AHFS Class:

• Parasympathomimetic (Cholinergic) Agents 12:04

Generic Name(s):

• Neostigmine Methylsulfate

Neostigmine methylsulfate is an anticholinesterase agent.105,  109,  120,  130

Reversal of Neuromuscular Blockade

Neostigmine methylsulfate is used for reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium) after surgery.23,  24,  39,  105,  119,  126,  139 An anticholinergic agent such as atropine sulfate or glycopyrrolate should be used in conjunction with neostigmine to minimize adverse muscarinic effects of the drug (e.g., bradycardia, bradyarrhythmias, increased secretions, bronchoconstriction).105,  120,  121

Anticholinesterase agents such as neostigmine are used to reverse the effects of nondepolarizing neuromuscular blocking agents and reduce the risk of postoperative residual neuromuscular blockade.105,  120,  125,  126 Evidence supporting the efficacy of neostigmine for reversal of neuromuscular blockade is based principally on data from the published literature.105,  119 In several randomized studies, neostigmine effectively reduced the time to recovery of neuromuscular blockade after surgery when compared with spontaneous recovery or placebo; all of the studies used recovery to a train-of-four (TOF) ratio of 0.9 as the primary measure of response, which is the currently accepted standard for adequate recovery of neuromuscular function.105,  119,  121,  123,  124,  126

Anticholinesterase agents are not effective in reversing deep levels of neuromuscular blockade and generally should not be used until some degree of spontaneous recovery occurs (e.g., when there is a detectable twitch response to the first TOF stimulus).105,  119,  121,  122,  129 However, administration of these drugs to fully recovered patients has resulted in paradoxical neuromuscular effects (e.g., weakness of upper airway muscles, increased airway collapsibility), and some clinicians recommend that this practice be avoided.122,  125,  127,  128,  129,  139 In contrast to these findings, other investigators have not reported any adverse respiratory effects in patients administered neostigmine at near or full neuromuscular recovery.139 Anticholinesterase agents do not antagonize the phase I block of depolarizing neuromuscular blocking agents such as succinylcholine and should not be used to reverse the effects of these drugs.140

It is important that the effects of neuromuscular blocking agents are quickly and effectively terminated after surgery to prevent postoperative residual neuromuscular blockade.123,  151 Incomplete neuromuscular recovery can cause prolonged weakness of the upper airway muscles and associated complications (e.g., airway obstruction, aspiration, hypoxemia, pneumonia, atelectasis, respiratory failure).120,  121,  122,  123,  150,  151 Risk of postoperative pulmonary complications may be further increased based on certain patient- and procedure-related factors.150 Therefore, residual neuromuscular block is an important patient safety issue that requires appropriate management.123,  150,  153 The available data indicate that reversal of neuromuscular blockade should be a standard practice unless there is quantitative evidence that no reversal is needed (TOF >0.9).122,  139,  154 Anticholinesterase agents such as neostigmine have been traditionally used for reversal of nondepolarizing neuromuscular agents.151 Sugammadex is another option that may be considered for reversing the effects of rocuronium or vecuronium.151,  155

Neostigmine has been compared to sugammadex for the reversal of moderate and deep neuromuscular blockade induced by rocuronium or vecuronium in randomized, active-controlled studies.134,  135,  136,  137 Results of these studies revealed that time to recovery of neuromuscular function (TOF ratio of 0.9) was substantially faster following administration of sugammadex compared with neostigmine.134,  135 In a Cochrane meta-analysis which included 41 randomized controlled studies comparing neostigmine and sugammadex for reversal of rocuronium-induced neuromuscular blockade in adults, sugammadex 2 mg/kg was 10.22 minutes (6.6 times) faster than neostigmine 0.05 mg/kg in reversing moderate paralysis, and sugammadex 4 mg/kg was 45.78 minutes (16.8 times) faster than neostigmine 0.07 mg/kg in reversing deep paralysis.151

Myasthenia Gravis

Neostigmine has been used in the symptomatic treatment of myasthenia gravis†,   principally to improve muscle strength.103,  106,  107,  108,  109,  110,  131 The oral preparation (Prostigmin^®) previously used for this indication is no longer commercially available in the US, and the currently available parenteral injection is not FDA-labeled for this use.105 Anticholinesterase agents are commonly used in the management of myasthenia gravis (both ocular and generalized forms).108 Although evidence from randomized controlled studies is limited, these drugs have demonstrated marked clinical effects in observational studies, case reports, case series, and during clinical experience.108 If an anticholinesterase agent is required for symptomatic treatment of myasthenia gravis, pyridostigmine is the preferred drug.107,  109,  132

GI Disorders

Neostigmine has been used for the treatment of acute colonic pseudo-obstruction or Ogilvie syndrome†,   a GI motility disorder characterized by marked dilation of the colon in the absence of mechanical obstruction.112,  113,  114,  133 Conservative therapy is considered the treatment of choice for this condition; however, there is some evidence suggesting that neostigmine may be an effective alternative for patients who fail to respond to conservative management.112,  113,  114 In several retrospective and prospective studies, IV administration of neostigmine produced rapid colonic decompression and improved symptoms of acute colonic pseudo-obstruction in such patients.112,  113,  114

Neostigmine also has been used as a prokinetic agent in patients with postoperative ileus following surgery†; however, the adverse muscarinic effects of the drug (e.g., bradycardia, increased bronchial secretions) may limit its clinical usefulness in this setting.115,  116,  117

Limited data suggest that neostigmine may be useful in the management of severe constipation in patients with thoracic spinal cord injury†.100,  101,  102

General

Patient Monitoring

• When used for reversal of neuromuscular blockade, patients must be well ventilated and have a patent airway prior to administration of neostigmine and until complete recovery of normal respiration.105 Continuous monitoring of neuromuscular function is recommended to ensure adequate reversal from the neuromuscular block.105 To exclude with certainty the possibility of residual paralysis, use an objective (quantitative) method of monitoring such as peripheral nerve stimulation in conjunction with other clinical assessments (e.g., observation of skeletal muscle tone, respiratory measurements).105,  120,  122,  123,  124,  127,  130 Adequate recovery of neuromuscular function generally is defined as a train-of-four (TOF) ratio of 0.9 in addition to the patient's ability to maintain satisfactory ventilation and a patent airway.105,  120 Recovery times may vary based on the patient's medical condition and duration of action of the specific neuromuscular blocking agent used.105,  119

Dispensing and Administration Precautions

• Administer only by trained clinicians experienced in the use of neuromuscular blocking agents and their reversal agents.105
• Always have atropine and medications to treat anaphylaxis (e.g., epinephrine) readily available in case of hypersensitivity reaction.103,  105

Other General Considerations

• Administer IV atropine sulfate or glycopyrrolate immediately prior to or concurrently (in separate syringes) with neostigmine to counteract adverse muscarinic effects.103 If patient is bradycardic, give IV antimuscarinic before neostigmine.105

Administration

Neostigmine methylsulfate is administered by slow IV injection (over a period of at least 1 minute).105 131 The drug also has been administered by IM or subcutaneous injection†,   138 but the manufacturer of the currently available injectable preparation labeled for reversal of neuromuscular blocking agents states that the injection is for IV use only.105

Neostigmine methylsulfate injection should be stored at controlled room temperature (20-25°C) but may be exposed to temperatures ranging from 15-30°C; the injection should be stored in the original carton until time of use and protected from light.105

Dosage

Reversal of Neuromuscular Block

Dosage of neostigmine methylsulfate should be based on individual patient requirements and response.105 A peripheral nerve stimulator capable of delivering a TOF stimulus should be used to determine when neostigmine should be administered and if additional doses are necessary.105 Neostigmine should be administered only after some degree of spontaneous recovery has occurred (i.e., at least 10% recovery of the first twitch response).105

For reversal of the effects of nondepolarizing neuromuscular blocking agents after surgery, the manufacturer states that a neostigmine methylsulfate dose of 0.03-0.07 mg/kg given by slow IV injection usually is sufficient to achieve adequate recovery of neuromuscular function (i.e., TOF ratio of 0.9) within 10-20 minutes of administration.105,  119 Selection of an appropriate dose should be based on the half-life of the neuromuscular blocking agent being reversed, degree of spontaneous recovery, and the need for rapid reversal.105 For reversal of neuromuscular blocking agents with a shorter half-life (e.g., rocuronium) or reversal of shallower blocks (i.e., when first twitch response is substantially greater than 10% of baseline or when a second twitch is present), the manufacturer recommends a neostigmine methylsulfate dose of 0.03 mg/kg.105 The higher dose of 0.07 mg/kg is recommended for reversal of longer-acting neuromuscular blocking agents (e.g., pancuronium, vecuronium), reversal of deeper blocks (i.e., when first twitch response is not substantially greater than 10% of baseline), or when more rapid recovery is needed.105 Although weight-based dosing of neostigmine methylsulfate is recommended by the manufacturer,105 the drug also has been administered in fixed IV doses of 0.5-2 mg for reversal of nondepolarizing neuromuscular blockade in adults.103 The recommended maximum total dose of neostigmine methylsulfate is 0.07 mg/kg or 5 mg, whichever is less;105 higher doses are unlikely to provide additional clinical benefit.125 The need for additional doses should be determined by TOF monitoring and the extent of recovery of neuromuscular function.105

The manufacturer states that the same dosage recommendations in adults should be applied to pediatric patients since dosing requirements generally are similar between the two populations.105 Other experts have recommended IV neostigmine methylsulfate doses of 0.025 to 0.07 mg/kg in neonates, 0.025-0.1 mg/kg in infants, and 0.025-0.08 mg/kg in children for reversal of nondepolarizing neuromuscular blocking agents.103

To counteract the adverse muscarinic effects of neostigmine methylsulfate, an IV anticholinergic agent (atropine sulfate or glycopyrrolate) should be administered prior to or concomitantly (in separate syringes) with neostigmine.105 In the presence of bradycardia, the anticholinergic agent should be given before neostigmine.105

Special Populations

Hepatic Impairment

Dosage adjustments do not appear to be necessary in patients with hepatic impairment undergoing reversal of neuromuscular blockade; however, such patients should be carefully monitored if neuromuscular blocking agents with hepatic elimination or active metabolites are administered because the effects of the neuromuscular blocking agent may be prolonged and persist beyond the effects of neostigmine.105

Renal Impairment

Dosage adjustments do not appear to be necessary in patients with renal impairment undergoing reversal of neuromuscular blockade; however, such patients should be closely monitored if renally eliminated neuromuscular blocking agents are administered because the effects of the neuromuscular blocking agent may persist beyond the effects of neostigmine.105

Geriatric Patients

Although dosage adjustments are not required in geriatric patients undergoing reversal of neuromuscular blockade, a longer period of monitoring is recommended in such patients to ensure that additional doses of neostigmine are not necessary to adequately reverse neuromuscular blockade.105

Contraindications

• Known hypersensitivity to neostigmine.105
• Mechanical obstruction of the intestinal or urinary tract.105
• Peritonitis.105

Warnings/Precautions

Bradycardia

Bradycardia may occur with neostigmine administration.105 Atropine sulfate or glycopyrrolate should be administered prior to neostigmine to lessen the risk of bradycardia.105

Serious Reactions with Coexisting Conditions

Because of the risk of blood pressure and heart rate complications, neostigmine should be used with caution in patients with certain cardiac conditions such as coronary artery disease, cardiac arrhythmias, or recent acute coronary syndrome.105 Patients with myasthenia gravis also may be at increased risk of cardiovascular complications.105 Concomitant use of an anticholinergic agent (e.g., atropine) generally will minimize the risk of adverse cardiovascular effects associated with neostigmine.105

Sensitivity Reactions

Hypersensitivity

Neostigmine administration may result in hypersensitivity reactions, including urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia, and anaphylaxis.105 Because of the possibility of hypersensitivity, atropine and other drugs for the treatment of anaphylaxis should be readily available during administration.105

Neuromuscular Dysfunction

Neostigmine can cause paradoxical neuromuscular effects (e.g., weakness of upper airway muscles and increased airway collapsibility) if used in patients with complete or near complete neuromuscular recovery.105,  122,  125,  127,  129 Neuromuscular dysfunction and other postoperative respiratory complications have occurred when high doses of neostigmine were administered during minimal neuromuscular blockade.105,  129 The dose of neostigmine methylsulfate should be reduced if neuromuscular recovery is almost complete.105

Cholinergic Crisis

Cholinergic crisis, a condition causing extreme muscle weakness, can occur in patients who receive an overdosage of neostigmine.105 Manifestations of cholinergic crisis include nausea, vomiting, diarrhea, excessive salivation and sweating, and bradycardia.105 Increasing muscle weakness can ultimately cause respiratory paralysis and death.105 Myasthenic crisis, a complication of myasthenia gravis, can also cause extreme muscle weakness and resemble cholinergic crisis.105,  141 It is extremely important to differentiate between the two conditions since treatment methods differ considerably.105 Whereas more intensive anticholinesterase therapy is required in patients with myasthenic crisis, administration of higher doses of neostigmine can have serious consequences in patients with cholinergic crisis.105

Specific Populations

Pregnancy

It is not known whether neostigmine can cause fetal harm when administered to pregnant women or affect reproductive capacity; the drug should be used during pregnancy only when clearly indicated as no adequate or well-controlled studies of the drug have been conducted in pregnant women.105 Administration of anticholinesterase drugs such as neostigmine to pregnant women near term may cause uterine irritability and induce premature labor.105

There are limited data from animal reproduction studies; in such studies, no teratogenic or other adverse effects were identified; however, drug exposure was well below the predicted exposures in humans.105

Lactation

It is not known whether neostigmine is distributed into human milk.105 Caution should be exercised when the drug is used in nursing women.105

Pediatric Use

Neostigmine may be used in pediatric patients of all ages to reverse the effects of nondepolarizing neuromuscular blocking agents after surgery.105,  119,  130 The available data indicate that efficacy and pharmacokinetics of neostigmine are similar across all pediatric age groups and also similar to those in adults when the same dosing guidelines are applied.105,  119

Based on limited data, neostigmine dosing requirements for reversal of neuromuscular blockade may be lower in infants and neonates than in older pediatric patients and adults;105,  119,  130 however, pediatric patients have a greater risk of incomplete reversal of neuromuscular blockade because of their decreased respiratory reserve.105 Therefore, the risks of administering higher doses of neostigmine (up to maximum recommended dosage) should not outweigh the risks associated with incomplete reversal in this age group.105

Because pediatric patients, particularly neonates and infants, may be more sensitive to changes in heart rate, the effects of anticholinergic agents should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.105

Geriatric Use

Because geriatric patients may have decreased renal function, neostigmine should be used with caution and increased monitoring in this age group.105 The duration of action of neostigmine is prolonged in geriatric patients; however, such patients also experience slower spontaneous recovery from neuromuscular blocking agents.105 Geriatric patients should be monitored for longer periods of time to ensure that additional doses of neostigmine are not necessary to adequately reverse neuromuscular blockade.105

Hepatic Impairment

The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied.105

Patients with hepatic impairment should be carefully monitored if neuromuscular blocking agents with hepatic elimination or active metabolites are concomitantly administered to patients with hepatic impairment; in such cases, the duration of the neuromuscular blocking agent may be prolonged and persist beyond the effects of neostigmine.105

Renal Impairment

Clearance of neostigmine is reduced in patients with renal impairment compared with individuals with normal renal function.119 In a study in patients with various states of renal function (normal, undergoing renal transplantation, or bilateral nephrectomy), the elimination half-life of neostigmine was prolonged in anephric individuals.105,  119

Patients with renal impairment should be carefully monitored if a renally eliminated neuromuscular blocking agent is concomitantly administered; in such cases, the effects of the neuromuscular blocking agent may persist beyond those of neostigmine.105

Common Adverse Effects

The most common adverse effects of neostigmine include bradycardia, nausea, and vomiting.105 Adverse effects of neostigmine methylsulfate generally are due to exaggerated pharmacologic effects of the drug, particularly at muscarinic-cholinergic receptors.105,  119

Drug interaction studies have not been conducted to date with neostigmine methylsulfate.105 Clinically important drug interactions are not likely to occur if neuromuscular monitoring is employed and both relaxants and reversal agents are titrated to effect.120

Drugs Affecting Hepatic Microsomal Enzymes

Neostigmine is metabolized by hepatic microsomal enzymes; caution is advised when used concomitantly with drugs that can alter the activity of these enzymes.105

Anticholinergic Agents

Anticholinergic agents such as atropine antagonize the muscarinic effects of neostigmine, and this interaction is utilized to counteract the muscarinic symptoms of neostigmine toxicity.105

Neuromuscular Blocking Agents

Neostigmine does not antagonize, and may in fact prolong, the phase I block of depolarizing muscle relaxants such as succinylcholine.140 Parenteral neostigmine effectively antagonizes the effect of nondepolarizing muscle relaxants (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium), and this interaction is used to therapeutic advantage to reverse muscle relaxation after surgery.105

Description

Neostigmine is an anticholinesterase agent; the drug inhibits the enzyme acetylcholinesterase, reducing the degradation of acetylcholine.105,  109,  120,  130 By competing with acetylcholine for binding to acetylcholinesterase, neostigmine slows the rate of hydrolysis of acetylcholine.109,  121,  130 As a consequence, acetylcholine accumulates in the synaptic cleft, and competes with and reverses the effects of nondepolarizing neuromuscular blocking agents.105,  121,  124 Neostigmine stimulates both muscarinic and nicotinic receptors, producing generalized cholinergic effects including miosis, increased tonus of intestinal and skeletal musculature, constriction of bronchi and ureters, bradycardia, and stimulation of secretion by salivary and sweat glands. In addition, neostigmine has a direct cholinomimetic effect on skeletal muscle.

Neostigmine does not cross the blood-brain barrier to produce CNS effects.105 Extremely high doses, however, produce CNS stimulation followed by CNS depression, in addition to a depolarizing neuromuscular blockade, and may result in respiratory depression, paralysis, and death.105

Neostigmine is 15-25% bound to serum albumin.105 Following administration of a single IV dose of neostigmine, the reported elimination half-life of the drug ranged from 24-113 minutes.105,  119 In a pharmacokinetic study in pediatric patients, the half-life of neostigmine (administered as an IV infusion over 2 minutes) was approximately 39, 48, or 67 minutes in infants 2-10 months of age, children 1-6 years of age, or adults 29-48 years of age, respectively.105,  119 Neostigmine is metabolized by microsomal enzymes in the liver.105,  121 Approximately 80% of the drug is excreted in urine within 24 hours (50% as unchanged drug).121

Advice to Patients

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.105
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.105
• Importance of informing patients of other important precautionary information. 105

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

23. De Angelis J. Clinical studies involving neostigmine reversal of d-tubocurarine, gallamine, and pancuronium in man. Anesth Analg . 1974 Mar-Apr; 53:268-70.

24. Miller RD, Larson CP, Way WL. Comparative antagonism of d-tubocurarine-, gallamine-, and pancuronium-induced neuromuscular blockades by neostigmine. Anesthesiology . 1972; 37:503-9. [PubMed 4263447]

39. Bridenbaugh PO, Churchll-Davidson HC. Response to tubocurarine chloride and its reversal by neostigmine methylsulfate in man. JAMA . 1968; 203:541-4. [PubMed 5694188]

100. Miller LS, Staas WE Jr, Herbison GJ. Abdominal problems in patients with spinal cord lesions. Arch Phys Med Rehabil . 1975; 56:405-8. [PubMed 1164181]

101. Glick ME, Meshkinpour H, Haldeman S et al. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology . 1984; 86:287-94. [PubMed 6690355]

102. Miller LS. Neostigmine for severe constipation with spinal cord lesions. Ann Intern Med . 1984; 101:279.

103. Kleinman K, McDaniel L, Molloy M, eds. The Harriet Lane handbook: a manual for pediatric house officers. 22nd ed. Philadelphia, PA: Elsevier, Inc; 2021.

105. Avadel Legacy. Bloxiverz^® (neostigmine methylsulfate injection) prescribing information. Chesterfield, MO; 2019 Sept.

106. Drachman DB. Myasthenia gravis. N Engl J Med . 1994; 330:1797-810. [PubMed 8190158]

107. Nicolle MW. Myasthenia gravis. Neurologist . 2002; 8:2-21. [PubMed 12803656]

108. Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev . 2014; 10:CD006986.

109. Myasthenia Gravis Foundation of America. Myasthenia Gravis: A manual for the healthcare provider (2008). From Myasthenia Gravis Foundation of American website. [Web]

110. Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology . 2003; 61:1652-61. [PubMed 14694025]

112. Elsner JL, Smith JM, Ensor CR. Intravenous neostigmine for postoperative acute colonic pseudo-obstruction. Ann Pharmacother . 2012; 46:430-5. [PubMed 22388328]

113. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med . 1999; 341:137-41. [PubMed 10403850]

114. Valle RG, Godoy FL. Neostigmine for acute colonic pseudo-obstruction: A meta-analysis. Ann Med Surg (Lond) . 2014; 3:60-4. [PubMed 25568788]

115. Traut U, Brügger L, Kunz R et al. Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults. Cochrane Database Syst Rev . 2008; :CD004930. [PubMed 18254064]

116. Gannon RH. Current strategies for preventing or ameliorating postoperative ileus: a multimodal approach. Am J Health Syst Pharm . 2007; 64(20 Suppl 13):S8-12. [PubMed 17909275]

117. Zeinali F, Stulberg JJ, Delaney CP. Pharmacological management of postoperative ileus. Can J Surg . 2009; 52:153-7. [PubMed 19399212]

119. Food and Drug Administration. Summary Review: NDA#204078/S-000. From FDA website. [Web]

120. Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade. Anesthesiology . 1992; 77:785-805. [PubMed 1416176]

121. Srivastava A, Hunter JM. Reversal of neuromuscular block. Br J Anaesth . 2009; 103:115-29. [PubMed 19468024]

122. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg . 2010; 111:129-40. [PubMed 20442261]

123. Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg . 2010; 111:120-8. [PubMed 20442260]

124. Murray MJ, DeBlock H, Erstad B et al. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med . 2016; 44:2079-2103. [PubMed 27755068]

125. Kopman AF, Eikermann M. Antagonism of non-depolarising neuromuscular block: current practice. Anaesthesia . 2009; 64 Suppl 1:22-30. [PubMed 19222428]

126. Lederer W, Reiner T, Khuenl-Brady KS. Neostigmine injected 5 minutes after low-dose rocuronium accelerates the recovery of neuromuscular function. J Clin Anesth . 2010; 22:420-4. [PubMed 20868962]

127. Herbstreit F, Zigrahn D, Ochterbeck C et al. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology . 2010; 113:1280-8. [PubMed 20980910]

128. Caldwell JE. Reversal of residual neuromuscular block with neostigmine at one to four hours after a single intubating dose of vecuronium. Anesth Analg . 1995; 80:1168-74. [PubMed 7762847]

129. Sasaki N, Meyer MJ, Malviya SA et al. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology . 2014; 121:959-68. [PubMed 25225821]

130. Meretoja OA. Neuromuscular block and current treatment strategies for its reversal in children. Paediatr Anaesth . 2010; 20:591-604. [PubMed 20642658]

131. Fresenius Kabi. Neostigmine methylsulfate injection prescribing information. Lake Zurich, IL; 2015 Sept.

132. Sanders DB, Wolfe GI, Benatar M et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology . 2016; 87:419-25. [PubMed 27358333]

133. Naveed M, Jamil LH, Fujii-Lau LL et al. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in the management of acute colonic pseudo-obstruction and colonic volvulus. Gastrointest Endosc . 2020; 91:228-235. [PubMed 31791596]

134. Blobner M, Eriksson LI, Scholz J et al. Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol . 2010; 27:874-81. [PubMed 20683334]

135. Khuenl-Brady KS, Wattwil M, Vanacker BF et al. Sugammadex provides faster reversal of vecuronium-induced neuromuscular blockade compared with neostigmine: a multicenter, randomized, controlled trial. Anesth Analg . 2010; 110:64-73. [PubMed 19713265]

136. Jones RK, Caldwell JE, Brull SJ et al. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology . 2008; 109:816-24. [PubMed 18946293]

137. Lemmens HJ, El-Orbany MI, Berry J et al. Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. BMC Anesthesiol . 2010; 10:15. [PubMed 20809967]

138. APP. Neostigmine methylsulfate injection prescribing information. Schaumburg, IL; 2008 Apr.

139. Murphy GS, Szokol JW, Avram MJ et al. Neostigmine Administration after Spontaneous Recovery to a Train-of-Four Ratio of 0.9 to 1.0: A Randomized Controlled Trial of the Effect on Neuromuscular and Clinical Recovery. Anesthesiology . 2018; 128:27-37. [PubMed 28953501]

140. Hospira. Quelicin® (succinylcholine chloride injection) prescribing information. Lake Forest, IL; 2019 Feb.

141. Wijdicks EFM. Breaking Down Myasthenic Crisis. Neurocrit Care . 2020; 32:875-879. [PubMed 31981022]

150. Miskovic A, Lumb AB. Postoperative pulmonary complications. Br J Anaesth . 2017; 118:317-334. [PubMed 28186222]

151. Hristovska AM, Duch P, Allingstrup M et al. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev . 2017; 8:CD012763. [PubMed 28806470]

153. Murphy GS. Neuromuscular Monitoring in the Perioperative Period. Anesth Analg . 2018; 126:464-468. [PubMed 28795964]

154. Bronsert MR, Henderson WG, Monk TG et al. Intermediate-Acting Nondepolarizing Neuromuscular Blocking Agents and Risk of Postoperative 30-Day Morbidity and Mortality, and Long-term Survival. Anesth Analg . 2017; 124:1476-1483. [PubMed 28244947]

155. Kheterpal S, Vaughn MT, Dubovoy TZ et al. Sugammadex versus Neostigmine for Reversal of Neuromuscular Blockade and Postoperative Pulmonary Complications (STRONGER): A Multicenter Matched Cohort Analysis. Anesthesiology . 2020; 132:1371-1381. [PubMed 32282427]