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, 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;74:247.) 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;67:196.)
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;10:10.)
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
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)
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;100:609.) 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.
Monday, February 1, 2016
A 50-year-old man with a past medical history of alcoholism presented to the ED with altered mental status, nausea, and vomiting. He is arousable but a poor historian. His girlfriend said he drinks a half-gallon of rum daily, and had his last drink two days earlier. She reported that he started to feel nauseous, vomit, and go through alcohol withdrawal. She said he also has been taking a lot of calcium carbonate for an upset stomach, but she was unable to say exactly how much.
His blood pressure was 146/70 mm Hg, heart rate was 110 bpm, respiratory rate was 14 bpm, PO2 was 96% on room air, and blood glucose was 167 mg/dL. Labs are remarkable for a significant metabolic alkalosis: ABG 7.65, pCO2 69, pO2 108, and HCO3 58. The chemistry is included below. The documented lactate was 9 mmol/L, and the ethanol level was negative. The patient's ECG demonstrated a prolonged QTc of 540.
The Five Toxicological Causes of Metabolic Alkalosis
- Loop or thiazide diuretics are a common cause of metabolic alkalosis even in therapeutic doses: Metabolic alkalosis is caused by the depletion of chloride ions and the increased delivery of sodium ions to the collecting duct. This enhances potassium ion and hydrogen ion secretion, resulting in metabolic alkalosis.
- Ingesting sodium bicarbonate (baking soda) for self-treatment as a home remedy: Ingesting a moderate amount of bicarbonate leads directly to an increase in serum bicarbonate and thus an alkalosis.
- Excessive ingestion of antacids (calcium carbonate, magnesium hydroxide, or aluminum hydroxide) leading to a milk-alkali syndrome: hypercalcemia, renal insufficiency, and metabolic alkalosis: With antacids, the likely pathogenesis is caused by volume depletion from calcium-induced diuresis, which results in the renal tubular absorption of bicarbonate. Metabolic alkalosis occurs because of the effects of volume depletion, increased alkali intake, and the decreased GFR.
- Excessive ingestion of black licorice contains glycyrrhizic acid, which has an effect similar to mineralocorticoid and may lead to metabolic alkalosis, hypokalemia, and edema.
- Exogenous mineralocorticoid or glucocorticoid ingestion that leads to Cushing syndrome.
Electrolyte Abnormalities Commonly Seen with Metabolic Alkalosis
- Hypokalemia impairs the kidneys' ability to correct alkalosis by stimulating acid secretion in the proximal and distal tubules.
- Hypomagnesemia, though the alkalosis is likely caused by hypokalemia induced by low magnesium.
- Hypercalcemia may lead to alkalosis by volume depletion and enhanced absorption in the proximal tubule. The development of nephrocalcinosis may decrease renal function and worsen alkalosis.
- Hypernatremia will commonly be seen in those patients who ingest sodium bicarbonate.
The Effects of Metabolic Alkalosis on the Body
Most of the effects you see are from electrolyte abnormalities secondary to the alkalosis. Patients may present with cardiac arrhythmias from hypokalemia or neuromuscular irritability caused by low-ionized calcium from the alkalosis. This occurs because calcium will bind with hydroxide ions, resulting in a low-ionized calcium despite hypercalcemia. Hypernatremia may lead patients to be confused or obtunded, and they may seize if it is severe enough.
Managing Metabolic Alkalosis
Treatment begins with identification and correction of the underlying cause of the metabolic alkalosis. IV normal saline is the first line of treatment if the patient has chloride depletion and volume contraction. Therapy for severe cases may include administering carbonic anhydrase inhibitors, acid infusion, and low-bicarbonate dialysis. Electrolyte replacement is important because hypokalemia and hypomagnesemia may precipitate worsening alkalosis.
This patient presented with a severe metabolic alkalosis, likely multifactorial secondary to vomiting, alcohol abuse, and chronic use of calcium carbonate and pantoprazole. This patient was admitted with the plan of administering IV normal saline, repleting electrolytes, avoiding QT-prolonging meds, and monitoring ECG every four hours until normalizing. Nephrology was consulted early, however, the patient improved prior to requiring dialysis. His alcohol withdrawal symptoms were treated with diazepam. The patient improved over the next couple of days, and we didn't have to intervene further.
Monday, January 4, 2016
A 17-year-old boy presented to the emergency department after having a seizure. Initial vital signs included a temperature of 38°C, heart rate of 134 beats/min, respiratory rate of 22 breaths/min, blood pressure of 142/93 mm Hg, and pulse oximetry of 97% on room air. His physical exam is significant for tachycardia and pupils are 5 mm bilaterally and reactive to light with horizontal nystagmus. He is awake, confused, and combative.
Paramedics report that his mother found him in his bedroom was acting strangely before he fell to the floor and began convulsing. ED staff administered 2 mg intravenous lorazepam, which caused his seizure to cease. The patient’s mother is in the room, and she says he has no history of seizures and is not taking any medications.
What are five eye manifestations that may be seen in an illicit drug abuser?
n Nystagmus from interference with extraocular movements resulting from acute intoxication with:
o Phencyclidine (PCP): Horizontal, vertical, or rotary nystagmus. These effects may also be seen with ketamine. Other common drugs associated with nystagmus include anticonvulsants (phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate), ethanol, lithium, dextromethorphan, and lysergic acid diethylamide (LSD).
n Impaired near-vision resulting from mydriasis
o Acute intoxication of sympathomimetics (amphetamines, cocaine) and anticholinergic agents (TCA, diphenhydramine)
n Talc retinopathy
o Seen in patients who inject heroin or cocaine contaminated with talc or in those patients who crush and inject pharmaceuticals such as methylphenidate. Typically occurs after repeated intravenous drug use. It is an embolic phenomenon affecting the retinal vasculature. Particulate matter may be seen on fundoscopic examination.
n “Crack eye”
o Corneal injury from inhalation of crack cocaine may be caused by direct toxic effect of crack cocaine on corneal epithelium, repeated exposure to the alkaloid smoke leading to chronic chemical burns, the drug acting as an anesthetic and decreasing the user’s blink reflex, and the smoke acting as an irritant and causing the user to rub his eyes often.
o Cases of vision loss resulting from cocaine-induced vasospasm of the retinal vessels have also been reported.
o This is commonly associated with opiates but also with the atypical antipsychotics such as olanzapine.
The patient’s presentation was concerning for PCP intoxication. The patient was aggressively treated with IV lorazepam and IV diazepam for sedation and was administered IV haloperidol for his psychotic symptoms. He was also hydrated with IV normal saline because these patients tend to lose a tremendous amount of fluid from their diaphoresis and may develop rhabdomyolysis from their psychomotor agitation. The patient was admitted, and his creatine kinase peaked at 6,800. Prior to his discharge, he admitted to smoking marijuana laced with “wet,” the street name for liquid PCP and for a marijuana cigarette dipped in liquid PCP.
Chemical sedation is preferred over physical restraints for these patients because physical restraint may lead to worsening rhabdomyolysis and hyperthermia, which can cause increased morbidity and mortality.
1. McLane NJ, Carroll DM. Ocular manifestations of drug abuse. Surv Ophthalmol 1986;30(5):298.
2. Hoffman RS, Reimer BI. “Crack” cocaine-induced bilateral amblyopia. Am J Emerg Med 1993;11(1):35.