A cholinergic crisis describes the condition of accumulating excess levels of the neurotransmitter acetylcholine in the neuromuscular junctions and synaptic gaps throughout the body and central nervous system. This results in overstimulation of many organs and glands including the parasympathetic nervous system. The main etiology is acetylcholinesterase inhibition, the enzyme that rapidly breaks down acetylcholine after it is released.
The signs and symptoms of cholinergic crisis are the results of excess acetylcholine in synaptic gap between neurons and the muscular junction between nerve fibers and muscles. Symptoms appear rapidly after exposure, usually within 24 hours. The muscarinic and nicotinic receptors are activated and stay activated resulting in overstimulation . Specific toxidromes can be isolated to the overstimulated receptor. There are several mnemonic devices that are useful to remember symptoms associated with muscarinic receptor overstimulation. For instance “SLUDGE” stands for Salivation, Lacrimation, Urination, Diarrhea, Gastric secretions and Emesis while the more inclusive “DUMBELS” stands for Diarrhea, Urination, Meiosis, Bradycardia, Bronchorrhea, Bronchospasm, Emesis, Lacrimation, and Seizures. The much shorter “Triple B” only stands for Bradycardia, Bronchospasm, and Bronchorrhea. Patients will often demonstrate at least two symptoms of the SLUDGE mnemonic , but other less common symptoms are also possible. Overstimulation of the nicotinic receptors at the neuromuscular junctions results in muscle symptoms including fasciculation, paralysis, and weakness. These signs and symptoms may be confused with myasthenia gravis. Cholinergic crisis can be distinguished from myasthenia gravis with the administration of the acetylcholinesterase inhibitor edrophonium which will improve muscle strength in myasthenia gravis but worsen paralysis in cholinergic crisis. Due to nicotinic receptor overstimulation, the diaphragm will also weaken which results in difficulty breathing, respiratory failure, and death without proper care. Overstimulation of the nicotinic receptors at the autonomic ganglia may result in sympathetic or parasympathetic autonomic excess. Symptoms of parasympathetic overstimulation look similar to muscarinic receptor overstimulation (MUDPILES and triple B’s). After all, the parasympathetic nervous system is primarily controlled by muscarinic receptors. Symptoms of sympathetic overstimulation include hypertension, mydriasis, and tachycardia. CNS toxicity is also very common with the cholinergic crisis. Symptoms include delirium, lethargy, and seizures. Altered mental status and coma, with a score of eight on the Glasgow Coma Scale, are also common .
A thorough history and physical exam are required for any patient where a cholinergic crisis is suspected. It is important to determine what caused the cholinergic crisis (medication, pesticide, or nerve gas) and how much time has passed since the acetylcholinesterase inhibitor was absorbed. There is a 48-hour window to administer the antidote pralidoxime that will reactivate the enzyme after contact with an irreversible inhibitor. A diagnosis is based on the recognition of the toxidrome associated with acetylcholinesterase inhibitor toxicity. The diagnosis can be confirmed by analyzing enzyme activity in plasma (pseudo-cholinesterase) or in red blood cells (RBC cholinesterase). Plasma analysis is available at most laboratories but red blood cell enzyme activity is more accurate . Additionally, cholinergic crisis may appear similar to myasthenia gravis. An edrophonium test can distinguish between the two conditions. Muscle weakness will improve with edrophonium if the patient has myasthenia gravis while muscle symptoms will worsen in a patient with cholinergic crisis.
Cholinergic crisis is an emergency condition. Multiple procedures should be done in parallel. Most importantly, the patient’s airway must be controlled. Intubation and ventilation may be required if the diaphragm is paralyzed. In the case of pesticide or nerve gas exposure, the physicians and nurses must wear protective gear and the patient must be decontaminated. All clothing must be removed. The patient must be washed with soap and water and their eyes must be irrigated with isotonic saline to remove any residual contaminant. Early and aggressive use of atropine may reverse some symptoms and protect the airway. Mydriasis and tachycardia are misleading and should not be taken as signs to stop atropine therapy . Atropine should be administered until pulmonary secretions have cleared and oxygenation is adequate. Pralidoxime may be administered within 48 hours of exposure to organophosphates and other irreversible inhibitors. This medication acts as a nucleophile that reactivates the acetylcholinesterase enzyme. Patients taking anticholinesterase inhibitors occasionally suffer from the accumulation of lung secretions.
The mortality rate for cholinergic crisis ranges between 3-25% depending on the inhibitor (reversible or irreversible), the amount consumed, and the method consumed (oral, respiratory, intravascularly). Neurological signs and muscle weakness usually occurs within 24 hours of consumption . Respiratory failure is the most common cause of death.
The most common cause of the cholinergic crisis is from medication or accidental exposure to insecticides such as Malathion and ethion or herbicides such as tribufos. Other sources include nerve gas such as sarin gas and VX gas. Use of these weapons is against the rules of warfare set by the Geneva Convention established in 1925. Recently they have been used as weapons of terrorism . There are several anticholinergic medications available. If these are taken inappropriately or at elevated doses then a cholinergic crisis may occur. Anticholinesterases are used to treat myasthenia gravis, glaucoma, Alzheimer disease, and to reverse surgical paralysis.
Cholinergic crisis is relatively common in two populations: children and patients with myasthenia gravis. Organophosphate insecticide accidental ingestion may be recorded in unsupervised children. This population is prone to exploring their environment and placing dangerous objects in their mouth. They do not understand the warning labels and have difficulty communicating when they feel ill or if they are concerned with a situation. Children in rural areas are especially at risk because of the high use of pesticides in these areas. The federal government has been limiting sales of organophosphate since 2013 and incidents of poisoning have been on the decline, but in the developing world, it is much more common. An overdose of acetylcholinesterase medication is rather rare . Nerve gas is also a cause of the cholinergic crisis. This method of mass poisoning has been limited. Its use is against the Geneva Convention and is considered a war crime.
Acetylcholine is synthesized in central and peripheral cholinergic neurons and muscle fibers. The neurotransmitter is stored in vesicles near the synaptic cleft once it is formed from acetyl-CoA and choline by the enzyme choline acetyltransferase. The concentration of acetylcholine in the vesicles are much higher than the concentration in the cytosol. Calcium ions stimulate the release of the acetylcholine into the synaptic cleft. It binds to nicotinic receptors that act as ligand-gated ion channels in a fast reaction and muscarinic receptors that act as secondary intracellular messengers in a slow reaction. The acetylcholine then dissociates from the receptors and is hydrolyzed into acetate and choline by the large concentration of acetylcholinesterase found in the synaptic cleft. This effectively neutralizes the signal.
Acetylcholine binds to two types of receptors: muscarinic and nicotinic. The muscarinic receptors are found throughout the body and are stimulated by the compound muscarine and acetylcholine. They are part of the G-protein coupled receptors family and, once activated, signal the cell to increase cyclic AMP concentrations and activate protein kinase A intracellularly. They form part of the parasympathetic nervous system and regulates heart rate, salivation, stomach secretions, bronchoconstriction and many other functions. The nicotinic receptors are members of the ligand-gated ion channel family of receptors. They respond to nicotine and acetylcholine and are found throughout the body and on muscle fibers at the neuromuscular junction and at the autonomic ganglia for both parasympathetic and sympathetic nervous systems. Therefore, the cholinergic crisis can result in either a parasympathetic response or a sympathetic response depending on the specificity of the acetylcholinesterase inhibitor. Also, nicotinic receptors are the only acetylcholine receptors found both postsynaptically and presynaptically. Under normal circumstances, the presynaptic receptors provide negative feedback.
Acetylcholinesterases inhibitors can be inhaled, injected, or absorbed through the skin or gastrointestinal tract. They affect the acetylcholinesterase found throughout the body, and especially in the synaptic gap between nerves and the neuromuscular junction. Without regular hydrolyzation, the neurotransmitter will accumulate and repeatedly activate both nicotinic and muscarinic receptors. All cholinergic post-synaptic nerves will relay this signal, effectively stuck in the activated position. Reversible acetylcholinesterase inhibitors act as noncompetitive inhibitors. Irreversible inhibitors pass through a two-step process of inhibition. First, they form a covalent bond via hydrolysis with the enzyme. At this point they are reversible. However, they undergo a process called “aging” that leads to irreversible binding and permanent inactivation. If an antidote can be administered before the aging process is complete (within 48 hours of exposure) then the inhibition can be reversed. Pralidoxime is an effective antidote when administered early. Medications should be regularly evaluated to minimize the side effect .
Aldicarb is a strong irreversible anticholinesterase inhibitor from the carbamate family . It is rapidly absorbed through the gastrointestinal mucosa and binds to acetylcholine esterase throughout the body, including the central nervous system . Acetylcholine accumulation results in the cholinergic crisis and death  .
Keep pesticides tightly sealed in properly labeled containers. Make sure they are away from the reach of children. Medication should also be carefully controlled. Proper protective clothing and equipment can be used when working with pesticides.
A cholinergic crisis describes the condition of excess acetylcholine at neuromuscular junctions and the synaptic gap in the central and peripheral nervous system. Acetylcholine acts as a neurotransmitter for muscle fibers, in the peripheral nervous system, and extensively in the brain. The enzyme acetylcholinesterase rapidly breaks down the neurotransmitter once it is released. Inhibition or an insufficient concentration of acetylcholinesterase leads to a buildup of acetylcholine and an increase in the level and duration of neurotransmitter signal.
There are many types of acetylcholinesterase inhibitors. They are used as nerve gas (sarin gas), pesticides (the organophosphate insecticide Malathion for example), and medications. Some unrelated medicines have enzyme inhibitor side effects and some venoms and poisons also act as inhibitors. These compounds are organized into two groups based on their mechanism of action and the reversibility of their inhibition. Generally speaking, medications are reversible inhibitors while pesticides and chemical weapons are irreversible inhibitors . Additionally, toxic dose of the medicines may result in a cholinergic crisis. Acetylcholinesterase inhibitors are used medically in treatment for myasthenia gravis, glaucoma, and in the process of reversing paralysis post-surgically. Symptoms of the cholinergic crisis include excess salivation, lacrimation, emesis, and diarrhea. Striated and smooth muscles eventually stop responding due to the accumulation of acetylcholine. The result is paralysis, muscle fasciculations, and respiratory failure. Treatment involves the use of the acetylcholine receptor antagonists such as atropine and mechanical ventilation. Atropine will reverse the muscarinic side effects including bradycardia but will have no effect on the nicotinic side effects of paralysis and respiratory failure.
What is a cholinergic crisis?
Cholinergic crisis describes a condition where excess levels of the neurotransmitter acetylcholine accumulate between in the synaptic clefts. Acetylcholine is used to regulate the autonomic nervous system (fight or flight response) and to control muscles. Under normal circumstances, nerve axons release acetylcholine to transmit a signal from one nerve to the next, a signal to target organs such as the heart or the lungs or to stimulate a muscle to contract. Once the acetylcholine is released and interacts with the receptors on the downstream structure it is rapidly degraded by an enzyme called acetylcholinesterase. Many medications and other chemicals such as nerve gas and some pesticides stop this enzyme from functioning which results in the accumulation of acetylcholine and overstimulation of the downstream organs, nerves, or muscles. Medication for the autoimmune disease myasthenia gravis targets acetylcholinesterase and should be carefully administered.
What are the symptoms of cholinergic crisis?
There are many symptoms of cholinergic crisis. Often patients will present with at least two. These symptoms include, but are not limited to, Salivation, Lacrimation, Urination, Diarrhea, Gastric secretions and Emesis (vomiting) (known by the mnemonic “SLUDGE”). Other symptoms include a slow heartbeat, difficulty breathing, muscle weakness or paralysis, and seizure or coma. Without rapid and appropriate treatment death is likely.
How is cholinergic crisis treated?
Cholinergic crisis is a medical emergency. First, the patient’s breathing must be carefully monitored. If respiration becomes difficult or if the patient stops breathing then artificial ventilation must be administered. If patients have had contact with nerve gas or pesticide then they must be decontaminated in such a way to prevent the contaminant from spreading. All clothing must be removed. The body should be washed with soap and eyes properly rinsed. An antidote is available called pralidoxime, but it can only be administered within 48 hours of inhibitor contact and is only effective against irreversible inhibitors. The acetylcholine receptor antagonist atropine effectively reverses many symptoms and is widely available.