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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, June 01, 2015

The urine drug screen commonly utilized in the emergency department is an immunoassay that uses antibodies to detect specific drugs or their metabolites. This allows for rapid screening for drugs of abuse, but it has many limitations.


Gas chromatography-mass spectrometry (GC-MS) is the confirmatory test, but it is more costly, time-consuming, and generally can only be performed by outside laboratories. This confirmatory test is generally not useful in the emergency department, but has a role in cases of pediatric exposures, research, or occupational drug testing.



One of the limitations of a urine drug screen are the false-positive results from the interference of other drugs with the immunoassay, many of which are from structural similarities. Diphenhydramine and quetiapine commonly cause a false-positive for tricyclic antidepressants (TCA).



TCA, left; diphenhydramine, center; quetiapine, right.


The specificity for phencyclidine (PCP) immunoassays is generally poor and false-positives may result from dextromethorphan, venlafaxine, tramadol, ketamine, and diphenhydramine.



PCP, left; dextromethorphan, center; venlafaxine, right.


The amphetamine/methamphetamine screen has many false-positives, including bupropion (Wellbutrin), dextroamphetamine (Adderall), methylphenidate (Ritalin), promethazine (Phenergan), pseudoephedrine, trazodone, and ranitidine.


Case reports have also documented false-positives for opiates (levofloxacin, poppy seeds), THC (pantoprazole, hemp-containing foods, efavirenz), cocaine (coca leaf tea), and amphetamine (ma huang and ephedrine).


False-negatives may result from drug concentrations below the cutoff limit as well as adulterating, substituting, and diluting urine samples. Specific drugs in a drug class also may not be detected depending on the immunoassay used.


The assay most commonly used in hospitals tests for opiates. The term opioids is a broad term that includes the naturally occurring opiates, semi-synthetic opioids, and synthetic opioids. Specific testing for fentanyl, methadone, buprenorphine, oxycodone, or hydrocodone may be requested depending on your laboratory’s resources.


















* Generally detected by the urine drug immunoassay.


Most benzodiazepine immunoassays detect oxazepam and nordiazepam, the metabolites of chlordiazepoxide (Librium), diazepam (Valium), and temazepam (Restoril). A false-negative benzodiazepine test result may occur despite the presence of other benzodiazepines, such as alprazolam (Xanax), lorazepam (Ativan), and versed (Midazolam).


The manufacturer’s package insert of the assay should be referenced if there are any questions about the immunoassay’s detection abilities to avoid incorrect interpretations. The detection time of a drug in urine may vary depending on pharmacokinetics of a drug, cutoff limits, metabolites, and chronicity of use. It is important to emphasize that the detection of a drug in the urine does not necessarily equate to intoxication.


Table 1. Duration of Detection Time of Drugs in Urine




48 hours


30 days

Cocaine metabolite (benzoylecgonine)

2-4 days

Cocaine metabolite: chronic user

Several weeks

Marijuana: single use

3 days

Marijuana: 4 times/week

5-7 days

Marijuana: daily use

10-15 days

Marijuana: long-term, heavy smoker

>30 days


48 hours


48-72 hours


2-4 days

Phencyclidine (PCP)

8 days

Adapted from Mayo Clinic Proceedings 2008;83[1]:66.

Urine drug screens can be thought of as the good, the bad, and the ugly. Screens that are positive for cocaine, THC, or barbiturates are usually true-positives. Screens that are negative for benzodiazepines or opiates could be false-negatives. Depending on the clinical scenario, urine drug screens positive for TCAs, amphetamines, or PCP are more likely to be a false-positive than a true-positive.



Moeller KE, Kelly CL, Kissack JC. "Urine drug screening: Practical guide for clinicians." Mayo Clinic Proceedings 2008;83[1]:66.


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Friday, May 01, 2015

A 40-year-old man presented with hypoglycemia following an intentional overdose with Humalog Mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection). He reported injecting 900 units into his abdomen one hour prior to ED presentation. He complained of lightheadedness and nausea. His initial vital signs were heart rate 110 bpm, blood pressure 112/70 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 99% on room air. His physical exam is remarkable for a visible injection site on the abdomen. Blood glucose is 50, potassium is 3.1, and creatinine is 0.8. The patient reports a prescribed dose of Humalog 75/25 20 units SQ before breakfast and again before dinner. (Table 1.)



The adverse effects of insulin overdose result from hypoglycemia, and include diaphoresis, tachycardia, anxiety, hunger, impaired cognition, agitation, and hypothermia. Severe or protracted cases may result in seizure, coma, permanent neurologic damage, and death. Hypokalemia may also occur because of insulin’s effect on the intracellular shifting of potassium.


These diagnostic tests should be considered in an insulin overdose:

n Blood glucose levels (bedside or laboratory)

n Insulin level and C-peptide

      - Insulin is endogenously secreted as proinsulin, which is cleaved to form insulin and C-peptide. A decreased or nonexistent level of C-peptide is an indicator of surreptitious insulin administration.

            n Potassium and phosphate levels should be checked.


Patients are at risk for hypoglycemia after an intentional injection of insulin. This patient had injected 45 times his recommended dose subcutaneously. For further perspective on dose, emergency physicians may administer 10 units of insulin intravenously in conjunction with an ampule of D50 to manage hyperkalemia. It is worth noting subcutaneous depot injections are erratically absorbed, making it challenging to predict the duration of toxicity. If appropriate, patients should be encouraged to drink or eat to provide and maintain their glucose levels. PO intake will provide a larger dose of glucose with longer duration of activity than anything we can administer by IV. (Table 2.)




If these patients are unable to eat or not responding to enteral nutrition, a dextrose infusion with D10 should be considered with repeated boluses of D50 as needed. Some of these patients may require concentrated dextrose infusions, such as D25W, to treat hypoglycemia. Once initial control is achieved, glucose concentration should be maintained between 100-150 mg/dl with oral intake and a dextrose infusion if needed.


Patients should be monitored for recurrent hypoglycemia with regular interval glucose measurements and recognition of signs or symptoms of hypoglycemia. Frequent glucose checks may require an admission to the ICU, depending on hospital protocols. Potassium should also be monitored because insulin causes intracellular shifting so it should be cautiously repleted to avoid rebound hyperkalemia. Phosphate concentrations should also be monitored because glucose-loading may cause hypophosphatemia.


This patient received orange juice, and was encouraged to eat. He had recurrent episodes of asymptomatic hypoglycemia in the emergency department, and was started on a D10W infusion at 100 ml/hr. He was admitted to the intensive care unit for hourly bedside glucose tests, and had several episodes of asymptomatic hypoglycemia as late as 14 hours post-exposure. He was weaned off the IV dextrose infusion, and no further hypoglycemic episodes were noted.



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Tuesday, March 31, 2015

A 42-year-old man presented with somnolence. His initial vital signs were heart rate 54 bpm, blood pressure 92/68 mm Hg, temperature 37°C, respiratory rate 6, and pulse oximetry 90% on room air. His physical examination was remarkable for depressed level of consciousness, miosis, and bradypnea. His mental status and respiratory rate temporarily improved with the administration of 0.04 mg naloxone. He reports swallowing several “patches” in a suicide attempt.


Popular transdermal patches are listed in the table. Others include diclofenac, buprenorphine, hormone patches (estrogen, contraceptive, testosterone), methylphenidate, and rivastigmine. It is important to consider the potentially significant quantity of drug contained in transdermal patches even after being used.



The patches are designed to deliver small quantities of the drug over a long period of time into the outer layers of skin, and it is absorbed into the deeper layers and then to the bloodstream, which circulates it throughout the body. Several types of transdermal delivery systems are available; fentanyl patches, for example, are available as a reservoir system and matrix system. (Figure 1.)


Reservoir system (left) and Matrix system (right). Derived from Duragesic and Mylan package inserts.


Swallowing, sucking, transmucosal absorption by placement of pieces in mouth, brewing it as a tea to ingest or inject, chewing whole or in pieces, extracting with a needle for injection, eluting with a solvent for injection, pyrolyzing patches for inhalation, rectal insertion, insufflation, transdermal application on abraded skin, applying heat to transdermally applied patch, and dermal application of multiple patches.


Some considerations for transdermal patch exposures include:

n Continued drug delivery from skin depots

    Blood nicotine levels remain elevated for six to 12 hours after removal of a patch.

    The apparent half-life of fentanyl delivered by transdermal patches is about 17 hours after removal of a patch from the skin.

n Supratherapeutic levels may result from skin conditions: application of external heat source (hot tubs, heating pad, etc.), abraded skin, multiple patches, or from physical patch damage resulting in uncontrolled drug release.

n Significant amount of drug remains in used patches

    Studies were conducted on 25 mcg/hour and 100 mcg/hour patches after three days of continuous use, and it was determined that there was 700 to 1220 mcg left in the 25ug/hour patches and 4460 and 8440 mcg in the 100 mcg/hour patches.


Initial management of transdermal patch ingestions includes the identification and standard treatment for the suspected drug. During the primary survey, the patient should be disrobed to allow for a complete survey for any transdermal patches, which should be removed and, subsequently, the skin should be decontaminated with copious amounts of water. GI decontamination with whole bowel irrigation should be strongly considered because these patches contain potentially lethal doses of each drug and their ingestion may lead to altered absorption of the drug.


There are no specific labs outside of the typical toxicology labs that should be ordered to help guide the treatment of these ingestions. It is worth noting that fentanyl is not detected on the standard urine drug screens. Imaging is not typically helpful because standard abdominal radiographs are not reliable in detecting patches. All patients should be admitted and monitored because the onset and duration of symptoms may be unpredictable.


The patient had recurrence of somnolence and bradypnea in the ED. He was started on a naloxone infusion and admitted to the intensive care unit. Whole bowel irrigation was administered. The following morning, the naloxone infusion was discontinued and the patient remained asymptomatic for 12 hours after the naloxone infusion was discontinued. He was medically cleared shortly after.



1. Package inserts for Catapres-TTS (clonidine), Duragesic (fentanyl), Lidoderm (lidocaine 5% patch), NicodermCQ (nicotine), Nitro-Dur (nitroglycerin), and Transderm Scōp (scopolamine).

2. Nelson L, Schwaner R. Transdermal Fentanyl: Pharmacology and Toxicology. J Med Toxicol 2009;5(4):230.

3. Prosser JM, Jones BE, Nelson L. Complications of Oral Exposure to Fentanyl Transdermal Delivery System Patches. J Med Toxicol 2010;6(4):443.

4. Montalto N, Brackett CC, Sobol T. Use of Transdermal Nicotine Systems in a Possible Suicide Attempt. J Am Board Fam Prac 1994;7(5):417.

5. Marquardt KA, Tharratt RS, Musallam NA. Fentanyl Remaining in a Transdermal System following Three Days of Continuous Use. Ann Pharmacother 1995;29(10):969.


Read more about transdermal patches in our archive.


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Monday, March 02, 2015

A 21-year-old man presented with palpitations, tremulousness, nausea, and vomiting. He reported ingesting one 14 mg nicotine patch in a suicide attempt. Initial vital signs include heart rate 132 bpm, blood pressure 140/80 mm Hg, temperature 37°C, respiratory rate 26 bpm, and pulse oximetry 100% on room air. Physical examination is remarkable for agitation, fine resting tremor, tachycardia, and pressured speech.


The lethal dose of nicotine is estimated to range from 1 mg/kg to 10 mg/kg. Reports of nicotine toxicity have occurred with the ingestion of as little as one whole cigarette or three cigarette butts in children under 6. E-cigarette consumption is on the rise, and cases of nicotine toxicity have been reported in children who have ingested the e-cigarette solution. The concentration of the nicotine refills is variable, containing 6 mg/ml (0.6%) to 100 mg/ml (10%). Assuming that 1 ml of solution is equal to 20 drops, one drop of the 10% solution would contain 5 mg of nicotine. Ingestion of as little as one drop of this concentrated solution would cause severe symptoms in children under 6.


Nicotine is well absorbed by various routes, the most rapid route being inhalation (5-60 seconds), followed by the buccal mucosa (15-30 minutes), GI tract (30-90 minutes), and dermal (4.2 hours). Nicotine has an elimination half-life of one to four hours, but the half-life may be shorter with habitual cigarette smoking and longer in dermal exposures.


The toxic effects of nicotine are caused by its stimulation of the postsynaptic nicotinic acetylcholine receptors in the autonomic nervous system. Symptoms are dose-dependent with lower doses producing stimulation of the sympathetic and parasympathetic nervous systems (tachycardia, diaphoresis, agitation) and higher doses producing stimulation of the neuromuscular endplates leading to neuromuscular blockade (seizures, weakness, paralysis, respiratory arrest).


Clinical symptoms of nicotine toxicity are divided into early and late symptoms. Early symptoms may include vomiting (the most common symptom, occurring in 50 percent of patients), salivation, diaphoresis, abdominal pain, hypertension, tachycardia, dizziness, headache, and seizures. Late symptoms may include diarrhea, hypoventilation, bradycardia, dysrhythmias, apnea, and paralysis. The duration of symptoms is typically one to two hours for mild toxicity while more severe symptoms generally resolve within 12 to 24 hours.


All contaminated clothing and nicotine patches should be removed and the skin decontaminated with soap and water. Medical staff should use standard precautions because nicotine can be transdermally absorbed. Activated charcoal adsorbs nicotine well, but it must be carefully considered because of the incidence of vomiting, seizures, and paralysis, which increase the risk for aspiration.


The use of whole bowel irrigation should be considered in patients who have ingested a nicotine patch because of the potential for significant toxicity. This is accomplished by administering 1-2 L of polyethylene glycol per hour (in adults) via a nasogastric tube until the rectal effluent is clear. No randomized control trials demonstrate a reduction in morbidity or mortality with its use, however.


Patients should be placed on a continuous cardiac monitor and pulse oximetry. Useful studies may include glucose, electrolytes, and electrocardiogram. Specific levels for nicotine and its metabolite cotinine may be available, but are not useful in acutely managing these patients.


Treatment for acute nicotine toxicity is supportive care. Patients manifesting signs of severe toxicity may need to be intubated early because of concern for paralysis and respiratory failure. Benzodiazepines should be used liberally to treat tachycardia, agitation, and seizures. Patients with protracted or intractable vomiting can be treated with antiemetics. Atropine can be used to treat bradycardia. IV fluids should be used to treat hypotension and potentially pressors for hypotension refractory to fluids.


This patient was admitted to a telemetry bed for nicotine toxicity. Whole bowel irrigation was administered, and the patient required Ativan for agitation. The following morning the patient’s vital signs and mental status normalized, and he was transferred to a psychiatric facility.


Suggest Reading

1. Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol. 2014;88(1):5.

2. Soghian S. Nicotine. In: Nelson LS, Lewin NA, et al., eds. Goldfrank's Toxicologic Emergencies. 9th ed. New York: McGraw-Hill, 2011:1185.

3. Cantrell L. Nicotine poisoning. California Poison Control System. 2005;3(2):



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Monday, February 02, 2015

A 27-year-old woman with no past medical history presented to the ED by EMS after being found unresponsive at home by her partner. EMS reported that she was unresponsive with a GCS of 3, pinpoint pupils, and sonorous breath sounds. Naloxone 0.4 mg IV was administered, and the patient became responsive. The patient was delirious, agitated, and tachycardic upon arrival to the ED. She was administered lorazepam 2 mg IV without improvement. Her agitation and delirium were so severe that she was intubated, paralyzed with rocuronium, and started on a midazolam infusion.


What is the appropriate dose of IV naloxone?

No consensus exists on the appropriate starting dose of naloxone, but many toxicologists recommend a starting dose of naloxone 0.04 mg IV in opioid-dependent patients, quickly titrating up every two minutes to a maximum of 10 mg. If no effects are seen after 10 mg, the patient’s respiratory or CNS depression are unlikely to be a result of opioid toxicity. Special considerations should be taken in certain populations, including opiate-naive patients and children where larger doses of Narcan can be used initially to reverse the respiratory depression.


Adverse effects have been reported at doses as low as 0.4 mg IV, which support a starting dose of 0.04 mg. It is important to remember that most adverse effects are from acute opioid withdrawal rather than to the naloxone itself.


To administer naloxone 0.04 mg IV, dilute a naloxone preparation of 0.4 mg/1ml ampule in a 10 ml syringe of normal saline, and then administer the medication 1 ml at a time.


What is the relationship between naloxone and pulmonary edema?

Pulmonary edema and acute lung injury following naloxone administration for opioid-toxic patients has been described, but it remains controversial whether acute lung injury is from acute withdrawal precipitated by naloxone or to opioid-induced complications.


Several mechanisms relating naloxone to pulmonary complications have been proposed, such as naloxone to reverse the profound respiratory depression leading to more apparent opioid-induced pulmonary findings. Another mechanism of action for naloxone-induced pulmonary edema is the catecholamine surge. A study by Kienbaum, et al., in 1998 demonstrated a 30-fold increase in epinephrine levels after naloxone administration in opioid-dependent patients. (Anesthesiology 1998;88[5]:1154.) Interestingly, this catecholamine surge has been shown to be exacerbated by hypoventilation or hypercapnia in canines.


Other explanations for pulmonary edema that occurs in the opioid-toxic or anesthesia patients who received naloxone include inherent toxicity of opioids themselves, co-administered drugs, or other underlying disease processes.


What serious cardiovascular complications have been reported in association with the administration of naloxone?

Serious cardiovascular effects include arrhythmias such as ventricular tachycardia, myocardial infarction, cardiomyopathy, and heart failure. These complications are rarely reported, and may actually be the result of hypoxia, inherent toxicity of the opioids themselves, co-intoxication with another agent (such as cocaine), or pre-existing cardiac disease. The mechanism is thought to be from catecholamine release induced by precipitated opioid withdrawal or unmasking of sympathomimetic agents.


What are other adverse effects related to the administration of naloxone?

Many of the adverse effects related to the administration of naloxone are from acute opioid withdrawal.




Managing patients who have received naloxone for opioid intoxication.

Prior to administering naloxone, one may consider providing sufficient ventilation to potentially reduce the catecholamine surge that is believed to be exacerbated by elevated CO2, and therefore possibly decrease the incidence of the more serious adverse effects listed above.


Patients who received naloxone for opioid intoxication should be closely monitored for recurrence of respiratory depression and sedation, particularly in patients who have ingested long-acting opiates or opioids (methadone) or transdermal patches. These patients should be on continuous cardiac and pulse oximetry monitoring because the half-life of naloxone (30-80 minutes) is generally shorter than most opioids. Redevelopment of respiratory depression requires repeat administration of naloxone. Oxygen should only be administered if the patient becomes hypoxic because it may delay detecting hypoventilation as a normal pulse oximetry reading and will not reflect developing hypercapnia. Some physicians for this reason recommend continuous end-tidal CO2 monitoring in these patients because this is a more accurate indicator of a patient’s ventilatory effort.


Symptomatic support should be provided to help alleviate the uncomfortable symptoms if opioid withdrawal occurs. Clonidine, an alpha-2 adrenergic receptor agonist, has been shown to be effective in cases of autonomic instability (i.e., tachycardia, hypertension).


Disposition of a patient who received naloxone for opioid intoxication.

The disposition of a patient who has received naloxone in the ED must be carefully considered. The pharmacological effects of naloxone are shorter than most opioids used, and some patients are at risk for re-sedation or respiratory depression after the effects of naloxone have worn off. It is prudent to monitor patients for at least six hours after they have been administered naloxone for redeveloping symptoms and to consider admission of patients who have required two or more doses of naloxone.


A special consideration must be made in patients who have ingested long-acting opioids/opiates. Patients who have ingested sustained-release formulations (e.g, MS Contin), long-acting opioids (methadone), or one or more fentanyl patches require admission for 24-hour observation.


This patient required sedation and eventually intubation because of her severe delirium and agitation, but the majority of patients rarely experience adverse effects as a result of naloxone administration.


Suggested Reading:

1. Clarke SF, Dargan PI, Jones AL. Naloxone in opioid poisoning: Walking the tightrope. Emerg Med J 2005;22(9):612.

2. Lameijer H, Azizi N, et al. Ventricular tachycardia after naloxone administration: A drug related complication? Case report and literature review. Drug Safety-Case Reports 2014;1:1.

3. Spadotto V, Zorzi A, et al. Heart failure due to ‘stress cardiomyopathy’: A severe manifestation of the opioid withdrawal syndrome. Eur Heart J Acute Cardiovasc Care 2013;2(1):84.


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About the Author

Gregory S. LaSala, MD; Rita G. McKeever, MD; and Jolene Okaneku, MD

Drs. LaSala, McKeever, and Okaneku are medical toxicology fellows at Drexel University College of Medicine in Philadelphia. Dr. LaSala, top, did his emergency medicine residency at Pennsylvania State University Hospital/Hershey Medical Center, and is a board member of the American College of Medical Toxicology Fellows in Training. Dr. McKeever, center, completed her residency at Drexel University College of Medicine and is a board member of the American College of Medical Toxicology Fellows in Training. Dr. Okaneku, bottom, is a graduate of Jefferson Medical College and of the emergency medicine residency at Drexel.

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