. La Rosa FG, Clarke SH, Lefkowitz JB. Brodifacoum intoxication with marijuana smoking. Arch Path Lab Med 1997;121(1):67.

3. Waien SA, Hayes D Jr, Leonardo JM. Severe coagulopathy as a consequence of smoking crack cocaine laced with rodenticide. New Engl J Med 2001;345(9):700.

4. Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning: A report of two cases and review of the literature. Am J Hematol 2007;82(7):656.

5. Outbreak Alert Update: Potential Life-Threatening Vitamin K-Dependent Antagonist Coagulopathy Associated with Synthetic Cannabinoids Use. Centers for Disease Control and Prevention, April 23, 2018; http://bit.ly/2Jo62Ky.​


Friday, June 1, 2018

Social media influences nearly every part of our lives—how we communicate, teach, and protest. It is powerful because it allows people around the world to connect instantaneously. One of those ways is the social media phenomenon popular since the early 2000s: internet challenges. These challenges range from funny, like the mannequin challenge, to charitable, such as the ice-water bucket challenge, to dangerous, like the blue whale challenge. Several of these can cause injury by ingestion or topical application.​

The Tide Pod Challenge

Concerns of safety arose shortly after laundry pods were introduced in 2012 when unintentional pediatric exposures were reported. Young children developed significant toxicity, including caustic injuries, respiratory distress, altered mental status, and even death. Those prompted efforts to make this household item safer. Some of the changes included making the packaging opaque, making the containers child-safe, and adding a bittering agent to the outer film. More recently, the Tide Pod Challenge has promoted the ingestion of laundry pods. Teenagers would record themselves chewing and gagging on these pods and then daring others to do it.

tox tide pods.jpg

Austin Kirk​

The Cinnamon Challenge

The challenge here was to eat a spoonful of cinnamon in 60 seconds without drinking anything to wash it down. Cinnamon is a caustic irritant composed of cellulose fibers that may cause a hypersensitivity reaction and pulmonary inflammation. Symptoms include coughing, gagging, vomiting, throat and nasal irritation, and chest tightness. Cinnamon may cause irritation and lead to aspiration. A Michigan teenager was hospitalized for four days in 2013 from a collapsed lung and pneumonia caused by the cinnamon challenge, and a 4-year-old died in 2015 after ingesting cinnamon. He accidently inhaled the cinnamon and asphyxiated. Treatment is supportive, and may include bronchodilators in those with asthma. (Pediatrics 2013;131[5]:833; Medical Daily, June 9, 2015; http://bit.ly/2vMrMJz.)

tox cinnamon.jpg

Wikimedia Commons​

The Nutmeg Challenge

The nutmeg challenge and nutmeg abuse involve ingesting or snorting nutmeg. It has been reported to produce a high. Nutmeg contains myristicin, an oil that acts as a deliriant. The mechanism of toxicity is not known, but may involve monoamine oxidase inhibition and conversion to amphetamine analogues. Symptoms include tachycardia, dry mouth, nausea, hallucinations, and delirium. Symptoms may last for 24 hours after a full dose of nutmeg, and are mostly described as unpleasant. Treatment is supportive with antiemetics, IV fluids, and benzodiazepines as needed.

tox nutmeg.jpg

Wikipedia Commons​

The Salt and Ice Challenge

The salt and ice challenge has users placing salt on the skin with ice placed over it for as long as possible. This causes a burning sensation, and the challenge is the length of time the pain is endured. This may lead to second- and third-degree burns. A 12-year-old boy was hospitalized in 2012 for severe second-degree burns on his back. (Photo of patient with burns on her hand from doing this challenge.) Treatment includes supportive care and topical antibiotics. Transfer to a burn center may be necessary if the burns are severe enough. (CBS News, June 7, 2012;https://cbsn.ws/2vPd0BN.)

tox salt ice.jpg

Biosthmors​

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Monday, April 2, 2018

Part 4 in a Four-Part Series

The United States is in the midst of a significant opioid epidemic, and a large proportion of the illegal opioids being sold contain fentanyl or fentanyl analogs. The Drug Enforcement Administration reported that U.S. law enforcement agencies seized at least 239 kilograms of illicitly produced fentanyl from August 2013 to the end of 2015. (http://bit.ly/2obUOLs.) This drug is responsible for many opioid overdoses and deaths because of its extremely low lethal dose.

First responders, a population not initially thought to be at risk, have been found to be exposed to synthetic fentanyl analogs. Some first responders have reported symptoms when they came into contact with these illicit fentanyls. Several agencies have published guidelines on how first responders can protect themselves. Recently, the American College of Medical Toxicology (ACMT) and the American Academy of Clinical Toxicology (AACT) published a position statement on this subject. (Clin Toxicol [Phila] 2017:1. doi: 10.1080/15563650.2017; http://bit.ly/2of1FEf.) Overall, they found that the risk of clinically significant exposure to first responders is very low, and recommended that first responders who may be exposed to fentanyl should be trained in recognizing the opioid toxidrome and should have naloxone readily available and know how to administer it.

tox cave first responders.jpg

Potential Routes of Exposure

Potential routes include inhalation, ingestion, mucous membrane contact, and transdermal and percutaneous exposure. Fentanyl is highly bioavailable by inhalation. It was suspected that carfentanil and remifentanil were used in an aerosolized form to subdue terrorists who had taken hostages at a Moscow movie theater in 2002. (J Anal Toxicol 2012;36[9]:647.) One hundred and twenty-five people died from that incident. First responders, however, are unlikely to encounter the aerosolized form of the drug because these particles would need to be suspended in air. Industrial producers of fentanyl estimated that an unprotected worker would have to be exposed for 200 minutes to reach a dose of 100 mcg of fentanyl. (Northern New England Poison Center. Sept. 6, 2017; http://bit.ly/2ocwCsy.)

Ocular-facial exposure is another possibility because fentanyl and its analogs are readily absorbed through mucous membranes. A veterinarian was splashed in the eye with carfentanil and developed opioid toxicity requiring naloxone, according to one case report. (Am J Emerg Med 2010;28[4]:530.)

Transdermal exposure is possible due to fentanyl's low molecular weight and lipophilicity. A clinically significant exposure, however, appears unlikely. If fentanyl patches were placed on both palmar surfaces, it would take 14 minutes to receive a 100-mcg dose of fentanyl. (Clin Toxicol [Phila] 2017:1. doi: 10.1080/15563650.2017.) This number presumes a transdermal preparation, and therefore the risk of absorption from the powdered form is much lower. Data are limited, however, on ultra-potent synthetic opioids.

The Use of Naloxone to Reverse Overt Opioid Toxicity

Little is available in the literature on the efficacy of naloxone in reversing fentanyl analogs. Anecdotally, it has been said that fentanyl requires larger doses of naloxone for reversal, but some animal studies have demonstrated that standard doses of naloxone are effective in reversing carfentanil. If a patient has been given 10 mg of naloxone without response, it is unlikely to be helpful, and securing the patient's airway would be recommended. (Clin Toxicol [Phila] 2017:1. doi: 10.1080/15563650.2017.)

First responders have reported myriad nonspecific findings such as dizziness, fatigue, weakness, "feeling like the body is shutting down," and "dying." All of these have been reported without objective evidence of opioid toxicity. (Clin Toxicol [Phila] 2017:1. doi: 10.1080/15563650.2017.)

Personal Protective Equipment and Decontamination

Recent guidelines for PPE have attempted to protect first responders while avoiding delay in treatment for this time-sensitive condition. The Centers for Disease Control and Prevention recommend that nitrile gloves be used for dermal protection and that a respirator be used when there is concern for aerosolized drug particles. (http://bit.ly/2ocqMYe.) Incidental dermal exposures should immediately be washed off with water. (Clin Toxicol [Phila] 2017:1. doi: 10.1080/15563650.2017.)

Special considerations should be made for canine units because they are closer to the drug with larger surface areas for inhalation and at greater risk for inhalational toxicity.​

Wednesday, February 28, 2018

Part 3 in a Four-Part Series​

A 26-year-old man presented with fatigue. He complained of body aches, diarrhea, and nausea. His history was significant for chronic back pain, for which he had been prescribed oxycodone that he has taken daily for three years. He reported that he had stopped taking it two days before his visit.

He denied other medication or drug use. He was alert but restless and diaphoretic. His ECG showed sinus tachycardia. His labs included a WBC of 12, Hgb of 12, glucose of 89 mg/dL, creatinine of 1.0 mg/dL, sodium of 140 mEq/L, potassium of 3.8 mEq/L, and CK of 140 U/L. He was experiencing opioid withdrawal.

The symptoms of opioid withdrawal include:

-Muscle aches

-Restlessness

-Anxiety

-Lacrimation

-Rhinorrhea

-Diaphoresis

-Insomnia

-Yawning

-Diarrhea

-Piloerection

-Abdominal cramping

-Nausea and vomiting

The Clinical Opiate Withdrawal Scale can be used to help quantify the severity of opiate withdrawal using some of the symptoms experienced in withdrawal. (http://bit.ly/MDCalcCOWS.)

Non-Opioid Treatments for Withdrawal Symptoms

Symptoms​
Treatment
Myalgias, arthralgias​
​NSAIDs/acetaminophen; also
muscle relaxers such as baclofen,
tizanidine, and methocarbamol
(use with caution)
​Autonomic effects​Clonidine
​Diarrhea​Octreotide/Lomotil
​Nausea, vomiting​O​ndansetron/metoclopramide


These medications may help withdrawal symptoms in the immediate future, but it is important to realize that these patients will have physical withdrawal symptoms for up to one week.

Medication-assisted treatment for opioid addiction includes methadone and buprenorphine. It is important to have a protocol to follow at your hospital if you choose to induce these patients or to have a working relationship with a drug rehabilitation facility to transfer these patients to. It is also worthy to note that there are many specific inclusion/exclusion criteria for opioid addiction treatment.

Methadone

-Mechanism of action

     o Agonist at the mu-receptor

-Formulations

     o Used as oral solution/tablet

-Potential adverse drug effects

     o Prolonged QT. In patients taking high doses of methadone or with a recent increase in methadone dose, torsade de pointes has been reported. There are also drug interactions with other drugs associated with prolonged QT.

     o Methadone is metabolized by cytochrome P3A4. Drugs such as nelfinavir, efavirenz, carbamazepine, phenytoin, and phenobarbital may induce this enzyme, leading to decreased serum levels precipitating withdrawal. Serum methadone levels may increase in patient taking some SSRIs.

Buprenorphine

-Mechanism of action

     o Mixed agonist-antagonist

       -Partial agonistic effect at mu-opioid receptors

       -Antagonistic effect at kappa-opioid receptors

-Formulations of buprenorphine-naloxone

     -Generic: sublingual tablet

     -Bunavail: buccal film

     -Suboxone: sublingual film

     -Zubsolv: sublingual tablet

-Potential adverse drug effects

     -Also metabolized by cytochrome P3A4

Naloxone is added to buprenorphine in these formulations to prevent its misuse. Naloxone is not orally bioavailable, but it can be used intravenously if its formulation is tampered with. The naloxone dose will likely precipitate withdrawal.

As a partial agonist, buprenorphine has a "ceiling effect" on respiratory depression, where escalating doses do not cause additional respiratory depression. This effect may not apply for pediatric ingestions, and children may develop profound, recurrent, or delayed CNS and respiratory depression.

The patient received IVF, octreotide, tizanidine, and a dose of clonidine. His tachycardia, nausea, myalgias, and diaphoresis had improved on reassessment. A discussion with the patient was made regarding opioid treatment options. The patient was referred to an outpatient treatment program and educated that his withdrawal symptoms could persist for up to one week.​

Suggested Reading

Center for Substance Abuse Treatment. Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2005. (Treatment Improvement Protocol (TIP) Series, No. 43.) Chapter 3. Pharmacology of Medications Used To Treat Opioid Addiction. Available from http://bit.ly/2FwH8ln.

Tuesday, January 2, 2018

Part 2 in a Four-part Series​

A 57-year-old man presented with acute onset altered mental status. His family said he had been behaving normally. Prior to dinner, however, he became difficult to arouse, and was speaking gibberish. He was somnolent but arousable to physical stimuli on arrival in the ED.

He answered questions inappropriately and would then go back to sleep. His past medical history was consistent with hypertension, hypercholesterolemia, and spinal fusion a month ago. His medications included lisinopril, atorvastatin, and hydrocodone. His vital signs were a blood pressure of 110/65 mm Hg, heart rate of 90 bpm, temperature of 98.5°F, respiratory rate of 6 bpm, and pulse oxygen of 95% on room air. He had no focal neurologic deficits and pupils at 3-2 mm bilaterally.

How Naloxone Works and the Correct Dosage

Naloxone works as a competitive mu opioid-receptor antagonist. The dosage is empirical and depends on the amount of opioid taken, the type of opioid, and how dependent the patient is on opioids.

All three factors should be considered before administering naloxone. The initial dose should be small (0.04 mg), followed by escalating doses (0.5 mg, 1 mg, 2 mg, 4 mg, 10 mg, 15 mg) every two to three minutes until there is a response. (N Engl J Med 2012;367[2]:146.) More potent opioids, such as synthetic fentanyl analogs and buprenorphine, may require higher levels of naloxone. Patients who are opioid-dependent like the patient in this case will have precipitated withdrawal even at levels as low as 0.4 mg. Use of the minimum effective dose followed by quick escalation to achieve reversal is the most prudent treatment strategy. A continuous infusion is indicated for recurrent symptoms.

Selecting Patients for Naloxone

The indication for administering naloxone is the presence of respiratory depression. These patients generally do not have a problem of oxygenation but rather of ventilation; they should not be automatically treated with supplemental oxygen. In fact, supplemental oxygen may be a detriment to these patients because it can cause a falsely elevated oxygen saturation on the pulse oximeter and subsequently a delay in the recognition of hypoventilation.

Optimal monitoring should be done with a continuous end-tidal CO2; otherwise a pulse oximeter that can measure the respiratory rate is useful. If patients develop respiratory depression as measured by their respiratory rate, end-tidal CO2, or CO2 measured on a VBG, they should be administered naloxone and observed.

Disposition of Opioid-Intoxicated Patients after Receiving Naloxone

Disposition depends on the opioid that the patient used. For patients who say they used heroin, a short-acting opiate, a single dose of naloxone should suffice. These patients can be monitored for three to four hours.

The vitals and observations that may predict safe discharge in these patients:

  • They can mobilize as usual.
  • Oxygen saturation of >92% on room air
  • Respiratory rate of >10 bpm and <20 bpm
  • Temperature >35°C and <37.5°C
  • Heart rate >50 bpm and <100 bpm Glasgow Coma Scale of 15

The patient should meet all of these criteria without verbal or physical stimuli.

Some clinicians recommend a prescription of naloxone for these patients to help in case of future overdoses. Patients taking longer-acting opioids (i.e., oxycodone, hydrocodone, methadone, and buprenorphine) or who require additional administration of naloxone during an observation period should be admitted to the hospital to a monitored bed. Pediatric patients with an accidental ingestion of one of these longer-acting opioids should be admitted for a 24-hour observation. Fentanyl derivatives generally require such large doses of naloxone for reversal that these patients should be admitted directly to an ICU or a step-down unit.

Timing of Naloxone Prescription

Due to the severity of the opioid epidemic, recent legislation has focused on increasing the availability of naloxone not only to emergency responders but also to the public. President Barack Obama signed the Comprehensive Addiction and Recovery Act in 2016 to increase the availability of naloxone to first responders and the public. There are several formulations from which providers can choose to prescribe to patients, but some are cost-prohibitive. The provider should educate the patient and his friends and family members about the use and limitations of naloxone.

Naloxone Product              Manufacturer           Previous cost    Cost (2016)

Injectable or intranasal,              Amphastar              $20.34 (2009)        $39.60

1 mg/mL vial (2 mL)

(mucosal atomizer separate)

 

Injectable

0.4 mg/mL vial (10 mL)               Hospira                  $62.29 (2012)        $142.49

0.4 mg/mL vial (1 mL)                Mylan                     $23.72 (2014)        $23.72

0.4 mg/mL vial (1 mL)                West-Ward             $20.40 (2015)        $20.40

 

Auto-injector, two-pack               Kaleo                     $690 (2014)           $4,500

of single-use prefilled

auto-injectors (Evzio)

 

Nasal spray, two-pack                 Adapt Pharma         $150 (2015)           $150

of single-use intranasal

devices (Narcan)​

Chart adapted N Engl J Med 2016;375[23]:2213.

tox cave narcan.jpg

Nasal Narcan produced by Adapt Pharma.​

The patient was a chronic opiate user, so was administered 0.04 mg IV naloxone. His respirations increased to 12 bpm, and he remained somnolent but was easily arousable to voice. When awake, he was alert and oriented. After one hour, he required another 0.04 mg IV naloxone. The patient was admitted to a step-down unit for observation because he was known to be prescribed oxycodone, and he was placed on a naloxone infusion at two-third of the effective naloxone dose.