UMEM Educational Pearls - Toxicology

When reviewing a patient's medication list, there are always some that should catch your eye. Digoxin is one since we can measure it, has a low therapeutic index and elimination is effected when renal function is diminished. Another drug that should catch your eye is SOTALOL. Renally cleared and affected by even a minimally lower than normal magnesium. The toxic effect even at therapeutic levels is torsades de pointes.

One study, in a 736 bed hospital, showed 89% of patients prescribed sotalol were on an inappropriate dose due to renal function and an odds ratio of 3.7 increased re-admission rate at 6 months for the patients on the inappropriate dose of sotalol.

We can catch this in the ED. Involve your pharmacist, ED pharmacist or local toxicologist for dosing calculations.

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In the treatment of acetaminophen poisoning with N-acetylcysteine (NAC), the PT/INR can be slightly elevated even in the absence of hepatotoxicity. Considering Prothombin Time (PT) is one of the criteria used to assess severity of liver damage in this setting, it is important to know how much the PT/INR can be affected by NAC and if it has an actual effect on coagulation factor levels.

1. N-acetylcysteine has been shown to slightly increase the PT) by up to 3.5 seconds in healthy volunteers.
2. A more recent study by the same authors demonstrated a reduction in vitamin K-dependent clotting factor activity (II, VI, IX, and X) after NAC administration in healthy volunteers.

Clinical Practice Pearls

• The elevation in PT/INR after NAC administration is real, not simply laboratory interference.
• However, the PT/INR elevation and decrease in coagulation factors is modest and not likely clinical signficant.
• Many poison center guidelines allow for an INR up to 2 to be considered 'normal' to account for this phenomenon in this setting.

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• Opioid analgesia can actually INCREASE sensitivity to pain in some cases

• The exact cause is unclear, but may be due to up-regulation of NDMA receptors in spinal cord dorsal horn neurons

• Pain tends to be DIFFERENT and DIFFUSE from the underlying condition for which the narcotics were prescribed

• Switching from shorter acting opiates to methadone may be effective, as it is a weak NDMA antagonist and has only partial cross tolerance with other opioids

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Hyperglycemia in the setting of antipsychotic use has been reported mostly with olanzapine (Zyprexa) but does occur with other antipsychotics. A recent study from the NYC medical examiner's office details 17 deaths of DKA due to antipsychotics and found that (from highest to lowest incidence) quetiapine > olanzapine > risperidone were the atypical antipsychotics found with these deaths.

Remember hyperglycemia occurs with patients on antipsychotics and can lead to hyperglycemia hyperosmolar coma or DKA. Both can be lethal.

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Utilizing 20% lipid emulsion at a dose of 1.5 mL/kg (100 mL Bolus) IV with repeat in 15 minutes in no response is being recommended in patients hemodynamic instabiity due to poisoning.

Probably more effective in lipophilic drugs is a current theory for the mechanism of action - the "lipid sink". The idea is that the lipids envelope the drug pulling it off its receptors or sequestering it in the intravascular space. A recent paper has added another mechanism - direct inotropic and lusiptropic effects.(1)

Also, if you think the therapy is experimental, think again. Another recent paper surveyed Poison Control Centers and found 30/45 Poison Centers in the US have a defined protocol for utilization of lipid emulsion therapy. The PCCs are recommending it more.(2)

What was once considered just a purely experimental therapy only used at the very end of code is becoming more mainstream. Comfort with its safety profile and anectodotal effiicacy continues to mount.

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Strychnine poisoning is still occasionally found in rat poisons and in adulterated street drugs and herbal products. The typical symptoms are involuntary, generalized muscular contractions resulting in neck, back, and limb pain. The contractions are easily triggered by trivial stimuli (such as turning on a light) and each episode usually lasts for 30 seconds to 2 minutes, for 12 to 24 hours. Classic signs include opisthotonus, facial trismus, and risus sardonicus.

Differential diagnosis includes:

• Tetanus: However, the onset of symptoms is more gradual and the duration much longer than in the case of strychnine poisoning.
• Generalized seizures: However, strychnine poisoning presents with a normal sensorium during the period of diffuse convulsions.
• Dystonic reaction: However, dystonic reactions are usually static, whereas strychnine poisoning results in dynamic muscular activity. 
• Serotonin syndrome
• Malignant hyperthermia
• Neuroleptic malignant syndrome
• Stimulant use

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If you are working in a community hospital and have an acetaminophen overdose, one of the criteria to transfer the patient to a tertiary care center is presence of the King's College Criteria.

The below is taken from mdcalc.com -  http://www.mdcalc.com/kings-college-criteria-for-acetaminophen-toxicity/

Each one is assigned points and can be prognostic for severe toxicity and need for transplant. The lactate and phosphorus are new ones and have modified the criteria. Phosphorus is utilized to create glycogen. If the liver is injured and trying to heal, your phosphorus will be low (good). If the liver is injured and unable to repair itself the phosphorus will be high (bad). This single test has an excellent prognostic ability.

With recent events, a few notes about ricin seems appropriate:

1. Easy to make from castor bean though heat labile
2. No antidote, though Fab like digibind is in development
3. Granule size of the grain of sand can kill
4. Inhalation, IM, IV all effective
5. After immediate exposure likely no symptoms
6. Vomiting and diarrhea initially, acute lung injury and death in 3-5 days

CDC website: http://www.bt.cdc.gov/agent/ricin/

Cocaine toxicity is characterized by the sympathomimetic toxidrome: tachycardia, hypertension, hyperpyrexia, diaphoresis as well as sodium channel blocking effects that can cause local anesthesia topically, QRS widening and even seizure.

Usual treatment for a cocaine toxic patient is benzodiazepines and cooling. Be wary of end organ damage, trauma and seizures.

There was a recent study that looked at dexmedetomidine to treat the sympathomimetic effects. Placebo-controlled trial used cocaine-addicted volunteer and applied intranasal cocaine. Measuring skin sympathetic nerve activity and skin vascular resistance, this study, unfortunately, showed as the dose increased  MAP did not fall further and increased paradoxically in 4 of 12 subjects.

This highlights the incredible physiologic mechanism of catecholamine release from the CNS with cocaine. This mechanism overlaps some with the centrally acting alpha agonist - dexmedetomidine and was shown in the study by Kontak et al. 

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In 2013, the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists published a second update to their position statement on gastric lavage for GI decontamination (original 1997, 1st update 2004).

• Gastric lavage should not be performed routinely, if at all, for the treatment of poisoned patients.
• Further, the evidence supporting gastric lavage as a beneficial treatment even in special situations is weak.
• In the rare instances in which gastric lavage is indicated, it should only be performed by individuals with proper training and expertise.

Bottom line: Gastric lavage generally causes more harm than good. It should not be thought of as a viable GI decontamination method.

Bonus: Dr. Leon Gussow (@poisonreview) reviews the position paper on his blog, The Poison Review, here: http://www.thepoisonreview.com/2013/02/23/gastric-lavage-fuggedaboutit/

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Question

A foley is inserted in a fire victim patient. Urine return is in picture. Describe the reason for this colored urine.

Special Thanks to Dr. Doug Sward for the urine picture 

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Attachments

Foley-Sward.jpg (4,224 Kb)

Typical opioid withdrawal include clinical symtpoms of piloerection, nausea, vomiting and diarrhea. If you were to see seizure, another etiology other than opioid withdrawal should be investigated. 

Except in the case of neonates borne to women who have been taking opioids chronically such as a methodone patient. Once the child is born, symptoms of withdrawal may take days to weeks to materialize though seizures typically occur <10 days. The child is at increased risk of SIDS as well.

Most antidotes have not been adequately studied in pregancy and hold a Pregnancy Risk Category 'C' by the FDA. However, there are a few antidotes that hold a category 'D' or 'X' rating (contraindicated).

1. Ethanol (toxic alcohols) - Category C
   • Reproduction studies have not been conducted with alcohol injection. Ethanol crosses the placenta, enters the fetal circulation, and has teratogenic effects in humans. When used as an antidote during the second or third trimester, Fetal Alcohol Syndrome AS is not likely to occur due to the short treatment period; use during the first trimester is controversial.
   • Alternative (preferred) antidote: fomepizole.
2. Methylene blue (methemoglobinemia) - Category X
   • Use during amniocentesis has shown evidence of fetal abnormalities, but it has been used orally without similar adverse events. IV may be ok.
3. Lorazepam and diazepam (seizures, nerve agents) - Category D
   • Teratogenic effects have been observed in some animal studies and in humans. Lorazepam/diazepam and their metabolite cross the human placenta.
4. Potassium iodide (radioactive iodine) - Category D
   • Iodide crosses the placenta (may cause hypothyroidism and goiter in fetus/newborn). Use for protection against thyroid cancer secondary to radioactive iodine exposure is considered acceptable based upon risk:benefit, keeping in mind the dose and duration.
5. Amyl nitrite (cyanide) - Category C (manufacturer contraindicates)
   • Animal reproduction studies have not been conducted. Because amyl nitrate significantly decreases systemic blood pressure and therefore blood flow to the fetus, use is contraindicated in pregnancy (per manufacturer).
   • Other options exist to treat cyanide exposure including sodium nitrite, sodium thiosulfate, and hydroxocobalamin.
6. Penicillamine (chelator) - Category D

In most cases, the benefits of short-term use probably outweigh the risk, especially when accounting for the health and prognosis of the mother.

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• Found as adulterant in street drugs

• Used in bodybuilding and for weight loss

• Long acting beta-2 agonist

• Has specific anabolic activity and increases lipolysis

• Toxicity presents with tachycardia, palpitations, tremor, and myocardial ischemia

There have been many attempts to reduce the incidence of contrast-induced nephropathy. Mechanism usually centers around antioxidant properties or free radical scavengers that prevent the acute kidney injury that may result after intravenous contrast. IV Fluid hydration, sodium bicarbonate and acetycysteine have been studied with only some evidence. There is also some controversial data that is beginning to surface regarding the use of atorvastatin with a recent article in Circulation 2012 that showed high dose atorvastatin (80mg) 24 hrs prior to angiography prevented contrast-induced acute kidney injury in patients with mild to medium risk. Link to article has been provided:

http://circ.ahajournals.org/content/126/25/3008

Cyclophosphamide-induced hemorrhagic cystitis is a well known to oncologists. This unique complication of this chemotherapeutic drug has a defined mechanism and could be seen in your Emergency Department.

- Hemorrhagic cystitis occurs in 46% of patients that receive cyclophosphamide

- Can occur even months after administration

- 5% can actually die from the hemorrhage

- Treatment: Bladder irrigation, hydration, supportive. Oral adminsitration of MESNA (2mercaptoethan sulfonate) and bladder irrigation with prostaglandins and even methylene blue have been attempted.

SSRIs and SNRIs like venlafaxine and sertraline are well known to cause hyponatremia. Usually considered safe, this adverse drug event can lead to weakness, confusion, seizure and even cerebral edema. Elderly are more susceptible to this adverse effect.

ADH is regulated by serotonin and thus the mechanism for the Hyponatremia is SIADH. 

Tolvaptan, a vasopressin receptor antagonist, has been a new treatment that has been used anecdotally in Europe. Waiting for the first US case report. 

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Several medications can produce a false-positive result for methadone on the urine drug screen: diphenhydramine, doxylamine, clomipramine, chlorpromazine, quetiapine, thioridazine, and verapamil.

Add a new one to the list. Tapentadol, a relatively new opioid analgesic similar to tramadol, can also produce a false-positive result for methadone on certain immunoassays.

A separate study concluded that tapentadol does not affect the amphetamine screen.

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Creatine

• is the most popular nutritional supplement, accounting for $400 million in sales annually
• a nonessential amino acid
• has been shown to improve performance in short, high intensity exercises, including weight lifting

Adverse effects: weight gain, edema, GI cramping, fatigue and diarrhea

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Despite a paucity of data, pain management clinics are administering topical gel mixtures that have included ketamine, tricyclics, calcium channel blockers and baclofen. Internet blogs have already identified this gel mixture as a way to "get high".  This is one of those google searches you have to do on your own.

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  1: Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical 2% amitriptyline and 1%  ketamine in neuropathic pain syndromes: a randomized, double-blind,  placebo-controlled trial. Anesthesiology. 2005 Jul;103(1):140-6.     2: Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain. 2003 Sep-Oct;19(5):323-8.    3: Uzaraga I, Gerbis B, Holwerda E, Gillis D, Wai E. Topical amitriptyline,  ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: a pilot study. Support Care Cancer. 2012 Jul;20(7):1515-24.