Anti-muscarinic toxidrome case file

Anti-muscarinic toxidrome case file

Eugene C. Toy, MD, Barry C. Simon, MD, Terrence H. Liu, MD, MHP, Katrin Y. Takenaka, MD, Adam J. Rosh, MD, MS

Case 56

An 18-year-old man presents to the emergency department (ED) ag itated, confused and hallucinating. The patient friends state that the group was walking around in the woods looking for some “weeds to smoke” in order to get “high.” The patient was first to smoke one of the weeds and subsequently became agitated. His friends decided to bring him to the ED for evaluation. On arrival to the ED, the patient vital signs are BP 180/100 mm Hg, HR 120 beats per minute, RR 18 breaths per minute, temperature 101°F, and pulse ox 98% on room air. On physical examination, his pupils are 6 mm, skin is erythematous and warm to the touch, axillae are dry, abdomen has decreased bowel sounds, and the patient is grabbing at things that are not there.

⯈ What is the most likely diagnosis?

⯈ What is the next step in treatment?

ANSWER TO CASE 56:

Anti-muscarinic Toxidrome

Summary: This is a case of an unknown plant ingestion in a patient who presents with several signs of toxicity. The key features of this case include recognizing signs and symptoms of a toxidrome and knowing how to stabilize and manage poisoned patients. The patient presents with anti-muscarinic toxicity after smoking jimson weed, which contains belladonna alkaloids. These alkaloids possess strong antimuscarinic properties.

• Most likely diagnosis: Jimson weed (anti-muscarinic) toxicity
• Best initial treatment: Benzodiazepines and consider physostigmine

ANALYSIS

Objectives

1. Develop an initial approach to the poisoned patient.
2. Learn the 5 basic classes of toxidromes.
3. Understand how to classify a patient into a toxidrome.
4. Understand the initial steps for stabilization of a symptomatic overdose.
5. Review the basic treatment for each of the toxidromes.

Considerations

This patient has several classic features of an anti-muscarinic toxidrome. The primary treatment efforts for the poisoned patient are the same as any other patient: maintenance and stabilization of the airway, breathing, and circulatory systems (ABCs). For any intentional overdose, levels of acetaminophen and salicylate levels should be checked due to their ubiquity in medications and great potential for morbidity and mortality.

In this case, the patient is febrile. Fever in the setting of a toxicologic problem is a predictor of increased morbidity and mortality. The cause of the fever is usually secondary to increased muscle activity. Initial treatment should include administration of benzodiazepines (eg diazepam, lorazepam) and intravenous fluids for hydration.

In general, symptomatic poisoned patients require hospital admission for continued monitoring. However, the majority does well with simple supportive care.

The local poison control center should be contacted early in the work-up of all symptomatic overdoses. This is critical both for epidemiologic purposes as well as management of complex patients and continuity of care. The national phone number for the nearest poison control center is 1-800-222-1222.

Approach To:

Toxidromes

DEFINITIONS

TOXIDROME: A clinical syndrome that is essential for the successful recognition of poisoning patterns. A toxidrome is the constellation of signs and symptoms that suggest a specific class of poisoning.

DECONTAMINATION: Prevention of the continued absorption of a toxicant.

DRUG ABSORPTION: The movement of drug from its site of administration into the bloodstream.

ADSORPTION: The binding of a chemical (eg, drug or poison) to a solid material such as activated charcoal.

ANTIDOTE: A remedy to counteract a poison or injury.

OPIATE: A compound found in opium poppies (eg, morphine, codeine, thebane, etc) that binds to the opiate receptor.

OPIOID: A synthetic (eg, fentanyl, methadone, tramadol, etc) or semi-synthetic (eg, heroin, oxycodone, hydrocodone, etc) compound that binds to the opiate receptor.

BODY PACKER: An individual who ingests wrapped packets of illicit drugs such as cocaine, heroin, amphetamines, ecstasy, marijuana, or hashish to transport them.

BODY STUFFER: Someone who admits to or is strongly suspected of ingesting illegal drugs in order to escape detection by authorities, and not for recreational purposes or to transport the drug across borders. Cocaine is the drug most commonly involved in the body stuffer syndrome.

CLINICAL APPROACH

General Overdose Management

Airway and Breathing The general approach to the overdose patient is to start with an initial assessment that includes evaluation of the patient airway, breathing, and circulation (ABCs). The most easily correctable cause of toxicologic death is airway support. Sedate patients may have a partially obstructed airway due to a relaxed tongue. In addition, obtunded patients may loose their gag reflex. Understand also, that breathing consists of both oxygenation and ventilation. A hypoxic patient with a suspected overdose and no history of known medical problems, is also at risk for poor ventilation. Masking this hypoventilation and hypoxia by applying supplemental oxygen may actually decrease the patient intrinsic respiratory drive and lead to further hypoventilation. Definitive airway management includes endotracheal or nasotracheal intubation.

Circulation Toxidromes can lead to both extreme hypertension and hypotension. Extreme hypertension (sympathomimetics) may require the use of a direct alpha1-receptor antagonist, such as phentermine. Hypotension should first be treated with intravenous fluids. Other agents such as vasopressors (norepinephrine, dopamine) may be required. Often, cardiac function is also affected in toxidromes. Tachy- and bradydysrhythmias are both common. Treatment depends on the underlying etiology of the dysrhythmia.

Decontamination In addition to the ABCs, it is also essential to consider decontamination and elimination (or ABCDE) in the management of a poisoned patient. Decontamination involves preventing further absorption into the system. For topical contaminations, removing the patient clothing, as well as washing off the affected area, may be all that is required. Another way of preventing absorption into the system is the administration of activated charcoal. Activated charcoal comes in two forms; with and without sorbitol. Sorbitol is thought to facilitate the movement of activated charcoal through the gastrointestinal (GI) tract. It is, however, a GI irritant and more than one dose of activated charcoal with sorbitol is not recommended. Patients who have the greatest benefit from activated charcoal include those who present early in their ingestion (<1 hour), are awake and can drink the activated charcoal without risk of aspiration, and ingestions whose chemicals are well absorbed by activated charcoal.

One main concern with the administration of activated charcoal is the potential for aspiration and subsequent charcoal pneumonitis. This risk can be decreased by administering activated charcoal only to patients who are awake and protecting their airway. In addition to this complication, activated charcoal poorly adsorbs certain chemicals (see Table 56–1), and therefore will have little benefit in these ingestions. Moreover, patients with caustic injuries often undergo endoscopy. Prior administration of activated charcoal may complicate the procedure.

Another method of decontamination is gastric lavage. This is accomplished by inserting a large oral gastric tube (eg, 40 French) into the stomach for the rapid administration and removal of large volumes (several liters) of fluid in an attempt to try to remove whole pills before they are dissolved and absorbed. One potential adverse effect is lavaging the lungs instead of the stomach. This can be avoided by intubating the patient prior to lavage. In addition, given the increasing number of bariatric surgery patients, a complication can occur if the tube gets stuck in the gastric band or causes gastric perforation. Given the large number of treatment options that are available for a wide variety of ingestions, gastric lavage should only be performed on patients who present early (<1 hour) and

have a potentially life-threatening ingestion for which there are limited treatment options. This technique is not to be confused with nasogastric lavage (the administration and subsequent removal of fluid from an NG tube), which has not been shown to substantially alter the course of any substantially poisoned patient and usually ends at just removing some of the excipients (starches, waxes, and binding agents).

Another method of decontamination is whole bowel irrigation. In this method, a large amount of polyethylene glycol electrolyte lavage solution (PEG-ELS) is administered through an NG tube at a rate of approximately 1 L an hour. The goal of this therapy is to push whole pills through the GI tract to prevent absorption. This method is especially helpful in treatment of body packers and body stuffers as well as with sustained release medications.

Elimination Once the drug is absorbed into the body, there are options that may help to increase elimination from the body. These options include multidose charcoal, hemodialysis, charcoal hemoperfusion, and urinary alkalinization. Multidose charcoal has been shown to be effective with certain drugs, namely dapsone, carbamazepine, phenobarbital, quinine, and theophylline. While the first dose of charcoal with these patients can be given with sorbitol, subsequent doses should not contain sorbitol as it is a GI irritant and can lead to dehydration and GI upset.

Hemodialysis is effective for certain drugs that have a low volume of distribution (ie, water soluble) and may be used if there is no better antidote or if the patient is critically ill. Examples of these drugs include lithium, methanol, and aspirin. Acetaminophen technically is also amenable to dialysis but there is a noninvasive antidote that is more commonly used.

Charcoal hemoperfusion is similar to arterial venous hemodialysis, except that the drug is passed through a charcoal filter prior to systemic return. This is particularly effective in phenobarbital and theophylline overdoses as they adsorb well to charcoal.

Urinary alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH >7.5. Alkaline urine facilitates ion trapping and excretion. This method is particularly useful for aspirin and phenobarbital toxicities.

Supplemental Testing

For any intentional overdose, an acetaminophen and salicylate level should be obtained. These medications are readily accessible and carry a high morbidity and mortality while being fairly easy to treat if caught early.

For acetaminophen, if the time of ingestion is known and it is a single acute ingestion, use of the Rumack-Matthew nomogram for acetaminophen toxicity can determine if the patient requires treatment. If the time of ingestion is unknown and any detectable acetaminophen level is found then strong consideration should be given towards treatment. Consideration should also be made with unexplained elevations in transaminases.

For salicylates, levels above 30 mg/dL should be treated with bicarbonate infusion and potassium supplementation to increase urinary elimination (prevent reabsorption). Certain patients may require dialysis. These include but are not limited to salicylate-induced pulmonary edema, salicylate-induced encephalopathy, severe acidosis, and levels greater than 80 mg/dL in the correct clinical setting.

Twelve-lead ECG may be helpful in early identification of sodium channel blocking drugs (eg, tricyclic antidepressants, diphenhydramine, and various other antidepressants and antipsychotics). Sodium channel blockade is manifested by a prolonged QRS complex. The first manifestation of this may be in lead aVR where it is possible to see an R-R-prime pattern and slurring of the terminal 30 msec of the QRS complex. Administering intravenous sodium bicarbonate until the QRS complex narrows helps treat this condition.

Patients with a wide QRS may also have QT prolongation. One should be careful to distinguish QRS prolongation from QT prolongation. Drugs that affect potassium efflux or influx or drugs that affect calcium influx will also cause QT prolongation. Treatment with sodium bicarbonate for a prolonged QRS can worsen a prolonged QT interval by pushing potassium into cells, which may lead to torsade de pointes.

Routine urine drug screen testing is not necessary for treatment of an acute overdose. Most urine drug screen testing is an immunoassay that tests for the presence of drug metabolites and are tailored to a specific core molecule. They do not necessarily detect the presence of the active compound and they do not tell you if the patient is under the effects of that particular compound. There are many false positives and false negatives in any given class of drugs tested on the urine drug screen. Treatment of an overdose should not wait until the return of the urine drug screen.

Toxidromes

Sedative Hypnotic This is a large class of drugs, which includes alcohols, benzodiazepines, barbiturates, chloral hydrate, propofol, carisoprodol, and many others. In general, the sedative hypnotic toxidrome is characterized by relatively normal vital signs (see Table 56–2) and a relatively normal examination except for a markedly decreased level of consciousness. The patient may be hypothermic but this would be due to environmental heat loss and loss of the shiver response. Treatment for this toxidrome is largely support of airway and breathing. In the undifferentiated sedative hypnotic patient, administration of flumazenil, a benzodiazepine antagonist, is not indicated as it may precipitate a benzodiazepine resistant seizure.

Opioid/Opiate This class of drugs includes synthetics and semi-synthetics such as fentanyl and meperidine, as well as compounds found in nature and close derivatives such as morphine and codeine. These agonize the opiate receptors in the body. Agonism at these receptors induces euphoria, analgesia, antidepressant effects, and sedation as well as respiratory depression, miosis, decreased GI motility, and dependence.

Vital signs in these patients may demonstrate decreased respirations and a low pulse ox. In severe overdoses the patient may be hypotensive or bradycardic or 

both. On physical examination the pupils will be small (miotic), bowel sounds are decreased, reflexes are decreased, and overall level of consciousness is decreased. Unless the patient has hypotension or bradycardia, the focus is maintaining ventilation and oxygenation. Treatment for hypoxia in the opiate or opioid overdose patient is either naloxone (Narcan) administration or endotracheal intubation. In the non-critically ill patient, the amount of naloxone administered should be based on the patient response. The goal of treatment is to get the patient breathing again, not necessarily to make the patient awake and conversant. Nalaxone administration should be avoided in an intubated patient with opiate or opioid overdose since this will lead to significant vomiting.

Sympathomimetic This class of drugs includes stimulants such as cocaine, ecstasy and methamphetamine, but may also include therapeutic medications such as albuterol, pseudoephedrine, and many others. Their mechanisms of action may vary, but the end result is increased stimulation of the α- and β-adrenergic receptors. This alpha and beta stimulation results in tachycardia, hypertension, and hyperthermia. Physical examination often reveals dilated pupils (mydriasis), increased CNS activity (hallucinations or seizures), increased reflexes, and diaphoretic skin. This toxidrome can look very similar to the anti-muscarinic toxidrome, but is usually distinguished by the presence of diaphoresis.

Mortality in these patients is typically from hyperthermia, so it is critical to keep them cool. Physically restraining a patient who is agitated or delirious without a sedative medication may lead to rhabdomyolysis and a dangerous increase in temperature. The mainstay in treatment includes the administration of benzodiazepines and intravenous fluids. If the patient is still agitated after receiving large doses of benzodiazepines, consideration should be given to administering barbiturates or paralysis and intubation.

Antimuscarinic There are a large variety of drugs that fall under the anti-muscarinic toxidrome. These may also be referred to as anticholinergic drugs, but very few medications have anti-nicotinic activity, and thus we should correctly refer to this as the anti-muscarinic toxidrome. Antagonism at the muscarinic receptors leads a physical examination that is very similar to the sympathomimetic toxidrome. The area in which the sympathomimetic toxidrome differs from the anti-muscarinic toxidrome is that the antimuscarinic toxidrome will have dry skin while the sympathomimetic toxidrome will have wet skin. Patients tend to be tachycardic, hypertensive, and febrile. On physical examination they will have mydriatic pupils, an altered level of consciousness (hallucinating or seizing), urinary retention, and decreased bowel sounds. There is a mnemonic for this toxidrome: Mad as a hatter (hallucinations), dry as a bone (anhydrosis), red as a beet (increased agitation and fever), and blind as a bat (mydriasis).

Treatment of the anti-muscarinic toxidrome varies depending on the severity of effects and whether the effects are acting more peripherally (anhydrosis) or centrally (seizure, heart rate, and blood pressure). Peripheral anti-muscarinic toxicity can be treated with benzodiazepines. Central anti-muscarinic toxicity should also be treated with benzodiazepines, and consideration to use a medication that increases levels of acetylcholine, such as physostigmine, an acetylcholinesterase inhibitor.

Cholinergic Cholinergic drugs are drugs that increase the level of acetylcholine. This is usually through inhibition of acetylcholinesterase. Examples of these medications include edrophonium and physostigmine. Other sources for cholinergic toxicity include insecticides such as carbamates and organophosphates. Organophosphates are notable in that they have the potential to irreversibly bind and inhibit acetylcholinesterase–this process is called aging and is highly dependent upon the type of organophosphate such that significant aging varies between 2 to 36 hours after initial binding.

Excess acetylcholine can cause effects at both muscarinic and nicotinic receptors and its effects depend on the time course and severity of toxicity. Classically, it is associated with bradycardia and hypoxia secondary to either increased fluid in the lungs or diaphragmatic paralysis. Other findings on physical examination include miotic pupils (pinpoint), hyperactive bowel sounds, and excessive secretions from the mouth, GI tract, and skin.

The mnemonic SLUDGE (Salivation, Lacrimation, Urination, Defecation, GI upset, and Emesis) covers some but not all aspects of this toxidrome. It does not account for the bradycardia, bronchospasm, and bronchorrhea or the miotic pupils that are noted on physical examination. An alternative mnemonic is DUMBBELLS (Defecation, Urination, Miosis, Bradycardia, Bronchorrhea/Bronchospasm, Emesis, Lacrimation, Lethargy, and Salivation).

Treatment involves the administration of anticholinergic medication such as atropine as well as pralidoxime (2-PAM). Atropine should be administered to help control bronchorrhea. Pralidoxime should be administered to prevent binding and aging of the acetylcholinesterase in the case of organophosphate poisoning.

COMPREHENSION QUESTIONS

56.1 A farmer presents to the ED with difficulty in breathing. His vitals are BP 85/55, HR 50, T 97.8°F, RR 28, and pulse ox 91% room air. His examination reveals wheezing; excessive perspiration, vomiting, and tearing, and 1 mm pupils. Which is the best treatment for this patient toxicity?

A. Benzodiazepines

B. Physostigmine

C. Pyridoxine

D. Pralidoxime

E. Naloxone

56.2 A teenager comes home after visiting his grandmother who is sick with cancer. His parents call 911 because he is minimally responsive. They find him with a BP 90/60, HR 65, T 98.5°F, RR 6, pulse ox 89% on room air. His examination includes 2 mm pupils, decreased bowel sounds, hyporeflexia, and responsiveness only to noxious stimuli. The paramedics check his blood sugar, which is normal, and administer which of the following?

A. Charcoal

B. Naloxone

C. Flumazenil

D. Lorazepam

E. Atropine

56.3 A college student with a history rhinorrhea comes in after being found by her roommate with an altered mental status. Her vitals are BP 160/90, HR 120, RR 18, T 100.5°F, pulse ox 100%. On examination she is picking at the air, has decreased bowel sounds, 6-mm pupils and no moisture in her axilla. Her blood sugar is normal. Which medication should they give her?

A. Atropine

B. Pralidoxime

C. Physostigmine

D. Flumazenil

E. Fomepizole

56.4 A 55-year-old homeless woman presents to the ED brought by ambulance. The police found her seizing in the street. Her vital signs are BP 220/150, HR 140, T 101°F, RR 16, pulse ox 100% on room air. On examination she has 6 mm pupils, very wet skin, decreased bowel sounds and is having uncontrollable limb movements. A check of her blood sugar is normal. What medication should this patient be administered?

A. Physostigmine

B. Lorazepam

C. Labetalol

D. Atropine then pralidoxime

E. Phytonadione

ANSWERS

56.1 D. This patient is exhibiting a cholinergic toxidrome. The mnemonic for this is DUMBBELLS (Defecation, Urination, Miosis, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Lethargy, and Salivation). The treatment is to prevent the patient from drowning in his or her own saliva by administering atropine 1 mg at a time until the secretions dry up. In addition, pralidoxime (2-PAM) is administered to increase acetylcholinesterase availability and reduce acetylcholine. Benzodiazepines would not help with this patient. Physostigmine is a treatment for anti-muscarinic toxicity and would worsen this patient condition. Pyridoxine is vitamin B6 and can be useful in treating seizures if they are caused by isoniazid (INH). Naloxone is an opiate antagonist and while this presentation has some overlap with the opiate toxidrome, this patient is tachypneic and has excessive secretions that are not seen in the opiate toxidrome. His exposure was from the pesticides on the farm.

56.2 B. This patient is exhibiting an opiate toxidrome. He has miotic pupils and decreased respirations, GI motility and mental status. The treatment for this is patient should include a trial of naloxone; enough to increase his oxygenation. This patient likely stole opiate medication from his grandmother. Charcoal would not help this patient as he is already severely symptomatic. Additionally, charcoal would be contraindicated in this patient because of the risk of aspiration. Flumazenil is a benzodiazepine antagonist. Lorazepam is a benzodiazepine. Atropine is a strong anti-muscarinic drug and would not be helpful in treating this patient.

56.3 C. This patient is exhibiting an antimuscarinic toxidrome. This is characterized by tachycardia, fever, hallucinosis, dilated pupils, hypoactive bowel sounds, and dry axilla. The mnemonic is: mad as a hatter (hallucinations), dry as a bone (anhydrosis), red as a beet (increased agitation and fever), and blind as a bat (mydriasis). Treatment should be either decreasing the agitation and temperature through benzodiazepines or increasing acetylcholine by preventing its metabolism (physostigmine, an acetylcholinesterase inhibitor). Atropine is an anti-muscarinic drug and would worsen this patient toxidrome. Pralidoxime is a drug which makes acetylcholinesterase work again after exposure to an organophosphate. This patient does not have signs of cholinergic excess, therefore, pralidoxime would not be helpful. Flumazenil should not be given to adult patients because, as acting benzodiazepine antagonist, it may precipitate seizures that are not responsive to benzodiazepines. Fomepizole is an inhibitor of alcohol dehydrogenase and is helpful in the treatment of patients poisoned with ethylene glycol, methanol or other toxic alcohols. This patient had an accidental overdose of her diphenhydramine for her seasonal allergies.

56.4 B. This patient is exhibiting a sympathomimetic toxidrome. Her presentation is very similar to the patient in question 3. However, the key difference is that this patient has wet skin, while the patient in question 3 has dry skin. The patient should receive as much lorazepam as is needed to stop the seizure and allow the temperature to fall. Physostigmine is a treatment for anti-muscarinic toxicity and would not be helpful in this patient. Labetalol is a β-blocker. This patient has signs of active sympathomimetic excess. Treatment with a β-blocker may lead to unopposed α-1 agonism and potentially may worsen a patient tissue perfusion. While this patient is wet, she has none of the other signs of a cholinergic toxicity. Therefore, atropine and pralidoxime are not recommended. Phytonadione is vitamin K and is the treatment for warfarin toxicity. This patient recently used crack cocaine.

CLINICAL PEARLS

⯈ Patients who are hypoxic from an overdose typically will require a definitive airway such as endotracheal or nasotracheal intubation.

⯈ Fever from an overdose is a poor prognostic indicator and should usually be addressed with large doses of benzodiazepines and intravenous fluids.

⯈ Symptomatic patients require observation or admission until they are asymptomatic.

⯈ In the undifferentiated altered mental status patient, blood sugar level should immediately be checked.

⯈ The nearest poison control center should be contacted (1-800-222-1222) for overdoses, accidental ingestions, and adverse drug effects.

REFERENCES

Aaron CK, Bora KM. Toxin ingestions in children. BMJ Point-of-Care. 2010; Available at: https:// online.epocrates.com/u/2911885/Toxic+ingestions+in+children 

Chyka PA, Seger D, Krenzelok EP, Vala JA. American Academy of Clinical Toxicology, European Association of Poisons Centres, Clinical Toxicologists. Position paper: single-dose activated charcoal. Clin Toxicol (Phila). 2005;43:61-87. 

Goldfrank L, Flomenbaum N, Lewin N, et al. Goldfrank’s Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2010. 

Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning. BMJ. 2007;334:629-634. 

Wu AH, McKay C, Broussard LA, et al. National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem. 2003;49:357-379.

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