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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.
Saturday, July 2, 2016

An 18-month-old boy presented to the emergency department with vomiting. His mother reported that he had three episodes of nonbloody emesis just prior to arrival. She is concerned that he may have ingested a laundry detergent pod. His vital signs were heart rate 140 bpm, blood pressure 102/65 mm Hg, respiratory rate 30 bpm, SPO2 96% on room air, and temperature 98.4° F.

The patient is drowsy, has no visible oropharyngeal lesions, his abdomen is soft and nontender, and his lungs are clear. His skin has mild erythema around the mouth. Toxicology was consulted regarding management.

The National Poison Data System collected data between 2013 and 2014 for more than 62,000 children under 6 who were exposed to laundry and dishwasher detergents. It was noted that overall detergent exposure increased, but the greatest increase were in the detergent pods (laundry 17% and dishwasher 14%).

tox cave.jpg
Photo Credit: Austin Kirk

Many side effects were associated with laundry detergent pod ingestion:

  • Gastrointestinal: Nausea, vomiting, caustic effects (esophagitis, ulcers)
  • Pulmonary: Coughing, stridor, aspiration, bronchospasm, oxygen desaturation, acute respiratory distress syndrome
  • Metabolic: Metabolic acidosis, lactic acidosis
  • Neurologic: Rapid onset of drowsiness, as early as 20 minutes after exposure in some cases
  • Contact irritation: Ocular irritation, corneal abrasion, keratitis, dermal irritation

The pod casing holds concentrated surfactants, detergents, and enzymes, which dissolve after contact with water. Toxicity is possibly multifactorial and possibly dependent on specific brands and formulations. One component, propylene glycol, is metabolized to lactate and contributes to the transient elevation of serum lactate and metabolic acidosis. Ethoxylated alcohols, a class of non-ionic surfactants, are associated with the vomiting, diarrhea, and lethargy after ingestion.

Laundry pods can deliver significantly higher concentrations of detergent when the casing is broken, as occurs upon biting the water-soluble casing. The incidence of ingestion is likely higher because their appealing appearance leads children to mistake them for candy.

The clinical effects are self-limited, and management is mostly supportive in most cases. Assessment of the airway is important for patients presenting with signs of respiratory distress or aspiration. Patients should also be closely observed for profound CNS depression and should be assessed for airway protection. Several cases have been reported of children presenting obtunded and requiring intubation. Bronchospasm symptoms may be treated with albuterol nebulizer. A chest radiograph should be obtained in these cases because of the risk of aspiration pneumonitis.

Dermal decontamination should be initiated with removal of contaminated clothing and thorough irrigation with copious amounts of water to prevent development of significant chemical burns. Gastric decontamination with activated charcoal is not recommended given the potential risk for aspiration with vomiting and CNS depression.

Endoscopic evaluation may be considered in patients with suspected significant caustic injury. These patients may present with persistent vomiting, drooling, difficulty or aversion to swallowing or eating, and abdominal tenderness. Though these criteria are not 100% sensitive for caustic injury, children who are asymptomatic and able to tolerate PO do not need endoscopic evaluation and can be safely discharged after observation.

Our patient was observed in the emergency department without further episodes of emesis. He tolerated sips of juice and crackers without difficulty. His lungs remained clear, and he was resting comfortably. The patient was discharged home with his mother. His parents were educated regarding potential dangers of laundry detergent pods and toxic exposure prevention.

Suggested Readings

  • Smith E, Liebelt E, Nogueira J. Laundry Detergent Pod Ingestions: Is There a Need for Endoscopy? J Med Toxicol 2014;10(3):286.
  • Beuhler MC, Gala PK, et al. Laundry Detergent "Pod" Ingestions: A Case Series and Discussion of Recent Literature. Pediatr Emerg Care 2013;29(6):743.
  • Davis MG, Casavant MJ, et al. Pediatric Exposures to Laundry and Dishwasher Detergents in the United States: 2013-2014. Pediatrics 2016;137(5):e20154529.
  • Russell JL, Wiles DA, et al. Significant Chemical Burns Associated with Dermal Exposure to Laundry Pod Detergent. J Med Toxicol 2014;10(3):292.

Thursday, June 2, 2016

A 24-year-old man with a history of schizophrenia presented with altered mental status. His mother said he had become more catatonic and rigid over the previous two days. She reported that he was prescribed Abilify 5 mg by mouth daily for three years, but a long-acting depot of Abilify 400 mg had been administered two days before by court order.


His vital signs include a heart rate of 120 bpm, blood pressure 140/90 mm Hg, temperature 38.5°C, respiratory rate is 14 bpm, and SPO2 is 98% on room air. The patient is alert and diaphoretic. Pupils are 3 mm. Cogwheeling, rigidity, and two beats of ankle clonus are also observed. Toxicology is consulted and asked about interventions and anticipated observation period.


Differential Diagnosis

< Neuroleptic malignant syndrome
< Serotonin syndrome
< Anticholinergic syndrome
< Sympathomimetic
< Malignant catatonia
< Heat stroke
< Infection
< Psychogenic
< Baclofen withdrawal
< Extrapyramidal symptom (tardive dyskinesia)

Neuroleptic malignant syndrome is a life-threatening idiosyncratic reaction associated with neuroleptic medication. It was first described in the 1960s in patients treated with haloperidol, but has been associated with virtually every antipsychotic. The incidence of NMS is reported to be 0.2-2.4 percent of patients receiving neuroleptic medications. The mechanism of NMS has not been completely elucidated, but the most accepted mechanism of action appears to be antagonism of the D2 receptors in the striatum, hypothalamus, and mesocortex, leading to a dopamine reduction in the CNS. The incidence of NMS is higher in first-generation antipsychotics (haloperidol) than in second-generation or atypical antipsychotics. NMS may also occur with withdrawal of pro-dopaminergic medications. Clinically, it manifests as a tetrad of altered mental status, muscle rigidity, hyperthermia, and autonomic dysfunction (tachycardia, cardiac dysrhythmia, blood pressure fluctuation).

Signs typically evolve over a period of several days, which distinguishes it from serotonin syndrome (which develops over several hours following inciting exposure). The greatest risk is within two weeks of a medication initiation, but NMS can also occur in prolonged use of an antipsychotic, especially following rapid dose escalation. Proposed risk factors include higher doses, long-acting injectable antipsychotics, change from one agent to another, history of NMS, and coingestants/polypharmacy.

The long-acting injectable antipsychotic medications used in treating schizophrenia are primarily indicated for those with poor adherence to medication, and are therefore at risk for relapse.

First-generation antipsychotics: Potent dopamine blockade
< Fluphenazine
< Haloperidol

​Second-generation antipsychotics: Dopamine and serotonin receptor blockade
< Olanzapine
< Risperidone
< Paliperidone (4-week and 12-week), a metabolite of risperidone


Complications Associated with NMS
< Compartment syndrome
< Hyperthermia
< Rhabdomyolysis and associated acute renal failure
< Respiratory failure
< Disseminated intravascular coagulation
< Dehydration
< Delirium
< Death

Management of patients with suspected NMS first involves the discontinuation of all antipsychotics or other offending agents. Treatment is mainly supportive. Hyperthermia needs to be recognized and aggressively treated. The patient also needs to be closely monitored for respiratory failure, cardiac arrhythmias, and renal failure. The use of antipyretics, dantrolene, amantadine, bromocriptine, and electroconvulsive therapy have also been proposed. Patients with symptoms concerning for NMS should be admitted. Symptoms typically resolve within two weeks. Symptoms may last as long as a month in cases related to the use of long-acting depot injections of antipsychotics.

The patient was administered IV lorazepam, which improved his tachycardia. He was admitted for observation and treated with IV hydration and lorazepam PRN for agitation and hallucinations. All psychiatric medications were discontinued, and the patient improved over the next couple of days.

​Suggested Readings

Brantley EJ, Cohn JV, Babu KM. Case Files of the Program in Medical Toxicology at Brown University: Amantadine Withdrawal and the Neuroleptic Malignant Syndrome. J Med Toxicol 2009;5(2):92.

Morris E, Green D, Graudins A. Neuroleptic Malignant Syndrome Developing after Acute Overdose with Olanzapine and Chlorpromazine. J Med Toxicol 2009;5(1):27.

Perry PJ, Wilborn CA. Serotonin Syndrome vs Neuroleptic Malignant Syndrome: A Contrast of Causes, Diagnosis, and Management. Ann Clin Psychiatry 2012;24(2):155.

Monday, May 2, 2016

A 21-year-old woman with no past medical history presented to the emergency department for evaluation of an overdose. She was brought in by ambulance after her boyfriend called the police because she admitted to him that she had ingested a large amount of acetaminophen (APAP). The patient was 21 weeks pregnant and admitted to having ingested half of a bottle of extra-strength Tylenol six hours before arrival. The ED contacted the poison control center, and asked if N-acetylcysteine (NAC) is safe in pregnancy and if the dosing regimen changes for the pregnant patient.

NAC's Mechanism of Action

APAP is primarily metabolized by conjugation via glutathione. When glutathione channels are depleted, APAP is then metabolized via the CYP P450 system to its toxic metabolite N-acetyl-P-benzoquinoneimine (NAPQI), which is what causes hepatotoxicity. NAC acts as a precursor for the synthesis of glutathione, replenishing glutathione channels and steering metabolism away from the CYP 450 system and away from the production of NAPQI. Minor mechanisms of NAC also include acting as a substrate for sulfation, another minor mechanism of metabolism, and NAC also binds directly to NAPQI reducing it and making it no longer hepatotoxic.

Pregnant Women and APAP Toxicity

Maternal absorption and metabolism of APAP are not affected by pregnancy. Both (APAP) and n-acetylcysteine (NAC) traverse the placenta. The conjugates of APAP do not cross, therefore NAPQI does not cross the placenta. The predominant metabolite of APAP differs between mother and fetus with the mother producing APAP-glucuronide and the fetus producing APAP-sulfate.

Beginning at 14 weeks, however, the fetus has cytochrome P540 activity and can produce its own toxic metabolite. Activity increases substantially between 18 and 23 weeks. Spontaneous abortion and fetal demise have been reported in pregnant women who develop APAP toxicity in the first two trimesters. Pregnant women in the third trimester who develop APAP toxicity have a potential risk for fetal hepatotoxicity because of fetal metabolism.

Risks of NAC Administration

NAC is classified by the FDA as a Pregnancy Risk Category: B. This means that adequate, well-controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals or that animal studies showed no fetal risk in the absence of adequate human studies. The chance of fetal harm is remote but remains a possibility. Other risks associated with NAC administration in pregnant and other patients include anaphylactoid reactions (acute hypersensitivity reactions, rash, hypotension, wheezing, dyspnea). Nausea, vomiting, and other GI symptoms are other reported adverse reactions.

Benefits of NAC in Pregnant OD Patients

Pregnant patients who demonstrate potentially hepatotoxic APAP levels when plotted on the Rumack-Matthew nomogram should be treated with NAC as soon as possible. NAC may provide hepatoprotection to the fetus. The likelihood of fetal and maternal survival are better if NAC is given sooner. A prospective study by Riggs, et al., demonstrated a correlation between time to administration of NAC and pregnancy outcome. (Obstet Gynecol 1989;74[2]:247.) No correlation was seen, though, between pregnancy outcomes and total number of doses of NAC, maternal APAP level, or peak AST level.

Pregnant vs. Non-Pregnant Patients

APAP toxicity should not be treated any differently in pregnant or non-pregnant patients. The administration of NAC should be initiated based on the Rumack-Matthew nomogram for acute APAP ingestions. The doses do not change, and the duration and end-points of treatment remain the same. IV NAC, however, is more appropriate than PO NAC because it has the advantage of ensuring delivery of NAC to the fetus due to reduction of first pass metabolism. NAC protocol should be initiated and labs trended for chronic ingestions with any elevation of APAP or of AST/ALT.

The patient was administered IV NAC 150 mg/kg after labs were drawn. Her six-hour APAP level returned at 160 ug/ml. She was continued on a 21-hour NAC protocol. OB-GYN was consulted, and an ultrasound and fetal monitoring were completed and showed no abnormalities. After the 21-hour protocol, the patient's APAP level was undetectable and LFTs never became elevated. She was then transferred to inpatient psychiatry.


1. Horowitz RS, Dart RC, et al. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol 1997;35(5):447.

2. Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med J 2005;98(11):1118.

Friday, April 1, 2016

An 88-year-old woman with a history of dementia presented with dizziness. Her daughter reported that she may have taken at least 12 tablets of diltiazem, which she mistook for her other medications. She is alert and oriented with normal vital signs. Her heart rate is 40 beats per minute and blood pressure is 70/45 mm Hg. Boluses of calcium gluconate and high-dose insulin therapy are initiated. The patient remains hypotensive at 80/40 mm Hg. Toxicology is consulted about intravenous lipid emulsion therapy.

How does lipid emulsion therapy work?
Two main theories describe the mechanism of action of intravenous lipid emulsion therapy (ILE): the metabolic theory and the lipid sink theory. The metabolic theory proposed that lipids increase the fatty acid uptake of the mitochondria in the cardiac myocytes and therefore acted as an energy substrate. This theory fails, however, to answer why ILE appears to have neuroprotective effects in some drug overdoses.

The lipid sink theory is generally more accepted and has been validated by several animal and in vitro studies. The infused intravascular lipids pull the offending agent from the target tissues into the intravascular space, lessening their organ toxicity. This theory is supported by the fact that all drug overdoses responding to this antidote are found to have an n-octanol:water partition coefficient, a measure of a drug's lipophilicity, greater than 2.

What drug overdoses benefit from ILE therapy?
ILE has been proven to be beneficial for anesthetic-induced cardiotoxicity, but its use has increased as an antidote for other lipophilic cardiotoxic xenobiotics.

ILE therapy is most commonly used for severe poisonings of many drugs, along with the n-octanol:water partition coefficients. (See table; N-octanol:water partition coefficients are obtained from https://pubchem.ncbi.nlm.nih.gov and expressed as LogP.)

It is important to remember that this is far from a comprehensive list, and that most of the information regarding the efficacy of ILE with specific drug poisonings is anecdotal and based on case reports. No double-blind, placebo-controlled trials in humans have examined the efficacy of this antidote with any specific drug poisonings. An example of the pitfalls of case reports has been the reporting of ILE therapy as an efficacious therapy for severe diphenhydramine poisoning. A recent animal study demonstrated no difference in diphenhydramine-induced hypotension or QRS widening when comparing swine treated with ILE with those treated with bicarbonate. (Ann Emerg Med 2016;67[2]:196.)

What are the complications associated with lipid emulsion therapy?
Pancreatitis, acute respiratory distress syndrome (ARDS), and interference with lab values are known complications. Complications caused by ILE when administered in a bolus as an antidote, however, are currently being discovered. A retrospective review spanning 2005-2012 by Levine, et al., attempted to review patients receiving ILE as an antidote for drug overdoses who developed complications. Six of the nine patients developed one or more complications: Two developed pancreatitis, four had lipemia-induced interference with lab values, and three patients developed ARDS. The authors point out that ILE is generally reserved for the most unstable patients, and the association of ILE and ARDS may be temporal rather than causal. (J Med Toxicol 2014;10[1]:10.)

A few case reports have found that patients developed a DVT after ILE administration, yet these have only shown a possible association. Because of these potential complications, the American Academy of Clinical Toxicology current recommends that ILE be reserved for hemodynamically unstable poisoned patients and that a medical toxicologist or regional poison control center be consulted if you plan to use this antidote.

How ILE is administered?
ILE is administered as a bolus dose of 1.5 ml/kg IV over one minute (~100 ml). This bolus dose can be repeated once or twice if efficacy is not seen or is transient after the first bolus. An infusion is started after the bolus at a dosing of 0.25 ml/kg/min IV. A good resource regarding any questions with ILE administration is www.lipidrescue.org.

This patient was admitted to the intensive care unit and her blood pressure remained at 100/60 mm Hg after the ILE infusion and while she was on a norepinephrine infusion at 4 mcg/min and insulin infusion. Her blood pressure normalized after two hours, and she was slowly weaned off the infusions. The patient remained hemodynamically stable for the rest of her hospital stay.

Drugs Most Commonly Receiving ILE Therapy

Xenobiotic              n-octanol:water partition

                             coefficient (LogP)

Lidocaine                         2.26

Bupivacaine                      3.41

Propranolol                      3.48

Amitriptyline                    4.92

Bupropion                        3.85

Diltiazem                         2.70

Verapamil                        3.79

Quetiapine                       2.29​

Tuesday, March 1, 2016

A 58-year-old man presented to the ED with a reported overdose of an unknown medication. The patient was agitated, combative, and altered. Initial vital signs included a heart rate of 115 beats/min, blood pressure of 154/93 mm Hg, respirations of 22/min, and temperature of 99.5°F.

The patient was difficult to evaluate because he was agitated, and he was given 5 mg of haloperidol IV and 2 mg of lorazepam IV. The patient continued to be agitated, and was given another 10 mg of haloperidol IV, followed by a repeat dose of 10 mg IV 15 minutes later. The patient then became unresponsive, and his cardiac monitor demonstrated the rhythm below.

What is the mechanism of drug-induced QT prolongation?

The causes of QT prolongation can be divided into congenital and acquired. These two entities occur by different mechanisms. Congenital prolonged QT syndrome is caused by, mutations in ion channel subunits or protein coding genes. The acquired form is more prevalent with drug-induced QT prolongation being the most frequent cause.

Most drugs that prolong the QT interval act by blocking the delayed rectifier potassium channel encoded by the human ether à go-go related gene (hERG). This inhibits the flow of potassium ions through the outward potassium channel, thereby delaying depolarization. Contributing factors include higher drug serum levels, polypharmacy, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), genetic factors, intrinsic heart disease, and dysrhythmias.

What are five common drugs/drug classes that cause QT prolongation?

n Antihistamines (diphenhydramine, hydroxyzine)

n Antibiotics, antifungal, and antimalarial drugs (erythromycin, moxifloxacin, azithromycin, ciprofloxacin, fluconazole, levofloxacin, moxifloxacin)

n Cardiac medications/antiarrhythmics (sotalol, procainamide, quinidine, amiodarone, flecainide)

n Psychotropics (phenothiazines, haldoperidol, TCAs, citalopram, escitalopram, droperidol)

n Methadone

Which drugs have been reported to cause torsades de pointes, and what are the risk factors?

The concern with QT prolongation is that it is associated with an increased risk of torsades de pointes (TdP), but no reliable length of QT prolongation is associated with an increased risk. Only a small number of drugs have been reported to cause TdP. The systematic review by Chan, et al. attempted to evaluate the performance of a QT nomogram retrospectively (below) in assessing the risk of TdP from QT prolongation (96.9% sensitive, 98.7% specific). (QJM 2007;100[10]:609.) It is regarded as at risk if the QT-HR is plotted above the line. This nomogram demonstrates how most cases of TdP have been associated with drugs that cause slower heart rates (30-90 bpm), rather than drugs that lead to a tachycardia.​

Commonly used drugs reported to have caused TdP include (not a comprehensive list):

n Type I antiarrhythmics (quinidine, procainamide, disopyramide)

n Type III antiarrhythmics (amiodarone, sotalol, ibutilide, dofetilide)

n All CCB reported to cause TdP have since been withdrawn

n Psychiatric drugs (thioridazine, haloperidol, chlorpromazine, droperidol, imipramine, doxepin, lithium)

n Antihistamines (diphenhydramine)

n Antibiotics (erythromycin, clarithromycin, chloroquine, amantadine)

n Immunosuppressant (tacrolimus)

How do you treat TdP?

Unsynchronized defibrillation is indicated for an unstable patient with TdP. One can attempt medical management for the conscious patient. One should administer a trial of 1-2 g of IV magnesium sulfate for those with acquired TdP. The timing depends on the stability of the patient. If the patient is conscious, magnesium sulfate can be given over 15 minutes, first over one to two minutes and then repeated in 10 minutes if necessary in unstable patients. Potassium and magnesium should be supplemented to normal levels. Other treatments include isoproterenol or transvenous overdrive pacing.


What drugs have been associated with a delayed onset of QT prolongation?

The serotonin reuptake inhibitors citalopram and escitalopram have been associated with delayed onset of cardiotoxicity due to a cardiotoxic metabolite didesmethylcitalopram. This is relevant in determining an appropriate observation for overdose patients because the onset of clinical cardiotoxicity may be delayed. Observe a patient for 24 hours if the QT is prolonged because of these medications, even if the data have shown that dysrhythmias rarely occur after 13 hours.

The patient was defibrillated immediately, magnesium sulfate 2 mg IV over two minutes was infused, and the patient had ROSC. The repeat ECG demonstrated a QTC of 489 with normal sinus rhythm. All QTc-prolonging medications were discontinued. The patient was somnolent, but no further interventions were necessary because he remained hemodynamically stable for the rest of the night.

About the Author

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

Drs. LaSala, McKeever, and Yehl completed medical toxicology fellowships at Drexel University College of Medicine in Philadelphia. Dr. LaSala is an emergency physician at St. Joseph's Hospital in California, Dr. McKeever is an assistant professor of emergency medicine at Drexel University College of Medicine, and Dr. Yehl is an emergency physician in Hawaii.

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