UMEM Educational Pearls - Toxicology

In the setting of acute cyanide poisoning, it is virtually impossible to obtain a timely cyanide level to help assess toxicity.  However, there are two diagnostic tests that can help confirm your diagnosis.

1. Anion gap metabolic acidosis with elevated lactate
2. Narrowing of the venous-arterial PO₂ gradient

Remember cyanide halts cellular respiration meaning the cells cannot utilize oxygen.  Therefore, the venous PO₂ should be about the same as the arterial PO₂.  The cells then switch to anaerobic metabolism, thereby producing lactate.

A recent study examined the effects of accidental digital epinephrine injection from auto-injectors. 127 cases with complete follow-up had the following effects:

• no effects were reported in 10%
• minor effects in 77%
• moderate effects in 13%
• major effects in 1 case

Pharmacologic vasodilators were used in 23%. Four patients had possible digital ischemia. All patients had complete resolution of symptoms, most within 2 hours. No patient was admitted, received hand surgery consultation, or had surgical care. 

Although this speaks for the safety of digital anesthesia using epinephrine, it underscores the importance of providing education to patients who are prescribed epinephrine auto-injectors.

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In a previous pearl we were discussing the need to perform EGD for any suicidal patient with a history of ingestion of a caustic to grade injury and assess chance of perforation and/or stricture formation. Suicidal patients are intentionally ingesting the caustic and can thus justify the risk/benefit ratio more easily than the pediatric unintentional ingestion. The concerned parent will bring the child in with a possible ingestion of a caustic. The container could be simply in the same room, spilled on the child and never be ingested. Even if ingested, the amount is less if the child tastes the caustic and will reflexively cause spitting. The literature is scant in regards to this type of patient but seems to point to this general algorithm:

Child displays 2 or more of the following symptoms there is enough evidence from case series that there will be a clinically signficant lesion found on EGD.

Vomiting, Drooling, Stridor, Presence of Oropharyngeal Burns

That being said, many clinicians would elect for EGD and assessment of airway with stridor alone. Do not be fooled into thinking if you see no oral lesions that there is no way the child ingested the caustic. Each case series showed a lack of correlation of physical exam findings to EGD findings.

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We will all get the patient presenting with low blood glucose on a regular basis. In general, barring any underlying infection, those who are insulin dependent can be corrected with IV dextrose and/or food and be discharged. Those on a sulfonylurea may experience repeated hypoglycemic episodes and require admission - perhaps even treatment with the antidote: octreotide.

Below is the duration of action and half-life of the sulfonylureas which illustrates the need for admission:

• Chlorpropamide (Diabinase): Duration: 24-27hrs; t 1/2: 36hrs
• Glipizide (Glucatrol): Duration 16-24hrs; t 1/2: 7hrs
• Glipizide XL (Glucatrol XL): Duration 24hrs
• Glyburide (Micronase others): Duration <24hrs; t 1/2 10hrs
• Glimepride (Amaryl): Duration 16-24hrs; t1/2: 5-9hrs

Duration of action is the physiologic effect whereas the half-life is the pharmacokinetics of elimination of the drug. Often these two numbers are different for drugs. Do not let the half-life fool you into thinking it is safe to discharge a hypoglycemic patient on a sulfonylurea.

If benzodiazepines and supportive care fail to improve agitation and correct vital signs, several case reports indicate the successful use of cyproheptadine, an antihistamine with nonspecific antagonist effects at 5-HT_1A and 5-HT_2A receptors.

Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup. When administered as an antidote for serotonin syndrome, an initial dose of 8-12 mg is recommended, followed by 2 mg every two hours until clinical response is seen. Cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric tube.

Cyproheptadine may lead to sedation, but this effect is consistent with the goals of management. It may also produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to IV fluids. Cyproheptadine is rated category B for safety in pregnancy by the FDA.

Ingestion of caustics can lead to immediate burns to mouth, esophagus, stomach as well as possible perforation. Months and years later, further complications are esophageal stenosis and increased incidence of esophageal carcinoma. The main benefit to EGD is to determine extent of injury within the esophagus. The lesions are graded much like a burn: 

Grade I: Mild burn, no risk for esophageal stenosis

Grade II: Moderate, if circumferential, patient is at risk for esophageal stenosis

Grade II: Eschar present, high risk of perforation as well as esophagel stenosis

You can make a case that all intentional-suicidal ingestions of caustics should undergo EGD since there should be some injury if ingestion truly occurred or at the least a higher probability. The difficult case is the pediatric unintentional ingestion. Utilizing clinical exam and history will assist with that determination - there is a little research to guide this decision (next pearl)

The attached picture is the post-mortem of a caustic injury showing grade II linear lesions in esophagus with eschar distally and in stomach (Grade III).

A patient arrives via EMS agitated with VS: P 140, BP 155/100, R 18, T 101F. There is an admitted drug exposure and you examine his eyes which are dilated. You shine the light in the eyes - if the pupil reacts, would that be consistent with anticholinergic or sympathomimetic toxidrome?

Answer: Anticholinergic exposure paralyzes pupillary constrictor muscles and causes dilated pupils that do not react to light. Think about when you go to the eye doctor's office. They put homoatropine in your eyes so that when they look with the slit lamp they can see the retina without interference from pupillary constriction. Sympathomimetic exposure like cocaine activates pupillary dilator muscles, the constrictors are still intact and will give a reflexive constriction to light.  This patient has reactive pupils and by the mere fact is in Baltimore probability dictates a sympathomimetic exposure like cocaine.

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Valproic Acid (Depakote) is a drug that uniquely has the ability to raise serum ammonia concentrations. It is able to do this without raising liver er enzymes and it can occur in overdose or at therapeutic levels. Do not think of this in the context of hepatic encephalopathy. This a metabolic derangement caused by VPA.

• Any patient with somnolence, lethargy, decreased responsiveness - order a serum ammonia level as well as Valproic acid level
• If the serum ammonia is elevated in conjunction with altered mental status consider a trial of carnitine
• L-carnitine is a safe drug that is used in nutritional supplementation. VPA and other anticonvulsants cause carnitine deficiency
• Most effective dose is unknown but from a recent review: IV 100 mg/kg once, followed by infusions of 50 mg/kg (to a maximum of 3 g per dose) every 8 hours until patient improves, ammonia decreases

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  Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic Acid overdose: a   systematic review of published cases. Ann Pharmacother. 2010  Jul-Aug;44(7-8):1287-93. Epub 2010 Jun 29.

In a patient with toxin-induced bradycardia and hypotension, here is a quick differential to help identify the responsible substance:

• Beta blockers
• Calcium channel blockers
• Cholinergics
• Clonidine (and other alpha-2 agonists)
• Digoxin (and other cardiac glycosides)
• Opioids
• Sedative hypnotics (such as benzodiazepines and barbiturates)

Less commonly seen causes include: magnesium, propafenone, and plant toxins (aconitine, andromedotoxin, veratrine).

In the state of Maryland, the most common venomous snake is the copperhead. Though not as dangerous as the rattlesnake, it can still cause loss of function of limb and mortality in the pediatric patient.

Treatment has involved the use of CroFab (Protherics, Atlanta). This ovine derived monovalent immunoglobolin is actually made against the following snakes:

• Eastern diamondback rattlesnake
• Western diamondback rattlesnake
• Mojave rattlsnake
• Cottonmouth (Water moccasin)

Though efficacy has been shown with these snakes, we are hoping for cross-reactivity when we treat copperheads. There are case series and case reports (1) that have shown anectdotal improvement. We are still awaiting a real randomized controlled trial - may never happen.

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Physostigmine has been used extensively in the fields of anesthesiology and emergency medicine.  The only use of physostigmine with sound scientific support is for the management of patients with an anticholinergic syndrome, particularly those without cardiovascular compromise who have an agitated delirium.  In this population, physostigmine has an excellent risk-to-benefit profile.

• Try benzodiazepines first.  They last longer and may diminish the need for physostigmine.
• Obtain ECG.  If there are signs of sodium channel blockade (QRS prolongation), do not use physostigmine.
• Administer 1-2 mg via slow IV push/infusion over at least 5 minutes.
• Have atropine available at the bedside.
• Effects last about 1 hour.

There are a several classes of medications that can kill a toddler with a single dose. Toddlers are particularly susceptible due to their low weights and propensity to place everything in their mouths.

1. Calcium channel blockers
2. Camphor-containing rubs
3. Opioids/opiates
4. Oil of wintergreen/ aspirin
5. Cyclic antidepressants
6. Topical blood pressure patches (clonidine)
7. Eye drops and nasal sprays (oxymetazoline)
8. Sulfonylureas
9. Antimalarial drugs (cloroquine)

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Scombroid is caused by ingestion of preformed histamine on skin of fish.

• Naturally occurring histidine on scaly fish converted to histamine by surface bacteria - often fish left out too long, refrigeration will prevent the conversion.
• Bacteria responsible are Morganelli morganii and K. pneumoniae
• Fish: tuna, mahi mahi, amberjack, bonito, mackerel, albacore
• Fish usually appears normal though meat may tast peppery
• Patient presents minutes/hrs flushed, urticaria, HA, N/V
• Self-limited and improve within hrs even without treatment
• Antihistamines and rarley epinephrine will be needed

We are all familiar with the classic ECG abnormalities caused by the sodium channel blocking properties of tricyclic antidepressants (QRS interval widening, R wave in aVR, S wave in I and aVL, and rightward deviation in terminal 40 msec of QRS). Here are some other medications that also block cardiac sodium channels in a similar manner:

• Cocaine
• Diphenhydramine
• Cyclobenzaprine (Flexeril)
• Carbamazepine (Tegretol)
• Phenothiazines
• Propoxyphene
• Class 1A antidysrhythmics (quinidine, procainamide, disopyramide)
• Class 1C antidysrhythmics (encainide, flecainide, propafenone, moricizine)
• Amantadine

It is likely that you will be asked questions about the huge recall by McNeil..

It stems from complaints received of black particles found in the pediatric liquid formulation, which are manufactured at one facility in Fort Washington, PA.  The FDA inspected the plant and found inadequate quality standard testing and facilities. Either there were potential bacteria in one of the raw products (which did not make it to the final product), or the final concentrations were stronger than specified.

McNeil recalled forty-three formulations of pediatric liquid tylenol, zyrtec, motrin and benadryl. Generic versions are unaffected.

Complete recall information:

www.mcneilproductrecall.com

For more information and links:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm210442.htm

Several drugs and compounds may be radiopaque on an abdominal radiograph. This may be helpful in an overdose to determine ingestion or amount ingested. Attached is a pic a patient that ingested potassium sustained release tables.

The mneumonic CHIPES will help you remember which are:

C - Calcium Carbonate, chloral hydrate

H - Heavy metal - like Mercury, lead

I - Iron and Iodine

P - Phenothiazines (compound that has S(C₆H₄)₂NH in it), drugs that include: antipsychotics like chlorpromazine (thorazine) and antiemetics like prochlorperazine (compazine)

E - Enteric coated pills

S - Solvents [halogenated ones like chloroform] and Sustained Release preparations [Lithobid and K-Dur]

Attachments

• 1004150936_KCl_patient_1.JPG (182 Kb)

Many drugs/toxins cause nystagmus, particularly in overdose.  Vertical, horizontal, or rotary nystagmus may be noted.

The most common drug/toxin overdoses that cause nystagmus are the following:

• Anticonvulsants (phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate)
• Ethanol
• Lithium
• Dextromethorphan
• Phencyclidine (PCP)
• Ketamine
• Lysergic acid diethylamide (LSD)

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When you draw a urine toxicology screen it can mislead more often than help you. Here is a quick list of the test followed by some medications that cause false positives - when in doubt, call your lab to find out specifics since results will vary lab to lab:

TCA - diphenhydramine, carbamazepine, cyclobenzaprine (side note: TCA screen should never be used to determine TCA toxicity, your ECG and physical exam should be enough to determine if the patient is toxic from TCA

Cocaine - the most accurate test on the screen, positive for up to 5 days

PCP - dextromethorphan and ketamine can turn it positive

Amphetamines - pseudoephedrine, ephedrine, phenylephrine and many other OTC cough decongestants can as well, the worst screening test with the largest number of false positives