Toxicology Pearls

-Ammonia

It is able to do this without raising liver 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

-L-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

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)

Black Widow Spider

It is thought to be caused by thoracic and abdominal muscle spasms

• Treatment of hypertension and shortness of breath
• IV Opioids and IV Benzodiazepines will provide symptomatic relief

If hypertension is unresponsive to this therapy, start an IV Nitroglycerin gtt or Nitroprusside.

If symptoms still persist, try the Antivenin, which usually works within 2 hours

Does the patient have a horse serum allergy

NO!!

Black widow spider envenomation does not cause a true anaphylaxis, so administering epinephrine, antihistamines, or prednisone will not improve the course.

Glucagon is generally given as a 5-mg bolus followed by a 1 to 5 mg/h infusion, which can be titrated up to 10 mg/h to achieve the desired patient response (EMCNA;26:759).

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.

Urine drug screens have become an integral part of emergency medicine practice. Two of the most common issues raised regarding such screens are (1) the length of time drugs can be detected and (2) causes if false positive results.

Clinical studies indicate that it is highly unlikely for an individual to test positive for THC through passive exposure to marijuana. However, children exposed to cocaine smoke in heavily contaminated environments can have positive cocaine screen results (2,3).

Urine screens have a low sensitivity for detection of MDMA (ecstasy) - high concentrations of MDMA in the urine are needed to elicit positive results (1,2,4).

Sertraline (Zoloft) and oxaprozin (Daypro) have cross-reactivity with benzodiazepines and can result in false-positive screens (1,2).

The benzodiazepines midazolam, chlordiazepoxide, and flunitrazepam are not detected in many assays. Detection tends to be manufacturer- and antibody-specific (2,5).

Quinolones have been known to cause false-positive results on urine screens for opiates (1,2,6).

Dextromethorphan can result in a false-positive for opiates and verapamil can result in a false-positive for methadone (1).

Fentanyl is usually not detected in urine screens because of lack of metabolites, and oxycodone (Percocet) is not usually detected because of its derivation from thebaine (a compound that is not detected in the urine) (2).

It is true that ingestion of poppy-seeds can produce positive results for opiates. In one study, a single poppy-seed bagel was estimated to contain 1.5 mg of morphine and 0.1 mg of codeine (2,7).

Fluoxetine, labetalol, and ranitidine have all been reported to cause false-positive screens for amphetamines (1).

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-HT1A and 5-HT2A 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.

• VALPROIC ACID OVERDOSE
• Valproic Acid - often prescribed as an anticonvulsant and as treatment for bipolar disorder - uniquely has the ability to raise serum ammonia concentrations without hepatic dysfunction.

In humans taking valproic acid, L-carnitine reduces serum ammonia concentrations; case studies and retrospective analyses provide evidence for the benefit of L-carnitine treatment in improving survival from valproic acid overdose.

L-carnitine is considered safe and there are no known contraindications. The recommended dose for the treatment of valproic acid overdose is IV 100 mg/kg once, followed by infusions of 50 mg/kg (to a maximum of 3 g per dose) every 8 hours continuing until ammonia levels are decreasing and the patient demonstrates signs of clinical improvement.

• References:(1) Perrott J, et al. L-carnitine for acute valproic Acid overdose: a systematic review of published cases Ann Pharmacother 2010 Jul-Aug;44(7-8):1287-93.(2) Lheureux PE, et al. Carnitine in the treatment of valproic acid-induced toxicityClin Toxicol (Phila) 2009 Feb;47(2):101-11.(3) Goldfrank's toxicologic emergencies, 9th Ed., ©2010, McGraw-Hill.

Hyponatremia, which can result in cerebral edema.

It is a result of SIADH caused by a breakdown product of ecstasy.

Hyponatremia is exacerbated by excessive water ingestion by users in attempts to avoid hyperthermia

(Mayo Clin Proc, 9/10, e61).

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.

• -Anion gap metabolic acidosis with elevated lactate
• -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.

Methylene chloride, a solvent found in paint remover and aerosol propellants, is converted in the body to CO after inhalational exposure and can produce CO poisoning

(EM Clin NA;22:985).

• 1) spontaneous clonus,
• (2) inducible clonus plus agitation or diaphoresis,
• (3) ocular clonus plus agitation or diaphoresis,
• (4) tremor and hyperreflexia,
• (5) hypertonia
• (6) Temp> 38°C plus ocular clonus or inducible clonus.

• 1) Discontinuation of serotonergic agents
• 2) Conservative management with administration of IV fluid andlow-dose benzodiazepines
• 3) Cyproheptadine
• 4) In severe cases (temperature >41°C), sedation, neuromuscular paralysis, and intubation may be necessary.

The cited reference points out that an association between cigarette smoking and AML has not been a universal finding. However, over the past two decades, the majority of studies have indeed reported a statistically significant, moderate relationship with a relative risk of about 1.4 for AML among cigarette smokers compared to nonsmokers and the relative risk approachs 2.0 for heavy smokers. In 2004, the US Surgeon General and the International Agency on Research in Cancer of the World Health Organization each concluded, based on the data available, that cigarette smoking does indeed cause AML.

(Lichtman MA. Cigarette smoking, cytogenetic abnormalities and acute myelogenous leukemia. 2007 Leukemia 21:1137-1140)

The most consistently described long-term effect of ecstasy use is memory impairment.

Verbal recall, both immediate and delayed, is the most compromised (Mayo Clin Proc, 9/10, pg. e61).

According to the cited reference, "Poppers" (slang for various forms of alkyl nitrite) are volatile nitric oxide donors that have been used for decades as recreational drugs." These authors report prolonged visual loss as a result of damage to foveal photoreceptors shortly after inhaling poppers. The authors of the cited reference detected isopropyl nitrite (a very potent nitric oxide donor) in the vapors from "popper" vials. They indicated "it is likely that the visual symptoms were due to acute, massive release of nitric oxide. Nitric oxide modulates photoreceptor metabolism and function. It also activates guanylate cyclase 4, a key enzyme for recovery of photoreceptor function after phototransduction. They reported Retinal damage was functionally and anatomically limited to the foveal center, a situation similar to that observed in photic injury. Experimentally, nitric oxide is indeed known to contribute to photic injury. Because nitric oxide is a potent vasodilator, acute changes in ocular perfusion pressure might have contributed to retinal damage. (Audo I, et al. Poppers-associated retinal toxicity. 2010 NEJM 363:1583-1585)

• The grey baby syndrome was first reported in 1959 in association with the use of the antibiotic chloramphenicol in infants. These babies developed abdominal distension, vomiting, cyanosis, cardiovascular collapse, irregular respirations and subsequent death shortly after initiation of therapy with chloramphenicol. Pharmacokinetic studies in neonates showed accumulation of chloramphenicol in plasma due to impaired drug metabolism. A reduction in the total daily dosage from 100 to 50 mg/kg prevented the development of the grey baby syndrome.
• (McIntyre J and Choonara I. Drug toxicity in the neonate. 2004 Biol of the Neonate 86:218-221)

Hyponatremia and yes-young women more commonly develop this sequelae

The onset for effects of MDMA is usually 20-60 minutes and the peak time of effect is 60-90 minutes after ingestion. The duration of effects of this substance ranges from 3 to 5 hours.

(Green AR. The pharmacology and clinical pharmacology of 3,4 methylenedioxymethamphetamine (MDMAA, Ecstasy) 2003 Pharm Rev 55(3):463-508)

1) Exactly what time did you eat the mushroom?

2) Exactly what time did you begin vomiting/diarrhea/GI Sx in general?

3) Are there are more mushrooms that can be brought to ED for identification?

The reason the first two questions are critically important is it determines the total time of onset of toxicity. As a very general rule of thumb, delayed GI symptoms >6hrs is predictive of a possible lethal ingestion of a cyclopeptide containing mushroom like Amanita Phalloides.

Immediate symptoms < 6hrs and even more so if within 2 hrs usually indicates ingestion of a nonlethal mushroom that causes GI distress (many mushrooms like Clitocybe nebularis)

Venous and arterial gas embolism, hemorrhagic gastritis, GI bleeding, shock and death are the serious problems that may result from the ingestion of concentrated hydrogen peroxide.

(French LK, et al Hydrogen peroxide ingestion associated with portal venous gas and treatment with hyperbaric oxygen: a case series and review of the literature. 2010 Clin Tox 48(6):533-538)

IDLH stands for "Immediately Dangerous to Life or Health" and generally refers to chemical inhalation hazards. The IDLH level is most often reported in parts per millions or mg/m3. IDLH's are promulgated by NIOSH and other organizations. One of the considerations for an IDLH value is: "The ability to escape without loss of life or immediate or delayed irreversible health effects. (Thirty minutes is considered the maximum time for escape so as to provide some margin of safety in calculating an IDLH value.)" (http://www.cdc.gov/niosh/idlh/idlh-1.html)

PEG is polyethylene glycol, a polymer made up of identical ethylene glycol subunits. PEG's have a descriptor associated with them that represents the mean molecular weight of the molecule. So PEG 200 has a molecular weight of 200; PEG 400 has a molecular weight of 400, etc, etc. Generally the toxicity of larger molecular weight PEG molecules is less than that of lower molecular weight molecules.

(Webster R, et al. PEGylated proteins: Evaluation of their safety in the absence of definitive metabolic studies. 2007 Drug Met Disposition 35:9-16)

Bowen's Disease has been noted as a complication of chronic arsenicosis.

(Mukherjee SC, et al. Murshidabad- One of the nine groundwater arsenic affected districts of West Bengal, India, part II: dermatological, neurological and obstetric findings. 2005 Clin Tox 43(7):835-848)

Unlike neostigmine and pyridostigmine, physostigmine has a tertiary amine structure that allows it to pass freely into the central nervous system causing reversal of both central and peripheral anticholinergic symptoms.

(Frascogna N. Physostigmine: is there a role for this antidote in pediatric poisonings? 2007 Current Opinion in Pediatrics, 19:201?205)

Following a large single dose of thallium, there is often initial hypotension and bradycardia owing to direct effects of the sinus node and cardiac muscle, followed by hypertension and tachycardia thought to be due to vagal nerve degeneration.

(Peter AL and Viraraghavan T. Thallium: a review of public health and environmental concerns. 2005 Env International 31:493-501)

!) Anticholinergic OD seen in following meds: diphenhydramine (Benadryl), dimenhydrinate (Dramamine), scopolamine, benztropine (Cogentin), some plants like datura stromonium (thorn apple)

2) Physostigmine 1mg IV slowly over a REAL 5 min. Administer to fast and patient may seize. Maximum dose of 2mg IV.

3) Contraindications: suspicion of TCA OD (anectdotal and from old case report) - screening EKG should be done prior to administration of physostigmine. Also glaucoma, closed angle, obstructive uropathy.

Remember your clinical endpoint needs to be measurable, thus hallucinations and agitation should be reversed. No indication if the patient is only experiencing dry mouth or other more mild anticholinergic symptoms.

Methacholine challenge testing is more useful in excluding a diagnosis of asthma than in establishing one because its negative predictive power is greater than its positive predictive power.

(American Thoracic Society. Guidelines for Methacholine and Exercise Challenge Testing-1999. 2000 Am J Respir Crit Care Med (161):309-329)

Tardive dyskinesia results from chronic exposure to dopamine receptor blocking agents and refers to a syndrome that presents with rapid, repetitive, stereotypic movement involving the oral, buccal, and lingual areas. Tardive dyskinesia was first described within five years following the introduction of the first dopamine receptor blocking agent, chlorpromazine in the 1950s.

(Soares-Weiser K and Fernandez H. Tardive dyskinesia. 2007 Seminars in Ne aurology, 27 (2): 159-169)

The cited study concluded that patients with metformin overdose with more profound acidemia and greater increases in their serum lactate and metformin concentrations were more likely to die than those with less significant laboratory derangements.

(Dell'Aglio, DM et al. Acute Metformin Overdose: Examining Serum pH, Lactate Level, and Metformin Concentrations in Survivors Versus Nonsurvivors: A Systematic Review of the Literature. 2009, Anns Emerg Med) 54 (6): 818-823)

The risk factors that have been identified with an increased mortality associated with valproate toxicity include patients less than 2 years of age, those with developmental delay and co-exisiting metabolic disease. The cited reference notes that the patients at greatest risk are those with complex neurological disorders requiring multiple anti-seizure medications.

(Katiyar A and Aaron C. Case files of the Childrens Hospital of Michigan Regional Poison Center: The use of carnitine for the management of acute valproic acid toxicity. 2007 J Med Tox, 3(3):129-138)

The visual disturbances reported to be associated with digoxin toxicity include flashing lights, halos, and color disturbances involving yellow-green patterns. However, the most commonly reported visual problem is hazy or blurred vision.

(Bauman JL, et al. Mechanisms, manifestation and management of digoxin toxicity in the modern era. 2006 Am J Cardiovasc Drugs 6(2):77-86)

Welders siderosis refers to the pneumoconiosis caused by inhalation of iron oxide particles produced in the welding process and is generally considered to be a benign form of lung disease.

(Patel RR, et al. Systemic iron overload associated with welders siderosis. 2009 Am J Med Sciences 337(1):57-59.

The use of cocaine more than two times per week for longer than six months has been reported to lead to mesenteric thrombosis, perforation, and visceral ischemia in the lower gastrointestinal tract.

(Ellis CN and McAlexander WW. Enterocolitis Associated With Cocaine Use. 2005 Dis Colon Rectum, 48: 2313?2316)

A wide variety of drugs and toxins have been reported to cause priapism including; chlorpromazine, thioridazine, fluphenazine, perphenazine, mesoridazine, thiothixine, haloperidol; zuclopenthixol, clozapine, risperidone, olanzapine, aripriprazole, quetiapine, Terazosin, tamsulosin, alfuzosin, prazosin, hydralazine, trazodone, nefazadone, fluoxetine, bupropion, citalopram, sertraline, buspirone, hydroxyzine, ethanol, cocaine, ecstasy, marijuana, tadalafil, sildenafil, vancomycin, testosterone, gonadotropin releasing hormone, propofol, scorpion sting, and black widow spider.

(Sood S., et al Priapism associated with atypical antipsychotic medications: a review. 2008 International Clinical Psychopharmacology 23 (1):9-17)