Cholinergic Crisis

Etiology

Cholinergic toxicity can arise from various causes. The most commonly encountered scenarios are discussed below.

Overmedication in Myasthenia Gravis Treatment

Myasthenia gravis is an autoimmune condition that affects the neuromuscular junction by producing autoantibodies against ACh receptors at the postsynaptic membrane.[4] This disorder is characterized by generalized weakness or easy fatigability, which can rapidly progress to respiratory failure.[5] Another form of myasthenia gravis, commonly seen in women, is associated with the production of antibodies against muscle-specific tyrosine kinase (MuSK).[6][7]

The condition may be treated with AChE inhibitors (AChE-Is), such as pyridostigmine. AChE-Is prevent ACh breakdown by inhibiting AChE. This action increases ACh levels and extends the neurotransmitter's action duration at the postsynaptic membrane. Excessive use of AChE-Is in patients with myasthenia gravis may precipitate cholinergic crisis, characterized by both muscarinic and nicotinic toxicity.

Myasthenic crisis is a complication of myasthenia gravis. Precipitants of myasthenic crisis include infection, surgery, menstruation, and medications that impair neuromuscular function, such as quinidine, calcium channel blockers (eg, verapamil, nifedipine, and felodipine), and some antibiotics (eg, gentamicin, ampicillin, streptomycin, erythromycin, and ciprofloxacin).[8][9] The clinical symptoms of myasthenic crisis and cholinergic crisis are very similar. Cholinergic crisis is uncommon in myasthenia but should always be considered in cases of myasthenic crisis.[10][11][12]

Identifying the underlying cause of muscular weakness is crucial, though it can be difficult clinically. Patients may transition from myasthenic weakness to cholinergic weakness without any noticeable change in signs or symptoms. The edrophonium test (administering 2 mg of the drug intravenously) can help differentiate the 2 conditions. A clinical improvement is observed in myasthenic crisis, while symptoms worsen in cholinergic crisis. However, the test is not without risks. Complications such as bradycardia, syncope, nausea, and even respiratory failure may occur. Thus, the test must be performed in a controlled setting, such as an intensive care unit.[13]

Organophosphate Exposure

Cholinergic crisis may be triggered by exposure to drugs that inhibit AChE, such as nerve agents and organophosphates found in pesticides, insecticides, and herbicides. Exposure may occur through inhalation of vapors, ingestion, or direct contact with the skin or mucous membranes.[14][15]

Organophosphates are widely used in chemical warfare. Nerve agents are among the deadliest chemicals in warfare and include Sarin, Tabun, Soman, GF, and VX. Organophosphates inhibit AChE, leading to excessive stimulation of muscarinic and nicotinic receptors at the postsynaptic membrane. ACh binds to smooth muscle endplates and secretory glands, causing symptoms such as nausea, vomiting, bronchospasm, miosis, blurry vision, bronchorrhea, and sialorrhea. The nicotinic effects on skeletal muscle can lead to fasciculations and flaccid paralysis. Nerve agent poisoning can range in severity from mild to severe.

Acute or chronic exposure to pesticides and insecticides containing organophosphates can also trigger a cholinergic crisis. Common organophosphate insecticides include malathion, parathion, diazinon, fenthion, and trichlorfon. Such exposures typically occur in rural settings where pesticides and herbicides are used extensively. Other types of pesticides, aside from organophosphates, include carbamate, organochlorine, and pyrethroid insecticides. In addition to muscarinic and nicotinic symptoms observed in cholinergic crises, individuals exposed to organophosphates may also display neurological symptoms such as headache, dizziness, tremors, and paresthesia.[16]

Reversal of Neuromuscular Blockage

The use of neostigmine or pyridostigmine as reversal agents for neuromuscular blockade can also trigger a cholinergic crisis.[17][18] Neostigmine inhibits AChE and is commonly used to reverse the effects of nondepolarizing paralytics such as vecuronium, rocuronium, mivacurium, and pancuronium. By inhibiting AChE, neostigmine increases ACh levels at the neuromuscular junction, overcoming the competitive inhibition caused by these blocking agents. However, like other AChE inhibitors, neostigmine can stimulate muscarinic receptors, leading to cholinergic crisis symptoms such as bronchospasm, miosis, increased peristalsis, and excessive secretions. To mitigate these muscarinic effects, an anticholinergic agent like glycopyrrolate is often administered alongside neostigmine during the reversal process.

Epidemiology

Epidemiological data on cholinergic crisis is limited. However, the condition is commonly observed in both the pediatric population and patients with myasthenia gravis. In children, cholinergic crisis typically arises from accidental exposure to or ingestion of organophosphates, with those living in rural areas being at particularly high risk. Since 2013, stricter federal regulations in the United States have been implemented to control the sale of organophosphates.

Globally, approximately 3 million people are exposed to organophosphate poisoning annually, resulting in around 220,000 deaths.[19] Poisoning occurs from the accidental or intentional ingestion of agricultural insecticides or pesticides. In cases of cholinergic crisis due to organophosphates, contamination may also occur through food products such as wheat, flour, cooking oil, fruits, and vegetables.

Since World War II, the production of nerve agents such as Sarin and Tabun has been restricted. Manufacturing these agents has been considered a war crime under the Geneva Convention of 1925. This decline in production has led to a significant reduction in nerve gas poisoning incidents in recent years. The most recent large-scale use of nerve gas occurred in Syria in 2013.

Pathophysiology

A cholinergic crisis results from overstimulation of the postsynaptic membrane by ACh. First identified as a neurotransmitter by Loewi in 1921, ACh is present in the synapses of ganglia, the neuromuscular junction, and the muscular system of visceral organs. This neurotransmitter is synthesized at the nerve terminal from acetyl coenzyme A (acetyl-CoA). Neurons cannot produce choline, though they can absorb it from the bloodstream, where it arrives following dietary intake and hepatic metabolism.[20]

Acetyl-CoA is produced from glucose and choline through a reaction catalyzed by çyltransferase (CAT). ACh is then packaged into vesicles at the presynaptic membrane. Each vesicle contains up to 10,000 molecules of ACh. Upon stimulation, calcium ions trigger the release of ACh. The neurotransmitter’s action at the postsynaptic membrane is terminated not by its reuptake but by the action of AChE, a powerful hydrolytic enzyme found in the synaptic cleft. AChE breaks down ACh into choline and acetate. The cholinergic nerve terminal contains a sodium-choline transporter that reabsorbs the choline produced during this hydrolysis process.[21][22]

ACh acts on both muscarinic and nicotinic receptors. Muscarinic receptors, which are activated by ACh and muscarine, are G protein-coupled receptors located throughout the body. When activated, these receptors increase intracellular cyclic adenosine monophosphate (cAMP) levels, which, in turn, activate protein kinase. Muscarinic receptors are part of the parasympathetic system, playing a role in regulating secretions (in both the bronchial tree and gastrointestinal tract), heart rate, pupillary response, and urination. Muscarinic effects of ACh include the following: 

• Eye: Miosis and blurred vision
• Gastrointestinal system: Nausea, vomiting, and diarrhea
• Respiratory system: Decreased lung compliance, bronchoconstriction, and bronchorrhea
• Secretory system: Increased secretions in the tracheobronchial and gastrointestinal systems
• Cardiovascular system: Bradycardia
• Genitourinary system: Increased urinary frequency and urgency

Nicotinic receptors, which are part of the ligand-gated ion receptor family, are activated by both ACh and nicotine. These receptors are located in muscle fibers at neuromuscular junctions and in autonomic ganglia, influencing both the sympathetic and parasympathetic nervous systems. Excessive stimulation of nicotinic receptors at the skeletal muscle endplate and synaptic ganglia leads to several effects, including voluntary muscle fasciculation, which can progress to flaccid paralysis. In the cardiovascular system, this overstimulation initially causes tachycardia, which may eventually shift to bradycardia due to the opposing actions of muscarinic and nicotinic receptor activation.

History and Physical

The evaluation of cholinergic crisis can be challenging, particularly for providers unfamiliar with its clinical signs and symptoms. A comprehensive history and thorough physical examination are essential. Time is paramount in the initial assessment. Determining when, how, and where the exposure or ingestion occurred is essential for appropriate management. Pralidoxime can reactivate AChE, which has been inhibited by the toxin, enabling the rapid breakdown of ACh and reducing the overactivation of the postsynaptic membrane.

During history taking, the cause of the crisis must be identified. Potential triggers include medications used for the treatment of myasthenia gravis or glaucoma, such as pyridostigmine; insecticides, pesticides, or herbicides; nerve agents; and reversal of neuromuscular blockade.

During the physical examination, special attention should be given to the nervous, respiratory, cardiovascular, and gastrointestinal systems, where clinical manifestations tend to be the most pronounced. Helpful mnemonics to remember the muscarinic effects of ACh are SLUDGEM and DUMBELS.

The muscarinic effects of ACh, remembered through the mnemonic SLUDGEM, include the following:

• Salivation
• Lacrimation
• Urinary frequency
• Diarrhea
• Gastrointestinal cramping and pain
• Emesis
• Miosis

An alternative mnemonic, DUMBELS, lists the symptoms in the following sequence:

• Diaphoresis and diarrhea
• Urinary frequency
• Miosis
• Bronchospasm and bronchorrhea
• Emesis
• Lacrimation
• Salivation

Excessive stimulation of nicotinic receptors can lead to several clinical signs, including muscular weakness, muscular fatigue and fasciculation, respiratory muscle weakness, tachycardia, and hypertension. In addition, stimulation of the central nervous system (CNS) can result in seizures, coma, ataxia, slurred speech, and agitation or restlessness. The clinical diagnosis of cholinergic crisis may be established based on these toxidromes.

Evaluation

The evaluation of patients with cholinergic crisis requires a detailed history and physical examination to identify the toxidromes associated with the condition. Additionally, ancillary studies that should be considered include the following:

• Complete blood count: Checks for leukocytosis suggestive of an infectious process
• Comprehensive metabolic panel: Rules out electrolyte abnormalities related to organophosphate poisoning
• Red blood cell cholinesterase activity: Typically decreased, which can help confirm the diagnosis. Plasma pseudocholinesterase may also be used but is less accurate than red blood cell cholinesterase activity.[23]
• Electrocardiography: Checks for the presence of arrhythmia associated with organophosphate poisoning
• Chest radiography: Evaluates for the presence of pulmonary edema or aspiration
• Computed axial tomography scan of the head: Rules out other causes of altered mental status

The combination of clinical evaluation and diagnostic tests enables a comprehensive understanding of the patient's condition. Prompt intervention based on these findings can significantly improve outcomes.

Treatment / Management

The treatment of cholinergic crisis follows a structured approach divided into 3 stages: prehospital care, emergency department management, and inpatient care. Effective management at each stage is vital to minimize complications and improve recovery.

Prehospital Care

Prehospital care focuses on stabilizing the patient and removing the toxic agent. If insecticide exposure is suspected, decontamination should begin immediately, and all clothing should be removed to prevent ongoing contamination and protect first responders from cross-contamination.

Emergency Room Management

Regardless of the etiology, the first step in managing cholinergic crisis is to prioritize the ABCs: airway, breathing, and circulation. The patient’s airway should be assessed to ensure it is patent, and spontaneous breathing should be confirmed. Intubation should be performed if concern for airway compromise arises. Advanced airway management and intubation are indicated when copious oral and nasal secretions compromise airway patency, the patient has an altered mental status with a Glasgow Coma Score of less than 8, evidence of hemodynamic instability is present, or profound weakness of the respiratory muscles occurs.

Vascular access should be promptly established with 2 large-bore peripheral intravenous lines. Fluids should be administered to maintain circulation, with continuous pulse oximetry and vital sign monitoring. If the patient shows signs of hemodynamic instability, central venous access should be obtained to administer vasoactive medications.

In the emergency department, initial management focuses on maintaining the airway and ensuring hemodynamic stability. Ventilatory support should be continued once the patient is intubated.

Inpatient Management

Inpatient care for cholinergic crisis focuses on continued cardiopulmonary support and monitoring, with patients typically requiring admission to the intensive care unit. The main treatment involves administering antidotes such as atropine and oximes—drugs that address different aspects of the crisis.

Atropine, which targets the muscarinic effects of ACh, works by competitively binding to postsynaptic muscarinic receptors, thereby preventing further ACh action. For pediatric patients, the dose is approximately 0.03 to 0.05 mg/kg, while adult patients typically receive 2 mg. Atropine should be administered until signs of atropinization appear, such as tachycardia, warm, dry, and flushed skin, and mydriasis. However, this agent does not affect nicotinic receptors. Oximes like pralidoxime and obidoxime are used to address nicotinic manifestations.[24](B3)

Pralidoxime chloride is the most commonly used oxime in the United States, acting as a "molecular crowbar" to separate organophosphates or nerve gases from AChE, allowing the enzyme to resume its normal function. Oximes must be given within a specific window before "aging" occurs, a process in which the bond between the nerve agent and AChE becomes irreversible.[25] The aging half-life ranges from 2 minutes for Soman to several hours for Sarin. Pralidoxime is particularly helpful for patients experiencing respiratory or generalized muscular weakness, though it does not cross the blood-brain barrier and thus does not address CNS effects. Atropine is used to manage CNS reactions.(B3)

Seizures and agitation associated with cholinergic crisis may be treated with benzodiazepines, such as midazolam or lorazepam. Certain drugs must be avoided, including loop diuretics, theophylline, caffeine, and succinylcholine, which can exacerbate ACh toxicity. In cases where cholinergic crisis is caused by the reversal of neuromuscular blockade with neostigmine, either atropine or glycopyrrolate is administered to mitigate the cholinergic effects. Given the complexity of managing cholinergic crisis, consultation with a clinical toxicologist and intensivist is strongly recommended.

Differential Diagnosis

Myasthenic crisis should be differentiated from cholinergic crisis using the edrophonium test. Administration of 2 mg of edrophonium will exacerbate symptoms in cholinergic crisis, but it has the opposite effect in myasthenic crisis. 

Clinicians should also keep in mind that cholinergic crisis can be triggered by various factors, including nerve agents, organophosphates, and neuromuscular blockade reversal agents. Accurate identification is essential for proper management.

Prognosis

The mortality rate in cholinergic crisis ranges from 3% to 25%. The most common cause of death is progressive respiratory failure.

Complications

Complications in cholinergic crisis arise from the overstimulation of both muscarinic and nicotinic receptors, affecting multiple systems within the body. In the respiratory system, complications include respiratory failure due to profound weakness of the respiratory muscles, aspiration pneumonia from hypersalivation and bronchorrhea, and severe bronchospasm. The cardiovascular system may develop bradycardia, hypotension, hypertension, and arrhythmias. CNS manifestations may include hallucinations, psychosis, seizures, and altered mental status. In the gastrointestinal system, electrolyte abnormalities can occur as a result of gastrointestinal losses from vomiting and diarrhea.