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.
Thursday, December 1, 2016
A 26-year-old man presented to the emergency department with nausea, vomiting, and abdominal pain. He said he had had the pain, which he said encompassed his entire abdomen, for three days.
He had been unable to tolerate anything by mouth. His vitals on presentation included a heart rate of 115 bpm, blood pressure of 126/70 mm Hg, respiratory rate of 22 bpm, and pulse oximetry of 100% on room air.
Physical examination revealed dry mucus membranes, dry skin, tachycardia without murmurs, and clear lungs. Abdominal examination demonstrates hyperactive bowel sounds without pain on palpation or hepatosplenomegaly. The patient had no medical history except for this chronic abdominal pain and vomiting, for which he takes metoclopramide and ondansetron.
This was his fourth visit in six months for the same complaint, and all workups, including CT of the abdomen/pelvis and labs, were negative. He had also been evaluated by a GI doctor who performed an endoscopy, which was negative. The patient stated that nothing relieved his symptoms except for hot showers, so he took three to four of them daily.
What is the differential for cyclic vomiting?
- Cyclic vomiting syndrome
- Cannabinoid hyperemesis syndrome (CHS)
- Hyperemesis gravidarum
- Metabolic disorders
- Motility disorders
- Psychogenic vomiting
- Diabetic gastroparesis
What are the clinical features of CHS?
- Long-term, regular cannabis use (essential)
- Severe cyclic nausea and vomiting
- Resolution with cannabis cessation
- Relief of symptoms with hot showers/baths
- Abdominal pain, epigastric or periumbilical
What is the pathophysiology of CHS?
The pathophysiology behind CHS is poorly understood. One hypothesis is that the disease is caused by the cannabinoid receptor type 1 (CB1). CB1 receptors are found in the brain and the GI tract. Delta-9-tetrahydrocannabinol is the main active metabolite of cannabis and exerts its psychotropic and antiemetic effects by binding to CB1 receptors in the brain. It also binds to CB1 receptors in the GI tract causing gastroparesis. With chronic use of cannabis, sensitization of the CB1 receptors in the brain may occur, leading to the pro-emetic CB1 effects in the gut and overriding the antiemetic CB1 effects in the brain.
What is the treatment for CHS?
The only definitive treatment is cessation of cannabinoid use. Supportive measures include electrolyte repletion, IV fluids for dehydration, and antiemetics. Case reports describe the successful use of topical capsaicin cream applied to the abdomen and haloperidol in cases where vomiting is refractory to common antiemetics.
What is thought to be the mechanism of action of capsaicin cream?
Topical capsaicin cream is hypothesized to stimulate the same receptors as hot showers for these patients. This has yet to be proven, and there is only anecdotal evidence for its use. The cream is a supplement, and it is very safe and relieves symptoms, aside from patient complaints of heat.
The toxicology service was called, and the patient admitted to drinking occasionally and smoking marijuana daily because it helped with his nausea. The patient was treated with IV Haldol and capsaicin cream, and his symptoms were resolved in the ED. He was counseled and advised to stop using marijuana. He was discharged with the rest of the capsaicin cream.
Tuesday, November 1, 2016
A 64-year old woman presented to the emergency department with nausea, vomiting, dry mouth, dry eyes, and difficulty keeping her eyes open. She admitted to eating mandarin oranges out of a can the night before, and at that time she thought they "tasted funny" but did not think much of it.
The next morning she noticed she was having trouble opening her eyes and that her mouth was dry. She looked inside the can of oranges and saw it was discolored.
Her presenting vital signs were unremarkable. The patient was alert and awake. She had ptosis bilaterally, with mydriatic pupils unresponsive to light. The patient had dry mucous membranes with no oropharyngeal erythema or exudates. Her heart rate and rhythm were regular without murmurs. Her lungs were clear to auscultation, and her abdominal exam demonstrated no tenderness, but she became nauseous with palpation. She was able to move all four extremities spontaneously, and her deep tendon reflexes were intact. Initial labs included a CBC, BMP, hepatic panel, lipase, VBG, UA, and CT of the head, all of which were unremarkable.
The Toxicologic Differential
- Buckthorn (Karwinskia humboldtiana)
- Botulinum toxin
- Carbon monoxide
- Elapid envenomation
- Organophosphorus compounds
- Paralytic shellfish poisoning
- Tick paralysis
- Exogenous thyroid hormone in patients who develop thyrotoxic periodic paralysis
Scenarios of Botulism Exposure
- Foodborne botulism occurs after ingestion of preformed toxin in food, including improperly canned foods. Botulism outbreaks in prison was associated with hooch or pruno (prison wine). The incubation period is around one day.
- Infant botulism results from ingestion of Clostridium botulinum spores, which produce toxins in the infant's GI tract that are absorbed into the bloodstream. Many cases are associated with raw honey.
- Adult colonization botulism is a disease where the predisposing factors to enteric colonization include history of GI surgery and inflammatory bowel disease.
- Wound botulism occurs when wounds have been contaminated by spores which then proliferate to form the toxin. The incubation period is typically one to two weeks. This is common among IV drug abusers.
- Iatrogenic botulism results from injection of Botox.
- The toxin can be aerosolized and used as a weapon. A lethal dose is 1 ng/kg via inhalation.
Clinical Presentation of Botulism
Onset of symptoms generally occurs the day following ingestion. It generally begins with nausea and vomiting. Neurologic signs may lag by 12 hours and include:
- Diplopia (often with lateral rectus palsy)
- Blurred vision
- Dry mouth
- Descending symmetrical flaccid paralysis
- Loss of deep tendon reflexes
- Mental status and sensation remain intact
Workup for Suspected Botulism
Diagnosis is based on clinical symptoms and history of exposure. Confirmatory testing takes days, so initial treatment should not be delayed. Testing involves demonstrating the toxin in the serum, stool, gastric aspirate, wound, or implicated food. A mouse bioassay is used. Fecal and gastric samples are cultured anaerobically. Routine labs tests and imaging may be helpful to exclude other etiologies.
Treatment for Botulism
Airway protection is important because respiratory failure is the usual cause of death. Methods for monitoring the patient's respiratory status may include negative inspiratory force (NIF), end-tidal CO2, SPO2, gag reflex, vital capacity, and peak expiratory flow rate.
An equine-derived botulinum antitoxin is available for foodborne, wound, adult intestinal colonization, and iatrogenic botulism. Early administration is helpful to stop the progression of paralysis. BabyBIG (botulism immune globulin intravenous) is indicated for infant botulism.
The state health department should be contacted, which will arrange clinical consultation with the Centers for Disease Control and Prevention. The CDC will request release of the antitoxin if it is determined that there is botulism exposure. The antitoxin is not available in hospital pharmacies and must be shipped from designated centers throughout the United States.
Food-associated botulism was suspected based on the patient's presentation. Consultation with the CDC concluded that this patient was likely exposed to botulinum toxin and administration of antitoxin was recommended.
The patient was admitted to the ICU, and the following day she experienced some blurred vision and had a mild dysarthria but no further neurologic progression. Botulinum toxin was confirmed in the patient's stool and in the can of oranges. The patient was downgraded from the ICU two days later when it became apparent that her paralysis was not progressing.
1. Arnon SS, et al. JAMA 2001;285(8):1059.
2. Zhang JC, Sun L, Nie QH. Clin Toxicol 2010;48(9):867.
Photo Credit: Centers for Disease Control and Prevention
Monday, October 3, 2016
A 29-year-old man presented to the emergency department with numbness and tingling of his entire body for three weeks. He said the symptoms started when he entered a drug rehab facility for benzodiazepine and opiate abuse, and that the last time he used either drug was more than a month ago. His initial vitals demonstrated a heart rate of 106 bpm, blood pressure of 115/70 mm Hg, temperature of 98.6°F, respiratory rate of 14 bpm, and SPO2 of 99% on room air.
He is well nourished, alert, and oriented but anxious-appearing. His neurologic exam demonstrates no ataxia on ambulation with cranial nerves II-XII intact. His motor exam of upper and lower extremities is intact, and he has no evidence of dysdiadochokinesia. His patellar reflexes are 2+ bilaterally. He has slightly diminished sensation in all extremities. The rest of his physical examination is unremarkable. CBC, BMP and UA are within normal limits. A noncontrast head CT demonstrates no acute intracranial abnormalities.
The Toxicologic Differential
- n-Hexane (in glue)
- Nitrous oxide
- Medications including pyridoxine, amiodarone, tacrolimus, vincristine, thalidomide, paclitaxel, and nucleoside reverse transcriptase inhibitors
- Drug-induced electrolyte (potassium and magnesium) abnormalities
- Drug intoxication leading to spinal cord or other physical trauma
The patient eventually admitted to abusing nitrous oxide for the past three weeks. He said he had been using an average of 50 cartridges a day. His reasoning was that he had become so anxious from withdrawing from benzodiazepines and opiates that this was the only available means of controlling his anxiety.
Nitrous Oxide Abuse
Nitrous oxide can be obtained in small cartridges or large tanks. The easiest form to obtain and most commonly abused is the cartridge and cracker system. (Photo.)
The cartridges are intended to be used for whipped cream and may be available in cooking stores, but they are also found in head shops, where the "crackers" and balloons are also legal to buy. Nitrous oxide may also be found in large tanks similar to helium. Balloons are filled with nitrous oxide and the contents are inhaled to achieve a high.
Chronic exposure to nitrous oxide leads to the oxidation of the cobalt ion in cyanocobalamin (vitamin B12). This blocks the formation of methylcobalamin, a coenzyme necessary for the production of myelin sheaths.
The most common complaints are numbness and tingling of the distal extremities. Physical exam may reveal diminished sensation to light touch, proprioception, gait ataxia, Lhermitte's sign, hyperreflexia, and spasticity. Nitrous oxide also has hematologic effects causing megaloblastic anemia.
Commonly Abused Inhalants
Solvents, glue, shoe polish, toluene, gasoline, lighter fluid, spray paint, and paint remover and thinner are also commonly abused. Their contents typically contain a mixture of hydrocarbons that may contain:
- Toluene: Acute effects include ataxia, disorientation, headache, hallucinations, and seizures. Chronic effects include cerebellar dysfunction, neurocognitive impairment, and peripheral neuropathy.
- Aliphatic nitrates (amyl nitrates): Side effects include methemoglobinemia, peripheral vasodilation, flushing, hypotension, headache, skin irritation, and allergic reactions.
- Xylene: A disulfiram-like reaction
- Halogenated hydrocarbons: CNS depression
- N-hexane: Peripheral neuropathy
The patient was given a shot of vitamin B12 (1000 mcg) and L-methionine (1 g). He was advised to abstain from inhaling nitrous oxide and referred to the neurology clinic for follow-up. He never went to the clinic and was lost to follow-up.
1. Lin CY, Guo WY, et al. "Neurotoxicity of Nitrous Oxide: Multimodal Evoked Potentials in an Abuser." Clin Toxicol 2007;45:67.
2. Meyers LE, Judge BS. "Myeloneuropathy in a Dentist." Clin Toxicol 2008;46:1095.
Thursday, September 1, 2016
A 76-year-old woman presented to the ED with altered mental status. Her family said she had increasing fatigue for two days. That morning, the patient had nausea, vomiting, and shoulder pain. EMS found she had a blood glucose of 34. She was given an ampule of D50 and brought to the ED.
The patient reported dizziness and fatigue in the ED, and stated that she had not eaten for a few days. Her initial vital signs included temperature 94.1℉, pulse 76 bpm, blood pressure 120/67 mm Hg, respiratory rate 18 bpm, and pulse oximetry 99% on room air. Her physical examination is unremarkable.
Initial laboratory values are remarkable for a pH 6.97, HCO3 4, PCO2 18, and lactate 13.5. Initial BMP was remarkable for a HCO3 5, BUN 75, creatinine 5.78, and an anion gap of 30. CBC demonstrated a WBC of 27.1, Hb 12.3, Hct 38.6, and Plt-395. The family said the patient had diabetes and Parkinson's disease. Her medications include sitagliptin, rosuvastatin, telmisartan, and metformin.
Differential for Elevated Lactic Acidosis
- Cyanide poisoning
- Metformin Associated Lactic Acidosis (MALA)
- Propylene glycol toxicity
- Antiretroviral drugs
- Erroneously elevated lactate levels due to interference of the assay with ethylene glycol
Metformin is a commonly prescribed medication for diabetes mellitus. It is in the biguanide class of medications, which maintain euglycemia by inhibiting gluconeogenesis, enhancing peripheral glucose uptake and increasing intestinal use of glucose. Metformin does not undergo hepatic metabolism and is mainly eliminated renally. It is not protein bound and has a volume of distribution of 3 L/Kg.
Acute overdose may present as abdominal pain, vomiting, and diarrhea. The remaining clinical manifestations are secondary to the profound lactic acidosis and include altered mental status, tachypnea, hypotension, hypothermia, shock, and death. MALA refers to a blood lactate concentration > 5 mmol/L and a pH < 7.35.
Metformin toxicity can lead to hyperlactatemia by inhibiting lactate conversion to glucose in the hepatocytes, which leads to elevation of lactate causing a decrease in hepatocellular pH. This decrease in pH then inhibits the lactate uptake by the hepatocytes.
MALA may occur from an acute intentional overdose or therapeutic chronic dosing. In acute overdose, the lactic acidosis is often delayed in presentation and can occur as far out as 24 hours after ingestion. During chronic therapy, there is a small but significant risk for MALA often precipitated by renal insufficiency or illness leading to renal failure (i.e., sepsis, alcohol abuse, liver disease, ischemia or shock, use of radiologic contrast media). Mortality from MALA ranges between 30 and 50 percent.
The management for an acute overdose is slightly different from chronic toxicity in that these patients may have some nausea and vomiting but appear well. The lactic acidosis may not appear until eight hours and in some cases as long as 20-24 hours out from ingestion. In cases where patients report a large ingestion, patients should be administered activated charcoal, serial lactate levels should be obtained every four hours, and the patient should be admitted for observation.
When the patient already has a metabolic acidosis with elevated lactate levels, treatment is resuscitation with good supportive care. A bicarbonate infusion can be administered to help reverse acidemia, and if the acidosis and lactatemia are severe enough, dialysis is recommended.
The indications for extracorporeal treatments (ECTR) in patients with MALA (from the Extracorporeal Treatments in Poisoning Workgroup) are:
- ECTR is indicated if:
- Lactate >20 mmol/L
- Blood pH <7.0
- Standard therapy fails
ECTR is suggested when:
- Lactate >15.0-20.0 mmol/
- Blood pH <7.0-7.1
- Comorbid conditions that lower the threshold for dialysis: Impaired kidney function, shock, decreased level of consciousness, and liver failure
Cessation of ECTR:
- Lactate <3.0 mmol/L
- pH >7.35
The patient was started on a bicarbonate infusion, and nephrology was consulted for hemodialysis. She was actively warmed with a bear hugger and warm IV fluids and was administered antibiotics for suspected sepsis. The patient received four days of intermittent hemodialysis, and creatinine improved to 2.25. She was discharged home with close follow-up with nephrology and metformin was removed from her medication list.
1. Calello DP, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations from the Extracorporeal Treatments in Poisoning Workgroup." Crit Care Med 2015;43(8):1716.
2. Spiller HA, Sawyer TS. Toxicology of Oral Antidiabetic Medications. Am J Health Syst Pharm 2006;63(10):929
3. Nelson L, ed. Goldfrank's Toxicologic Emergencies. New York: McGraw-Hill Medical, 2011.
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.
Clinical Manifestations of Methotrexate Toxicity
- Mucositis manifesting as stomatitis, esophagitis, or diarrhea
- 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.
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.