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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, August 1, 2016

A 78-year-old man was advised to go to the emergency department by his rheumatologist after reporting symptoms of nausea, severe fatigue, and feeling "off" for two days. The patient had recently been prescribed methotrexate for his polymyalgia rheumatica, and was instructed to take 5 mg once a week, but he misunderstood and took 5 mg daily for six days.

The patient's heart rate was 80 beats per minute, his blood pressure was 155/75 mm Hg, his pulse ox was 98% on room air, and his temperature was 98°F. His initial labs included a CBC with no abnormalities, but his creatinine was 2.5 mg/dL with a GFR of 25. Baseline levels from previous visits were creatinine 1.2 mg/dL and GFR >50.

​What is the mechanism of methotrexate toxicity?
As a structural analog of folate, methotrexate competitively inhibits dihydrofolate reductase. (Figure below.) This ultimately leads to interference with DNA and RNA synthesis so rapidly proliferating cells are most sensitive to this effect. Renal toxicity is associated with the precipitation of methotrexate and its metabolites in the renal tubules causing acute tubular necrosis. Most reported toxicity occurs with chronic oral administration, but other routes of reported toxicity include inadvertent high-dose intrathecal, intravenous, and intramuscular administration. Toxicity from acute intentional overdose is mostly benign.

 

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Clinical Manifestations of Methotrexate Toxicity

  • Mucositis manifesting as stomatitis, esophagitis, or diarrhea
  • Dermatitis
  • Pulmonary toxicity manifesting as acute interstitial pneumonitis, interstitial fibrosis, noncardiogenic pulmonary edema, pleuritis, and pleural effusions
  • Bone marrow suppression with leukopenia, anemia, thrombocytopenia, and pancytopenia may occur within a week after exposure.
  • Hepatic toxicity
  • Renal insufficiency
  • Neurologic dysfunction may occur in high-dose methotrexate therapy or intrathecal administration. Chemical arachnoiditis may present with fever, headache, meningismus, paraplegia, and seizures. Chronic leukoencephalopathy presents with behavior disturbances, dementia, and coma.

What is the diagnostic testing for patients suspected to have methotrexate toxicity?
Serum methotrexate levels are useful, but results may not be rapidly available. Other useful tests to evaluate for toxicity include creatinine, complete blood cell count, liver function tests, and chest radiography. In patients with signs of neurotoxicity, MRI of the brain and CSF analysis to evaluate for infection should be considered.

What are antidotal strategies for methotrexate toxicity?
Leucovorin (folinic acid) should be administered in patients at risk for or with signs of methotrexate toxicity. Folinic acid is the reduced active form of folate, and it does not require DHFR, an enzyme blocked by methotrexate. Folic acid is unable to counteract the effects of methotrexate.

Dosing of leucovorin after an overdose should approximate the same plasma concentration as the methotrexate. It is important not to underdose the leucovorin: It is safe, and methotrexate is very toxic. Leucovorin should be administered as soon as possible and preferably within the first hour after overdose.

Leucovorin "rescue" treatment refers to therapy used for patients receiving intentional high-dose methotrexate. Dosing ranges from 10 to 25 mg/m2 IV or IM q six hours for 72 hours. The dosing for patients with renal compromise is 150 mg/m2 every three hours. Both forms of leucovorin therapy are dependent on patient renal clearance. Adverse effects from leucovorin are not common. Allergic or anaphylactoid reactions have been reported.

Glucarpidase (carboxypeptidase G2) is available on a compassionate use basis in the United States. It may be considered in cases of methotrexate toxicity with impaired renal clearance. It works by hydrolyzing methotrexate to inactive metabolites via IV or intrathecal administration. The recommended dose is 50 units/kg IV bolus over five minutes.

Other treatment strategies include adequate hydration and urinary alkalinization. Significant bone marrow suppression may be treated with granulocyte colony-stimulating factor and blood transfusions, and the case is ideally managed with a hematologist. Methotrexate is dialyzable, and hemodialysis may be considered for patients with renal failure with anticipated high methotrexate levels.

Urinary alkalinization was initiated with 3 amps of NaHCO3 mixed with D5W and run at 200 ml/hr because of this patient's history and symptoms. Leucovorin therapy was started as well, and the patient was admitted to the ICU for frequent neurologic checks. The patient's initial methotrexate level was 1.0 umol/L. A repeat methotrexate level the following day was negligible and undetectable the day after that. The patient's CBC remained normal throughout his hospital stay. His renal function slowly improved, and his creatinine had returned to baseline on day 4 when he was discharged.

References:
1. LoVecchio F, Katz K, et al. Four-Year Experience with Methotrexate Exposures. J Medical Toxicol 2008;4(3):149.
2. Smith SW, Nelson LS. Case Files of the New York City Poison Control Center: Antidotal Strategies for the Management of Methotrexate Toxicity. J Med Toxicol 2008;4(2):132.


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)

​NMS
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.

References

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​

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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