Cholinergic Crisis

Etiology

Several clinical conditions can trigger a cholinergic crisis. Outlined below are the most commonly encountered disorders:

Overmedication with Acetylcholine Esterase Inhibitors AChEI in the Treatment of Myasthenia Gravis

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

One of the treatment modalities for myasthenia gravis is the use of acetylcholinesterase inhibitors (AChEI) such as pyridostigmine. AChEI prevents the breakdown of ACh by inactivating AChE. This stops the breakdown of ACh and increases its level and duration of action at the postsynaptic membrane. Excessive use of AChEI in the treatment of a patient with MG may precipitate a cholinergic crisis which is characterized by both muscarinic and nicotinic toxicity[2].

Myasthenic crisis is a complication of MG. Precipitants of the myasthenic crisis include infection, surgery, menstruation, and certain medications like quinidine, calcium channel blockers (verapamil, nifedipine, felodipine) and antibiotics (gentamicin, ampicillin, streptomycin, erythromycin, ciprofloxacin)[8][9]. The clinical symptomatology of myasthenic crisis and cholinergic crisis are very similar. The cholinergic crisis should always be considered in myasthenic crisis although the cholinergic crisis is not that common in myasthenia crisis[10][11][12].

It is important to identify which of the two conditions is causing muscular weakness. A simple test that can be done involves giving a dose of edrophonium, 2 mg intravenous. The medication produces clinical improvement in myasthenic crisis but worsening of symptoms in cholinergic crisis

Exposure to Organophosphates

Cholinergic crisis can be precipitated by exposure to drugs that inhibit AChE, for example, nerve gas and organophosphate compounds used in pesticides, insecticides, and herbicides. Exposure might be via inhalation of vapors, ingestion, or direct contact of the chemical with the skin or mucous membrane[13][14].

Organophosphates are chemical compounds used extensively as agents of chemical warfare. Nerve gases are one of the deadliest agents in chemical warfare. Examples of such chemicals are sarin, tabun, soman, GF, and VX. Organophosphates work by inhibiting the action of AChE. This causes excessive stimulation of muscarinic and nicotinic receptors at the postsynaptic membrane. ACh binds to the endplates of smooth muscles and secretory glands causing nausea, vomiting, bronchospasm, miosis, blurry vision, bronchorrea, and sialohorrea. Nicotinic effect on skeletal muscle can cause fasciculation and flaccid paralysis. Nerve gas poisoning can vary in severity from mild to moderate or severe.

Acute or chronic exposure to pesticides and insecticides containing organophosphates also can trigger a cholinergic crisis. Commonly used insecticides are malathion, parathion, diazinon, fenthion, and trichlorfon. Typically, patients are encountered in rural settings where pesticides and herbicides are used extensively. Examples of pesticides apart from organophosphates are carbamate, organochlorine, and pyrethroid insecticides. Apart from the muscarinic and nicotinic effects seen in cholinergic crisis, patients exposed to organophosphates might also exhibit neurological symptoms like a headache, dizziness, tremor, and paresthesia[15].

Reversal of Neuromuscular Blockage

Lastly, use of a reversal agent like neostigmine or pyridostigmine for neuromuscular blockages can also trigger a cholinergic crisis[16][17]. Neostigmine is a compound that inhibits AChE and is commonly used to reverse the effects of non-depolarizing paralytic agents like vecuronium, rocuronium, mivacurium, and pancuronium. Inhibiting AChE allows for the accumulation of ACh at the neuromuscular junction thus overcoming the competitive inhibition of non-depolarizing blocking agents. Neostigmine, like other AChE inhibitors, can stimulate the muscarinic receptors and cause the cholinergic crisis. Bronchospasm, miosis, increased peristalsis, and secretions are usually seen after administration of neostigmine. To minimize these effects on muscarinic receptors, an anticholinergic agent like glycopyrrolate is concomitantly administered during reversal of neuromuscular blocking agents.

Epidemiology

Data on the epidemiology of cholinergic crisis is very scant. Nevertheless, it is a known fact that cholinergic crisis is commonly seen in the pediatric population and patients with myasthenia gravis. In the pediatric age group, this crisis is usually as a result of accidental contact or ingestion of organophosphates. Children living in rural areas are at a very high risk. Since 2013, there are stricter federal regulations in the United States for the sale of organophosphates.

Globally, about three million people have been exposed to organophosphate poisoning annually with approximately 300,000 deaths. Poisoning is from either accidental or intentional ingestion of agricultural insecticides or pesticides. In cholinergic crisis related to organophosphates, poisoning can be sourced to food products like wheat, flour, cooking oil, fruits, and vegetables.

Since World War II, production of nerve gases like sarin and tabun has been limited. Manufacturing nerve gasses has been considered a war crime since the Geneva Convention in 1925[2]. Decreased production has significantly reduced the incidence of nerve gas poisoning in modern times. The most recent large-scale use of nerve gas was in Syria in 2013[15].

Pathophysiology

Synthesis of the Neurotransmitter Acetylcholine

Cholinergic crisis is caused by overstimulation of the postsynaptic membrane by the neurotransmitter acetylcholine (ACh). ACh is a chemical substance that was first proven to be a neurotransmitter by Loewi in 1921. ACh is found in at the synapses of ganglia, the neuromuscular junction, and the muscular system of the visceral organs. It is synthesized at the nerve terminal from acetyl coenzyme A (acetyl CoA).

Acetyl CoA is derived from glucose and choline by a reaction catalyzed by choline acetyltransferase (CAT). ACh is then packaged in the presynaptic membrane in vesicles. Each vesicle can contain up to about 10,000 molecules of ACh which is subsequently released upon stimulation. Calcium ion stimulates the release of ACh. The action of ACh at the postsynaptic membrane is not terminated by reuptake of the neurotransmitter but rather by the action of a powerful hydrolytic enzyme acetylcholine esterase AChE. This enzyme is found in the synaptic cleft. The action of this enzyme breaks up ACh into choline and acetate. The cholinergic nerve terminal has a sodium choline transporter that takes up choline produced from hydrolysis of ACh[18][19].

ACh acts on both muscarinic and nicotinic receptors.

Muscarinic receptors are located throughout the body. They are activated by the action of muscarine and ACh. These receptors are part of the G protein-coupled receptors. On activation, there is an increase in intracellular cyclic adenosine monophosphate (AMP). Activation of cyclic AMP triggers the action of protein kinase. The muscarinic receptors form part of the parasympathetic that helps with the regulation of secretions (both in the bronchial tree and the gastrointestinal tract), heart rate, pupillary response, and urination.

Muscarinic Effects of ACh

• Eye miosis and blurry vision,
• Gastrointestinal system: nausea, vomiting, and diarrhea
• Respiratory system: low lung compliance, bronchoconstriction, and bronchorrhea
• Secretory system: increased secretions in the tracheobronchial and gastrointestinal system
• Cardiovascular system: bradycardia
• Genitourinary: urinary frequency and urgency

Nicotinic receptors belong to the ligand-gated ion family of receptors. They are stimulated by ACh and nicotine. They are located in muscle fiber at the neuromuscular junctions and autonomic ganglia for both the sympathetic and parasympathetic nervous systems [2].

Nicotinic Effects of ACh

ACh binds to the endplate of skeletal muscle and synaptic ganglia causing the following effects

• Voluntary muscle fasciculation: flaccid paralysis
• Cardiovascular effects: tachycardia that may progress to bradycardia from the opposing effects of the stimulation of muscarinic and nicotinic receptors.

History and Physical

The diagnostic work of cholinergic crisis can pose a clinical challenge, especially for those unfamiliar with the clinical signs and symptoms. A very detailed history taking with a thorough physical examination is necessary. In the physical examination, particular attention should be paid to the nervous, respiratory, cardiovascular, and gastrointestinal system as this is where the clinical manifestation is most profound.  A good mnemonic to remember is SLUDGEM and DUMBELS for the muscarinic effect of ACh.

Clinical Findings Related to Stimulation of Muscarinic Receptors

S- Salivation

L- Lacrimation

U -Urinary frequency

D-Diarrhea

G- Gastrointestinal cramping and pain

E- Emesis

M- Miosis

Another mnemonic that is commonly used for symptoms is "DUMBELS."

D- Diaphoresis and Diarrhea

U -Urinary frequency

M-Miosis

B-Bronchospasm and Bronchorrhea

E – Emesis

L – Lacrimation

S – Salivation

Clinical Findings Related to Stimulation of Nicotinic Receptors

• Muscular weakness
• Muscular fatigue and fasciculation
• Respiratory muscle weakness
• Tachycardia
• Hypertension

Clinical Findings Related to Stimulation of  the Central Nervous System

• Seizures
• Coma
• Ataxia
• Slurred speech
• Agitation and restlessness

Clinical diagnosis of cholinergic crisis can be established based on the toxidromes listed above.

In the history taking, it is very pertinent to determine the cause of the cholinergic crises:

• Medications for the treatment of myasthenia gravis or glaucoma, including pyridostigmine
• Ingestion or exposure to insecticides, pesticides,  or herbicides
• Exposure to nerve gas
• Reversal of neuromuscular blockage

Time is paramount in the initial assessment. When, how, and where the ingestion or exposure took place is necessary to elicit from the history. This is because there is a 48-hour window during which to administer pralidoxime as an antidote. Pralidoxime will react with the enzyme that breaks down ACh after contact with the inhibitor of AChE, in this instance the nerve gas or insecticide. The reactivated enzyme AChE will expedite the molecular degradation of ACh. The degradation of ACh will terminate the overstimulation of the postsynaptic membrane by ACh.

Evaluation

Evaluation of patients with cholinergic crisis involves a detailed history taking and physical examination for the toxidromes associated with the crisis.

Included in the evaluation are ancillary studies:

• Complete Blood Count (CBC) to check if there is an elevation of white blood cell count to rule out an infectious process.
• Comprehensive Metabolic Panel (CMP) to rule out electrolytes abnormalities related to organophosphate poisoning
• Red Blood Cell Cholinesterase activity is usually decreased, and this can help in confirming the diagnosis. Plasma pseudocholinesterase can also be used but is less accurate than red blood cell cholinesterase activity[20].
• Electrocardiography to check for the presence of arrhythmia associated with organophosphate poisoning.
• Chest X-Ray to evaluate for the presence of pulmonary edema or aspiration.
• Head CAT scan is indicated if the patient's mental status is altered or there are significant changes in the Glasgow Coma Scale.

Treatment / Management

The management of cholinergic crisis encompasses three stages: (1) prehospital care, (2) emergency department management, and (3) Inpatient care.

Prehospital Care

Prehospital care includes the initial stabilization of the patient and the removal of the offending toxic agent. Decontamination should be initiated as soon as possible if poisoning with organophosphate or nerve gas is the primary culprit of cholinergic crisis. All clothing should be removed from the patient’s body to prevent continued contamination and to prevent cross-contamination of first responders.

Emergency Room Management

Regardless of the etiology  of cholinergic crises, the core principle in stabilization is ABC: Airway, Breathing, and Circulation.

Airway and Breathing

Care should be taken to ensure that the airway is patent and the patient is breathing spontaneously. The airway should be secured if there is a concern for airway compromise.

Indications for advanced airway management and intubation in cholinergic crisis are :

• Copious oral and nasal  secretions compromising the patency of the airway
• Altered mental status with a Glasgow Coma Score less than 8 
• Evidence of hemodynamic instability
• Profound weakness of the respiratory muscles

Circulation

Vascular access should be established immediately with two large-bore peripheral intravenous access. Fluid should be started to maintain adequate circulation with continuous pulse oximetry and monitoring of vital signs. In the case of hemodynamic instability, central venous access should be established for infusion of vasoactive medications.

In the emergency department, the primary focus on initial management is the maintenance of the airway and hemodynamic stability. If the patient is already intubated, ventilatory support should be continued .

Inpatient Management

Inpatient care includes continued cardiopulmonary support and monitoring. Patients with a cholinergic crisis should be admitted to the intensive care unit.

Antidotes for cholinergic crisis

Two types of antidotes are used for a cholinergic crisis: atropine and oximes.

Atropine

The first antidote is atropine. It is an effective agent for the muscarinic effect of acetylcholine. It competitively binds to the postsynaptic muscarinic receptor thereby preventing further action of ACh. Atropine dose is about 0.03- 0.05 mg/kg for pediatric and about 2 mg for adult patients. It is recommended to give atropine until signs of atropinization is present:

Signs of atropinization

• Tachycardia
• Warm, dry, and flushed skin
• Mydriasis  

Atropine does not have any effect on the nicotinic receptors.

Oximes

For the nicotinic effect in cholinergic crisis, the antidote is a class of drugs called the “oximes.” Examples of oximes are pralidoxime and obidoxime[21].(B3)

In the United States, pralidoxime chloride is the most commonly used antidote. Its mechanism of action is like that of a "molecular crowbar" that separates the bonded nerve gas or organophosphate from acetylcholinesterase. The separated AChE can then continue the process of chemical breakdown of ACh. There is a window period during which oximes can be given before there is an irreversible bonding of nerve gas to AChE. This phenomenon is known as "aging[22]." The aging half-life ranges from two minutes for soman to several hours for sarin(B3)

Pralidoxime should be given to patients with signs of respiratory muscle weakness or generalized muscular weakness. It should be administered until there is an improvement in muscle weakness. It does not cross the blood-brain barrier hence the central nervous system effect of organophosphate poisoning is not neutralized. This is achieved by using atropine.

Other medications in cholinergic crisis

Seizure and agitation in cholinergic crisis can be treated with benzodiazepine-like midazolam or lorazepam. Care should also be taken to avoid drugs like loop diuretics, theophylline, and caffeine and succinylcholine in organophosphate poisoning as this can make the symptoms of toxicity worse.

In the management of cholinergic crisis secondary to reversal of neuromuscular blockage with neostigmine, atropine or glycopyrrolate can be administered to lessen the cholinergic effects of the neuromuscular blockage reversal.

Consultation with a clinical toxicologist and intensivist is recommended in the treatment of cholinergic crisis.

Differential Diagnosis

The myasthenic crisis should be differentiated from the cholinergic crisis with edrophonium test. Administration of 2 mg of edrophonium will worsen the clinical symptom in cholinergic crisis. The contrary is the case in myasthenic crisis. Other causes of cholinergic crisis like exposure to nerve gas, organophosphates and use of reversal agent for neuromuscular blockage should be considered in the differential diagnosis.

Prognosis

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

Complications

The following complications can develop in cholinergic crisis. These problems are related to the overstimulation of the muscarinic and nicotinic receptors.

Outlined below are the complications as it affects each system.

Respiratory System

• Respiratory failure from profound weakness of respiratory muscles
• Aspiration pneumonia from hypersalivation and bronchorrhea
• Severe bronchospasm

Cardiovascular System

• Bradycardia
• Hypotension
• Hypertension
• Arrhythmia

Central Nervous System

• Hallucination
• Psychosis
• Seizure
• Altered mental status

Gastrointestinal System

• Electrolytes abnormalities related to gastrointestinal losses from vomiting and diarrhea