Article Topic: Cholinergic Crisis
Author: Noha El Masri
Editor: Odette El Ghawi, Joseph Akiki
Reviewer: Ethar Hazaimeh
Abstract
Cholinergic crisis is a life-threatening condition characterized by excessive stimulation of the parasympathetic nervous system, typically resulting from exposure to cholinesterase inhibitors, including those used in the treatment of myasthenia gravis, as well as organophosphates and nerve agents. This leads to the accumulation of acetylcholine at the neuromuscular junction, causing both muscarinic and nicotinic symptoms. Muscarinic effects include bradycardia, bronchoconstriction, miosis, and gastrointestinal disturbances, while nicotinic symptoms include muscle twitching, fasciculations, and respiratory muscle paralysis. Diagnosis is based on clinical assessment and measurement of cholinesterase levels. Treatment focuses on airway protection, respiratory support, and administration of atropine and pralidoxime. Early intervention is critical for patient survival and prevention of complications.
Overview
Cholinergic crisis occurs due to excessive accumulation of acetylcholine at the neuromuscular junction, leading to overstimulation of cholinergic receptors. This condition is often associated with cholinesterase inhibitors, which are used therapeutically in myasthenia gravis and encountered in toxic exposures such as organophosphates and nerve agents [1].
Acetylcholine is a crucial neurotransmitter in the parasympathetic nervous system, and its excessive presence results in a range of muscarinic and nicotinic symptoms. Muscarinic manifestations include bradycardia, bronchoconstriction, miosis, and excessive secretions, while nicotinic involvement leads to muscle weakness, fasciculations, and in severe cases, respiratory failure. Other complications can include cardiac arrhythmias, fluctuating blood pressure, and central nervous system effects such as confusion, hallucinations, and seizures [10,11].
Diagnosis relies on clinical evaluation and confirmation through red blood cell (RBC) cholinesterase level measurement, which is particularly sensitive in correlating with poisoning severity [12]. Immediate management involves securing the airway, ensuring ventilation, and administering atropine and pralidoxime to reverse the effects of acetylcholine. Given the life-threatening nature of the crisis, prompt treatment is vital for preventing mortality and serious complications.
Etiology
Cholinergic crisis typically develops from the use of substances that inhibit acetylcholinesterase, an enzyme responsible for breaking down acetylcholine [1].
A common cause is the use of acetylcholinesterase inhibitors, which are employed in the treatment of myasthenia gravis [2]. Myasthenia gravis is an autoimmune disorder in which autoantibodies target acetylcholine receptors at the postsynaptic membrane, leading to muscle weakness [3]. Inhibiting acetylcholinesterase in these patients increases acetylcholine concentration and prolongs its action. Consequently, excessive use of this therapy precipitates a cholinergic crisis [2].
Additionally, cholinergic crisis can arise from the use of reversal neuromuscular blockers, such as neostigmine, which also inhibit acetylcholinesterase to reverse non-depolarizing neuromuscular blockers [1]. Other significant causes include exposure to organophosphate insecticides and chemical warfare agents, such as nerve agents, which are potent acetylcholinesterase inhibitors [4,5].
Pathogenesis
Cholinergic crisis is fundamentally caused by the overstimulation of the postsynaptic membrane due to excessive accumulation of acetylcholine at the neuromuscular junction [1].
Acetylcholine is released from the nerve terminal into the synapse in response to a nerve impulse, facilitating communication between neurons and muscle cells [1]. Once its function is complete, acetylcholine is rapidly degraded by acetylcholinesterase into choline and acetate to terminate the signal and prevent prolonged stimulation [1].
When acetylcholinesterase is inhibited, acetylcholine accumulates and overstimulates both nicotinic and muscarinic receptors. Nicotinic receptors are found at the motor end plates in skeletal muscles (N1) and within the central and peripheral nervous systems (N2) [6,7]. Muscarinic receptors, on the other hand, are classified into five subtypes (M1 to M5), with M1 and M5 receptors in the brain, M2 receptors located in the heart, and M3 receptors in smooth muscles such as those in the gastrointestinal tract, blood vessels, pupils, and bronchi [9]. M4 receptors are primarily distributed throughout the central nervous system [9].
Clinical Presentation
When excess acetylcholine is present in the synaptic cleft, it can cause overstimulation of the cholinergic system, leading to a cholinergic crisis. This crisis can manifest with both muscarinic and nicotinic symptoms.
Muscarinic Symptoms
Muscarinic symptoms include excessive salivation, lacrimation, urination, defecation, gastrointestinal cramps, and emesis [6,10,11]. Additionally, affected individuals may experience bradycardia, bronchoconstriction, and miosis [6,10,11].
These symptoms reflect overstimulation of the parasympathetic nervous system, which acetylcholine primarily influences via muscarinic receptors [6].
Nicotinic Symptoms
Nicotinic symptoms are characterized by muscle twitching, muscle weakness, fasciculations, and cramps [10,11]. In severe cases, respiratory muscle paralysis can occur, leading to breathing difficulties [10,11]. This may also be accompanied by hypertension and tachycardia [10,11].
Complications
The overstimulation of the cholinergic system can result in numerous complications. Excessive stimulation of the respiratory system may cause hypersalivation, bronchorrhea, and respiratory muscle weakness, potentially leading to aspiration pneumonia [1]. Additionally, cardiac arrhythmias and variations in blood pressure—such as hypo- or hypertension—can occur depending on the situation [1].
Overstimulation of the central nervous system may lead to hallucinations, psychosis, seizures, and alterations in mental status [1]. Moreover, vomiting and diarrhea can lead to a range of electrolyte imbalances [1].
Workup and Diagnosis
A cholinergic crisis can be diagnosed by assessing clinical symptoms and the patient’s history, which may include recent exposure to a cholinergic agent [12]. The diagnosis is supported by key indicators such as increased salivation, muscle twitching, and respiratory difficulty [12].
To confirm the diagnosis, cholinesterase activity levels can be measured [12]. The blood contains two forms of cholinesterase: RBC cholinesterase and plasma cholinesterase [12]. While plasma cholinesterase is more readily available and is frequently evaluated in laboratory testing, RBC cholinesterase is more sensitive and its levels correlate more closely with the severity of poisoning [12].
Treatment
Managing a cholinergic crisis is an emergency and should not be delayed.
The initial steps in managing the condition include ensuring adequate breathing, maintaining circulation, securing the airways, and closely monitoring the patient’s symptoms [13]. The patient may experience excessive secretions and respiratory muscle paralysis, which can lead to hypoxia; therefore, addressing breathing and airway management is critical [12,13].
Once the patient is stable, medications that target acetylcholine receptors can be administered [12,13]. In this context, atropine is frequently utilized because it inhibits the muscarinic effects of acetylcholine, helping to alleviate symptoms such as bronchoconstriction and excessive salivation [14]. Pralidoxime is another important medication; it acts at the neuromuscular junction to reactivate acetylcholinesterase that has been inhibited by toxins, thus deactivating the excess acetylcholine [14].
When these drugs are used in conjunction, the effects of excess acetylcholine are mitigated, and normal physiological function is restored [12–14]. Effective management of a cholinergic crisis requires prompt intervention and careful monitoring to prevent severe complications or even death.
