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 [10]. 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 [11], 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 [12].

• Fatigue

  Nclex 26 Review on Myasthenia Gravis – Neuromuscular disease: weakness and fatigue of the voluntary muscles. – Is usually due to insufficient amount of Acetycholine. CAUSES: – An autoimmune response – Inadequate release of Ach. [allnursingnotes.com]

  Monitor pulse oximetry and report O2 saturation Rationale: O2 sat of Nursing Diagnosis Self-Care Deficit related to muscle weakness, general fatigue. [rnpedia.com]

  Generalized fatigue is a common complaint in many neurologic and non-neurologic disorders. In MG and other disorders of the NMJ, fatigue is limited to muscular fatigue alone and often progresses to frank muscle weakness. [casemed.case.edu]

  Muscle fatigues more readily after exercise: This is a feature used in making the diagnosis. For example, getting the patient to count up to 50. As the patient nears 50 their voice becomes less audible as they are fatiguing. [patient.info]

  After your muscles have been fatigued, a larger dose of Tensilon is given. [healthcommunities.com]

• Dyspnea

  The second inhibitory phase is delayed and often heralded by hypotension, bradycardia, and dyspnea, finally leading to coma and respiratory failure. Management. [doi.org]

  Symptoms can include: dysphagia dyspnea respiratory and muscle weakness2 2. Myasthenic Crisis = Increase the anticholinesterase dose. [allnursingnotes.com]

  It seemed that administration slightly improved his symptom but he developed bradycardia, dyspnea and drowsiness suddenly on the 4th day. [repository.kulib.kyoto-u.ac.jp]

  The patient may have evidence of pneumonia (i.e., fever, cough, dyspnea and consolidation). [enotes.tripod.com]

  Rationale: Dyspnea on exertion, palpitations, headaches, or dizziness or patient states increased exertion level, are all signs of activity intolerance and decreased tissue oxygenation. [rnpedia.com]

• Bronchorrhea

  Intubation may be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate aggressive use of atropine may eliminate the need for intubation. [openanesthesia.org]

  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. [symptoma.com]

  The patient may also have bronchospasm with wheezing, bronchorrhea, respiratory failure, diaphoresis and cyanosis from either cause. [enotes.tripod.com]

• Bronchospasm and Wheezing

  The patient may also have bronchospasm with wheezing, bronchorrhea, respiratory failure, diaphoresis and cyanosis from either cause. [enotes.tripod.com]

• Diarrhea

  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 [symptoma.com]

  After 9 months, she developed intractable diarrhea, vomiting, and finally cardiopulmonary arrest. She was resuscitated, but was finally pronounced dead despite the treatment. Her serum concentration of distigmine bromide found to be 69.9 ng/d l. [jstage.jst.go.jp]

  […] crisis An acute ↓ in the need for anticholinesterase medication, resulting in 'overmedication' with the customary doses; the Tensilon test exacerbates this form of myasthenic crisis; cholinergic crises may be either • Muscarinic crisis Abdominal pain, diarrhea [medical-dictionary.thefreedictionary.com]

  Overview Effects Effects of parasympathomimetics References: [1] Side effects Indirect parasympathomimetics Cardiovascular symptoms: bradycardia, hypotension Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased [amboss.com]

• Vomiting

  After 9 months, she developed intractable diarrhea, vomiting, and finally cardiopulmonary arrest. She was resuscitated, but was finally pronounced dead despite the treatment. Her serum concentration of distigmine bromide found to be 69.9 ng/d l. [jstage.jst.go.jp]

  […] the need for anticholinesterase medication, resulting in 'overmedication' with the customary doses; the Tensilon test exacerbates this form of myasthenic crisis; cholinergic crises may be either • Muscarinic crisis Abdominal pain, diarrhea, nausea, vomiting [medical-dictionary.thefreedictionary.com]

  […] glands (tearing) Urination: relaxation of the internal sphincter muscle of urethra, and contraction of the detrusor muscles Defecation Gastrointestinal distress: Smooth muscle tone changes causing gastrointestinal problems, including cramping Emesis: Vomiting [en.wikipedia.org]

  Paediatric dose = 0.02 mg/kg to a maximum of 0.5mg Adverse drug reactions: (the cholinergic crisis) Seizures following rapid administration Bradycardia Bronchospasm Bronchorrhoea Nausea, vomiting and diarrhoea If a cholinergic crisis occurs treat with [lifeinthefastlane.com]

  Moderate symptoms included: fasciculations, miosis, vomiting, and any eye pain or blurred vision reported verbally in the videos. [ncbi.nlm.nih.gov]

• Nausea

  […] acute ↓ in the need for anticholinesterase medication, resulting in 'overmedication' with the customary doses; the Tensilon test exacerbates this form of myasthenic crisis; cholinergic crises may be either • Muscarinic crisis Abdominal pain, diarrhea, nausea [medical-dictionary.thefreedictionary.com]

  References: [1] Side effects Indirect parasympathomimetics Cardiovascular symptoms: bradycardia, hypotension Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased sweating, salivation, and gastric secretion Nausea [amboss.com]

  Paediatric dose = 0.02 mg/kg to a maximum of 0.5mg Adverse drug reactions: (the cholinergic crisis) Seizures following rapid administration Bradycardia Bronchospasm Bronchorrhoea Nausea, vomiting and diarrhoea If a cholinergic crisis occurs treat with [lifeinthefastlane.com]

  […] side effects: muscle weakness, involuntary muscle twitches, inability to swallow and cramping [5] Muscarinic Crisis Arises from excess activation of the muscarinic acetylcholine receptors Associated with: blurry vision, pain in the abdomen, vomiting, nausea [brainprotips.com]

• Abdominal Cramps

  Increased salivary, gastric and intestinal secretion, nausea, vomiting, increased peristalsis, diarrhea, abdominal cramps. Skeletal Muscle: Weakness, fasciculations. Miscellaneous: Increased urinary frequency and incontinence, diaphoresis. [drugs.com]

  cramps excessive secretions sweating bradycardia Precipitating factors intercurrent infection pregnancy drugs: antibiotics, eg aminoglycosides, polymyxins, tetracycline anti-arrhythmics, eg quinidine, quinine, procainamide local anaesthetics, eg procaine [aic.cuhk.edu.hk]

  Among those in the former group are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis and diaphoresis. [rxlist.com]

  Abdominal cramps and diarrhea may also occur. The following additional adverse reactions have been reported following the use of pyridostigmine: Respiratory: increased bronchial secretions. Gastrointestinal: nausea, vomiting, increased peristalsis. [rxmed.com]

  The major side effects are those of cholinergic excess, especially abdominal cramping and diarrhea, excessive perspiration, and salivation. Of course, excessive amounts can also cause weakness (cholinergic crisis). [casemed.case.edu]

• Abdominal Pain

  pain, diarrhea, nausea, vomiting, lacrimation, blurred vision, bronchial hypersecretion due to parasympathetic hyperresponse • Nicotinic crisis Muscle weakness, fasciculations, cramping and dysphagia, due to overdepolarization at the neuromuscular junction [medical-dictionary.thefreedictionary.com]

  The early phase consists of nicotinic cholinergic stimulation resulting in symptoms such as abdominal pain, hypertension, tachycardia, and tremors. [doi.org]

  Overview Effects Effects of parasympathomimetics References: [1] Side effects Indirect parasympathomimetics Cardiovascular symptoms: bradycardia, hypotension Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased [amboss.com]

  Rarely, patients develop an acute, toxic hypersensitivity reaction to AZA with fever, abdominal pain, and rash, which requires prompt and permanent discontinuance of the drug. [casemed.case.edu]

• Hypotension

  If not treated early, hypotension and respiratory failure may occur. [cram.com]

  The second inhibitory phase is delayed and often heralded by hypotension, bradycardia, and dyspnea, finally leading to coma and respiratory failure. Management. [doi.org]

  Watch out for signs and symptoms of exacerbations: Myasthenia Crisis – Increase in vital signs: tachycardia, tachypnea, high blood pressure – Cyanosis, restlessness – Increased secretions – Bowel and urinary incontinence Cholinergic Crisis – Hypotension [rnspeak.com]

  Overview Effects Effects of parasympathomimetics References: [1] Side effects Indirect parasympathomimetics Cardiovascular symptoms: bradycardia, hypotension Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased [amboss.com]

  Cholinergic crisis happens when too much cholinergic medications are taken and if not treated accordingly, respiratory failure and hypotension might happen. [healthsurgical.com]

• Hypersalivation

  Features suggestive of a cholinergic crisis (too much medication) include muscle fasciculation, pallor, sweating, hypersalivation and small pupils. If in doubt, perform an edrophonium test. [patient.info]

  […] inhibition of this enzyme by a nerve agent can cause cholinergic crisis and hyperstimulation by excess acetylcholine, eventually leading to death. 4 Symptoms of OP poisoning include, but are not limited to: miosis, sustained muscle contraction, twitching, hypersalivation [ncbi.nlm.nih.gov]

• Increased Sweating

  Other symptoms include increased sweating, salivation, bronchial secretions along with miosis. This crisis may be masked by the concomitant use of atropine along with anticholinesterase inhibitors in order to prevent side effects. [wikidoc.org]

  Other symptoms include increased sweating, salivation, bronchial secretions along with miosis (constricted pupils). This crisis may be masked by the concomitant use of atropine along with cholinesterase inhibitor in order to prevent side effects. [en.wikipedia.org]

  sweating, salivation, and gastric secretion Nausea Ocular symptoms: miosis, lacrimation CNS -related symptoms: restlessness, anxiety, ataxia, tremor possibly culminating in coma Musculoskeletal symptoms: fasciculations, weakness ;, spasms, paralysis [amboss.com]

  Consequently, while sympathomimetics such as cocaine will typically cause increased sweating, anticholinergics will block the function of sweat glands and cause anhidrosis. [epmonthly.com]

• Miosis

  Other symptoms include increased sweating, salivation, bronchial secretions along with miosis (constricted pupils). This crisis may be masked by the concomitant use of atropine along with cholinesterase inhibitor in order to prevent side effects. [en.wikipedia.org]

  Direct agonists of ACh are used topically in ophthalmology to induce miosis, while indirect agonists are used to treat, e.g., postoperative ileus or urinary retention and myasthenia gravis. [amboss.com]

  Other symptoms include increased sweating, salivation, bronchial secretions along with miosis. This crisis may be masked by the concomitant use of atropine along with anticholinesterase inhibitors in order to prevent side effects. [wikidoc.org]

  In reply to Instructor, NCSBN : In addition, The Myasthenia Crisis caused Pupils-mydriasis but The Cholinergic crisis caused Pupils-Miosis [learningext.com]

  Failure of the respiratory system due to the insufficient gas exchange Flaccid paralysis wherein the muscle tone is decreased by paralysis or enfeeblement that might be caused by a disease or trauma Too much sweating Bronchial secretions together with miosis [healthsurgical.com]

• Lacrimation

  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 [symptoma.com]

  It is useful to remember some of the symptoms of increased cholinergic stimulation that include: Salivation: stimulation of the salivary glands Lacrimation: stimulation of the lacrimal glands (tearing) Urination: relaxation of the internal sphincter muscle [en.wikipedia.org]

  […] for anticholinesterase medication, resulting in 'overmedication' with the customary doses; the Tensilon test exacerbates this form of myasthenic crisis; cholinergic crises may be either • Muscarinic crisis Abdominal pain, diarrhea, nausea, vomiting, lacrimation [medical-dictionary.thefreedictionary.com]

  Ep12 Cholinergic, Anticholinergic (SLUDGE) Anticholinergics- side effects Can’t see – burred vision Can’t pee – urinary retention Can’t spit – dry mouth Can’t s*** – constipation Cholinergic Crisis – Signs and symptoms SLUDGE Salivation Lacrimation Urination [podbay.fm]

• Eye Pain

  Moderate symptoms included: fasciculations, miosis, vomiting, and any eye pain or blurred vision reported verbally in the videos. [ncbi.nlm.nih.gov]

• Muscle Weakness

  An overdosage of pyridostigmine (or any cholinergic drug) may result in a cholinergic crisis - this is characterized by increasing muscle weakness; if the respiratory muscles are affected, it can lead to respiratory failure and death. [learningext.com]

  Atropine only reverses the ---------- effects of cholinergic drugs, primarily heart, smooth muscle, and glands. It does not reverse the nicotinic effects of skeletal muscle weakness or paralysis. [cram.com]

  Decreased muscle strength. Outcomes Full muscle strength. Atrophy does not occur. Good muscle tone. Patients can perform the activity gradually. Muscle weakness does not occur. [rnpedia.com]

  Muscle weakness, respiratory failure and excess salivation are likely to follow. [wisegeek.com]

  Neurological signs and muscle weakness usually occurs within 24 hours of consumption. Respiratory failure is the most common cause of death. [symptoma.com]

• Muscle Twitch

  There is muscle twitching and paralysis, sweating, salivation and pallor and the pupils are very small. These are the effects of military ‘nerve gases’. [medical-dictionary.thefreedictionary.com]

  Their activation leads to their twitching 3. - Nicotinic Ach-receptors are expressed on the skeletal muscles of the diaphragm and their activation mediates the process of breathing 3. [brainprotips.com]

  twitching and blurring of vision – Nausea and vomiting and excessive pulmonary secretion – Dysphagia accompanied by difficulty in chewing, speaking and breathing During myasthenia crisis, the nurse should: – Administer anti-cholinergic medication as [rnspeak.com]

• Skeletal Muscle Fasciculation

  Skeletal Muscle: Weakness, fasciculations. Miscellaneous: Increased urinary frequency and incontinence, diaphoresis. [drugs.com]

• Urinary Incontinence

  Watch out for signs and symptoms of exacerbations: Myasthenia Crisis – Increase in vital signs: tachycardia, tachypnea, high blood pressure – Cyanosis, restlessness – Increased secretions – Bowel and urinary incontinence Cholinergic Crisis – Hypotension [rnspeak.com]

  Cholinergic crisis may also be marked by miosis and the SLUDGE syndrome (i.e., salivation, lacrimation, urinary incontinence, diarrhea, GI upset, hypermotility and emesis). However, these findings are not inevitably present. [enotes.tripod.com]

• Seizure

  seizures, benzodiazepines such as diazepam or midazolam are recommended for controlling seizures and status epilepticus. 5 Pyridostigmine bromide is currently available in the United States for military personnel at risk for a nerve agent exposure; it [ncbi.nlm.nih.gov]

  Symptoms include delirium, lethargy, and seizures. Altered mental status and coma, with a score of eight on the Glasgow Coma Scale, are also common. [symptoma.com]

  It can also be considered in the management of a recovering TCA overdose but not in the acute management as you will precipitate seizures. Contraindications include bradydysrhythmias, intraventricular and AV block and bronchospasm. [lifeinthefastlane.com]

  Intubation may be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate aggressive use of atropine may eliminate the need for intubation. [openanesthesia.org]

  Most patients can be safely treated without it, but it is recommended when tachydysrhythmia with subsequent hemodynamic compromise, intractable seizure, severe agitation or psychosis, or some combination thereof is present. [emedicine.medscape.com]

• Confusion

  Signs and Symptoms Muscarinic signs (SLUDGE) salivation, lacrimation, urination, diaphoresis, gastrointestinal upset, emesis and progressing to bronchospasm, bronchorrhea, blurred vision, bradycardia or tachycardia, hypotension, confusion, and shock. [openanesthesia.org]

  […] life-threatening events 6 : Respiratory system failure as a result of insufficient gas exchange Decrease in muscle tone caused by paralysis or enfeeblement, also known as flaccid paralysis Cholinergic Crisis vs Myasthenia Gravis Cholinergic crisis can often be confused [brainprotips.com]

  These signs and symptoms may be confused with myasthenia gravis. [symptoma.com]

  Cholinergic Crisis: One of the confusing factors in managing patients with MG is that insufficient medication (myasthenic crisis) and excessive medication (cholinergic crisis) can present in similar ways. [enotes.tripod.com]

  Female children Long‐term Follow‐up N/A ○ Low plasma cholinesterase ○ Decreased psychomotor performance ○ PTSD ○ Increased sister chromatid exchanges (genetic effects) N/A Acute neurological signs ○ Tonic clonic seizures ○ Seizure/muscle Convulsions ○ Confusion [ncbi.nlm.nih.gov]

• Flaccid Paralysis

  Flaccid paralysis resulting from cholinergic crisis can be distinguished from myasthenia gravis by the use of the drug edrophonium (Tensilon), which worsens the paralysis caused by cholinergic crisis, but strengthens the muscle in the case of myasthenia [en.wikipedia.org]

  These include: Salivation Failure of the respiratory system due to the insufficient gas exchange Flaccid paralysis wherein the muscle tone is decreased by paralysis or enfeeblement that might be caused by a disease or trauma Too much sweating Bronchial [healthsurgical.com]

  When a cholinergic crisis occurs, muscles can no longer react to the influx of ACh, and respiratory failure, flaccid paralysis, excessive salivation and perspiration are likely to follow. [wisegeek.com]

  As a result of cholinergic crisis, the muscles stop responding to the bombardment of ACh, leading to flaccid paralysis, respiratory failure, and other signs and symptoms reminiscent of organophosphate poisoning. [wikidoc.org]

  […] or enfeeblement, also known as flaccid paralysis Cholinergic Crisis vs Myasthenia Gravis Cholinergic crisis can often be confused with another medical condition known as myasthenic crisis. [brainprotips.com]

• Altered Mental Status

  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. [symptoma.com]

  Common manifestations are as follows: Flushing Dry skin and mucous membranes Mydriasis with loss of accommodation Altered mental status (AMS) Fever Additional manifestations include the following: Sinus tachycardia Decreased bowel sounds Functional ileus [emedicine.medscape.com]

• Ataxia

  […] bradycardia, hypotension Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased sweating, salivation, and gastric secretion Nausea Ocular symptoms: miosis, lacrimation CNS -related symptoms: restlessness, anxiety, ataxia [amboss.com]

  […] akinesia無動［症］ akinetic mutism無動無言［症］ alcoholic neuropathyアルコールニューロパチ(シ)ー(神経障害) alternating hemiplegia交代性片麻痺 amnesia健忘［症］、記憶消失(喪失) amyotrophic lateral sclerosis (ALS)筋萎縮性側索硬化症 ankle clonus足クローヌス、足間代 aphasia失語［症］ apoplexy脳卒中 aseptic meningitis無菌［性］髄膜炎 ataxia [tokyo-med.ac.jp]

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 [13]. 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 [14]. 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 [9]. 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 [2]. 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 [3]. 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 [4].

Aldicarb is a strong irreversible anticholinesterase inhibitor from the carbamate family [5]. It is rapidly absorbed through the gastrointestinal mucosa and binds to acetylcholine esterase throughout the body, including the central nervous system [6]. Acetylcholine accumulation results in the cholinergic crisis and death [7] [8].

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 [1]. 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.

1. Pohanka, M. Acetylcholinesterase inhibitors; a patent review (2008–present). Expert Opinion on Therapeutic Patents.2012; 22 (8): 871–886.
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