Prolonged Administration of Pyridostigmine Impairs Neuromuscular Function with and without Down-regulation of Acetylcholine Receptors

Abstract Background: The acetylcholinesterase inhibitor, pyridostigmine, is prophylactically administered to mitigate the toxic effects of nerve gas poisoning. The authors tested the hypothesis that prolonged pyridostigmine administration can lead to neuromuscular dysfunction and even down-regulation of acetylcholine receptors. Methods: Pyridostigmine (5 or 25 mg·kg−1·day−1) or saline was continuously administered via osmotic pumps to rats, and infused for either 14 or 28 days until the day of neuromuscular assessment (at day 14 or 28), or discontinued 24 h before neuromuscular assessment. Neurotransmission and muscle function were examined by single-twitch, train-of-four stimulation and 100-Hz tetanic stimulation. Sensitivity to atracurium and acetylcholine receptor number (quantitated by 125I-α-bungarotoxin) provided additional measures of neuromuscular integrity. Results: Specific tetanic tensions (Newton [N]/muscle weight [g]) were significantly (P < 0.05) decreased at 14 (10.3 N/g) and 28 (11.1 N/g) days of 25 mg·kg−1·day−1 pyridostigmine compared with controls (13.1–13.6 N/g). Decreased effective dose (0.81–1.05 vs. 0.16–0.45 mg/kg; P < 0.05) and decreased plasma concentration (3.02–3.27 vs. 0.45–1.37 μg/ml; P < 0.05) of atracurium for 50% paralysis (controls vs. 25 mg·kg−1·day−1 pyridostigmine, respectively), irrespective of discontinuation of pyridostigmine, confirmed the pyridostigmine-induced altered neurotransmission. Pyridostigmine (25 mg·kg−1·day−1) down-regulated acetylcholine receptors at 28 days. Conclusions: Prolonged administration of pyridostigmine (25 mg·kg−1·day−1) leads to neuromuscular impairment, which can persist even when pyridostigmine is discontinued 24 h before assessment of neuromuscular function. Pyridostigmine has the potential to down-regulate acetylcholine receptors, but induces neuromuscular dysfunction even in the absence of receptor changes.

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Prolonged Administration of Pyridostigmine Impairs Neuromuscular Function With and Without Down-Regulation of Acetylcholine Receptors

Survey of Anesthesiology ◽

10.1097/01.sa.0000452818.10046.46 ◽

2014 ◽

Vol 58 (5) ◽

pp. 251-252

Author(s):

Martina Richtsfeld ◽

Shingo Yasuhara ◽

Heidrun Fink ◽

Manfred Blobner ◽

J. A. Jeevendra Martyn

Keyword(s):

Acetylcholine Receptors ◽

Neuromuscular Function ◽

Prolonged Administration ◽

Down Regulation

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Neuromuscular blockade effects of cisatracurium in 11 cats undergoing ophthalmological surgery anaesthetised with isoflurane

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x211021829 ◽

2021 ◽

pp. 1098612X2110218

Author(s):

Anne-Sophie Van Wijnsberghe ◽

Keila K Ida ◽

Petra Dmitrovic ◽

Alexandru Tutunaru ◽

Charlotte Sandersen

Keyword(s):

Neuromuscular Blockade ◽

Case Series ◽

Neuromuscular Function ◽

Duration Of Action ◽

Cardiovascular Side Effects ◽

Train Of Four ◽

Physical Classification ◽

The Mean ◽

American Society ◽

American Society Of Anesthesiologists

Case series summary This case series describes the neuromuscular blockade (NMB) following 0.15 mg/kg intravenous (IV) cisatracurium administration in 11 cats undergoing ophthalmological surgery and anaesthetised with isoflurane. Anaesthetic records were analysed retrospectively. Neuromuscular function was assessed by a calibrated train-of-four (TOF) monitor. Cats were 73 ± 53 months old, weighed 4 ± 1 kg and were of American Society of Anesthesiologists’ physical classification 2. Duration of anaesthesia and surgery were 144 ± 27 and 94 ± 24 mins, respectively. The lowest TOF count was zero in four cats, four in six cats and for one cat the TOF ratio never decreased below 31%. The time of onset was between 1 and 6 mins after the administration of cisatracurium and the mean duration of action was 20.4 ± 10.1 mins. Relevance and novel information Cisatracurium at a dose of 0.15 mg/kg IV did not consistently induce a TOF count of zero in all cats. The dose used in these cats did not produce any remarkable cardiovascular side effects. Although the NMB was not complete, the dose given was sufficient to produce central eyeball position, which was the goal of the ophthalmic surgeries.

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Enhancing Autophagy Protects Against Sepsis-Induced Neuromuscular Dysfunction Associated with Qualitative Changes to Acetylcholine Receptors

Shock ◽

10.1097/shk.0000000000001189 ◽

2019 ◽

Vol 52 (1) ◽

pp. 111-121 ◽

Cited By ~ 4

Author(s):

Jingyuan Chen ◽

Su Min ◽

Fei Xie ◽

Jun Yang ◽

Xin Wang

Keyword(s):

Acetylcholine Receptors ◽

Neuromuscular Dysfunction ◽

Qualitative Changes

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Postoperative Neuromuscular Function

Anaesthesia and Intensive Care ◽

10.1177/0310057x8601400110 ◽

1986 ◽

Vol 14 (1) ◽

pp. 41-45 ◽

Cited By ~ 81

Author(s):

G. H. Beemer ◽

P. Rozental

Keyword(s):

Recovery Room ◽

Neuromuscular Transmission ◽

Blocking Agent ◽

Neuromuscular Function ◽

Neuromuscular Blocking ◽

Neuromuscular Blocking Agent ◽

Number Of Patients ◽

Clinical Methods ◽

Train Of Four ◽

Bedside Tests

One hundred patients who received a competitive neuromuscular blocking agent during anaesthesia were randomly selected for evaluation of neuromuscular function immediately on their arrival in the recovery room. The anaesthetist was not aware that the patient would be evaluated in the recovery room. Neuromuscular function was assessed by a train-of-four (TOF) ratio, and in conscious and co-operative patients by a series of bedside tests of neuromuscular function. Twenty-one patients had a TOF ratio of less than 0.70 and seven patients a TOF ratio of less than 0.60. Bedside tests of neuromuscular function did not reliably detect this defect in neuromuscular transmission. It is concluded that a relatively large number of patients have a defect in neuromuscular transmission on their arrival in the recovery room, and suggested that this reflects the inadequacy of clinical methods used for the administration and antagonism of competitive neuromuscular blocking agents at this institution.

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Comparison of the TOFscan and the TOF-Watch SX during Recovery of Neuromuscular Function

Anesthesiology ◽

10.1097/aln.0000000000002400 ◽

2018 ◽

Vol 129 (5) ◽

pp. 880-888 ◽

Cited By ~ 14

Author(s):

Glenn S. Murphy ◽

Joseph W. Szokol ◽

Michael J. Avram ◽

Steven B. Greenberg ◽

Torin D. Shear ◽

...

Keyword(s):

Neuromuscular Blockade ◽

Spontaneous Recovery ◽

Three Dimensional ◽

Tracheal Extubation ◽

Neuromuscular Function ◽

Neuromuscular Monitoring ◽

Limits Of Agreement ◽

Train Of Four ◽

Good Agreement

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Quantitative neuromuscular monitoring is required to ensure neuromuscular function has recovered completely at the time of tracheal extubation. The TOFscan (Drager Technologies, Canada) is a new three-dimensional acceleromyography device that measures movement of the thumb in multiple planes. The aim of this observational investigation was to assess the agreement between nonnormalized and normalized train-of-four values obtained with the TOF-Watch SX (Organon, Ireland) and those obtained with the TOFscan during recovery from neuromuscular blockade. Methods Twenty-five patients were administered rocuronium, and spontaneous recovery of neuromuscular blockade was allowed to occur. The TOFscan and TOF-Watch SX devices were applied to opposite arms. A preload was applied to the TOF-Watch SX, and calibration was performed before rocuronium administration. Both devices were activated, and train-of-four values were obtained every 15 s. Modified Bland–Altman analyses were conducted to compare train-of-four ratios measured with the TOFscan to those measured with the TOF-Watch SX (when train-of-four thresholds of 0.2 to 1.0 were achieved). Results Bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at nonnormalized train-of-four ratios between 0.2 and 1.0 were 0.021 and −0.100 to 0.141, respectively. When train-of-four measures with the TOF-Watch SX were normalized, bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at ratios between 0.2 and 1.0 were 0.015 and −0.097 to 0.126, respectively. Conclusions Good agreement between the TOF-Watch SX with calibration and preload application and the uncalibrated TOFscan was observed throughout all stages of neuromuscular recovery.

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Block of postjunctional muscle-type acetylcholine receptors in vivo causes train-of-four fade in mice

British Journal of Anaesthesia ◽

10.1093/bja/aev037 ◽

2015 ◽

Vol 115 (1) ◽

pp. 122-127 ◽

Cited By ~ 2

Author(s):

M. Nagashima ◽

T. Sasakawa ◽

S.J. Schaller ◽

J.A.J. Martyn

Keyword(s):

Acetylcholine Receptors ◽

Muscle Type ◽

Train Of Four

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Glial cell-derived neurotrophic factor alleviates sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nicotinic acetylcholine receptors in an experimental rat model of neuromyopathy

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2018.01.020 ◽

2018 ◽

Vol 496 (2) ◽

pp. 260-266 ◽

Cited By ~ 4

Author(s):

Xin Wang ◽

Su Min ◽

Fei Xie ◽

Jun Yang ◽

Liang Li ◽

...

Keyword(s):

Glial Cell ◽

Rat Model ◽

Nicotinic Acetylcholine Receptors ◽

Neurotrophic Factor ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine ◽

Neuromuscular Dysfunction ◽

Α7 Nicotinic Acetylcholine Receptors ◽

Experimental Rat Model

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Relationship of the Train-of-four Fade Ratio to Clinical Signs and Symptoms of Residual Paralysis in Awake Volunteers

Anesthesiology ◽

10.1097/00000542-199704000-00005 ◽

1997 ◽

Vol 86 (4) ◽

pp. 765-771 ◽

Cited By ~ 242

Author(s):

Aaron F. Kopman ◽

Pamela S. Yee ◽

George G. Neuman

Keyword(s):

Grip Strength ◽

Subjective Experience ◽

Moving Objects ◽

Neuromuscular Block ◽

Clinical Signs ◽

Signs And Symptoms ◽

Neuromuscular Function ◽

Tongue Depressor ◽

A Value ◽

Train Of Four

Background Recovery of the train-of-four (TOF) ratio to a value > 0.70 is synonymous with adequate return of neuromuscular function, but there is little information available concerning the subjective experience that accompanies residual neuromuscular block wherein the TOF ratio is in the range of 0.70 to 0.90. Methods Ten American Society of Anesthesiologists' (ASA) physical status 1 volunteers were studied. Control measurements including grip strength in kilograms and ability to perform a 5-s head- and leg-lift. In addition, a standard wooden tongue depressor was placed between each subject's incisor teeth, and he or she was told not to let the investigator remove it. All subjects were easily able to retain the device despite vigorous attempts to dislodge it. Neuromuscular function was monitored with a Datex (Datex Medical Instrumentation, Inc., Tewksbury, MA) 221 electromyographic (EMG) monitor. TOF stimulation was given every 20 s, and the measured TOF fade ratio was continuously recorded. A 5 mg/kg bolus of mivacurium was then administered, and an infusion at 2 mg.kg-1.min-1 was begun. The infusion was continued until the TOF ratio decreased to < 0.70 and was adjusted to keep it in the range of 0.65 to 0.75. Signs and symptoms of weakness were recorded when the TOF ratio had been stable +/-0.03 for at least 10 min during an interval when there were no adjustments in the infusion. All tests noted previously were repeated at this time. The TOF ratio was then allowed to recover to 0.85-0.90. When stable at this level, all tests were repeated, and the infusion was discontinued. TOF measurements were continued until a ratio of 1.0 was attained and until a final set of observations was recorded. Results The TOF ratio in all subjects was reduced to < 0.70. No volunteers required intervention to maintain a patient airway, and the hemoglobin oxygen saturation while breathing air was > or = 96% at all times. TOF ratios < or = 0.90 were accompanied by diplopia and difficulty in tracking moving objects in all subjects. The ability to strongly oppose the incisor teeth did not return until the TOF ratio (on average) exceeded 0.85. A sustained 5-s head-lift was not achieved until the TOF ratio averaged 0.60 (range, 0.45-0.75). At a TOF ratio of 0.70, grip strength averaged 59% of control (range, 50-75%). With certain exceptions (vision, ability to clench the teeth tightly), there was wide variation in symptomatology between patients for any given TOF ratio. It is impossible to give reliable TOF break-points at which symptoms and signs will be present or absent. Conclusions All subjects had significant signs and symptoms of residual block at a TOF ratio of 0.70; none considered themselves remotely "street ready" at this time. The authors believe that satisfactory recovery of neuromuscular function after mivacurium-induced neuromuscular block requires return of the TOF ratio to a value > 0.90 and ideally to unity.

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