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.

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.

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.)

tox-opioidcrisis1.jpg

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.​

tox-opioidcrisis21.jpg

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.

tox cave-alcohol1.jpg

Credit:

Rick/Creative Commons​