New Neuromuscular Blocking Agents: Basic and Applied Aspects

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However, the slope at IC50 was significantly steeper in Dexa7 group. This difference in the Dexa7 group may have two possible explanations. One, difference in the age of the experimental rats in Dexa7 group; rats in this group were one week older than those in the control and Dexa1 groups, and 4 days older than Dexa3 group. The 7-week-old rats were treated for 2 weeks; hence, the diaphragms harvested from 9—week-old rats were used in this study. The rat age of 9—10 weeks is in the period from peri-adolescence 7 weeks to young adulthood 10 weeks.

For a rat in adolescence and young adulthood, one day is approximately equivalent to Second possible explanation is the change in sensitivity enhancement after dexamethasone withdrawal by an unknown mechanism. This kind of enhanced response to acetylcholine after discontinuing corticosteroid treatment with was reported by a previous study, though in a different animal model dog and in a different target organ airway The mechanism of this enhancement has not been discovered yet but may be due to an abrupt withdrawal of corticosteroid treatment. Since the presence of nAChRs has been reported in the airway epithelium 27 , 28 , a similar phenomenon could have occurred at the nAChRs in the neuromuscular junction.

To our knowledge, the pharmacodynamic change after withdrawal from long-term dexamethasone treatment has never been explored previously; therefore, further study may be needed to identify this phenomenon. Only a few in vitro or ex vivo studies exist regarding the interaction of rocuronium and sugammadex 29 , 30 , 31 , 32 , 33 ; thus, there is no consensus on the recommended dose of sugammadex to be used in an ex vivo study. Previously, we have used an equimolar dose of sugammadex and rocuronium 30 , 33 ; this was based on the mechanism of action of sugammadex which encapsulates the free rocuronium molecules in 1: 1 molecular ratio However, in a clinical setting, a 0.

Furthermore, considering the diminished plasma concentration of rocuronium until the administration of sugammadex, the ratio would be increased when the two drugs are binding. Therefore, an equimolar dose of sugammadex was considered to be insufficient to reflect routine clinical practice; therefore, twice the equimolar dose of sugammadex was planned for use in this study. Time to recovery of a TOF ratio of at least 0. T1 recovery in the Dexa7 group was faster than that in the control and Dexa1 groups. These results were inconsistent with our hypothesis that the dexamethasone-treated group especially Dexa1 group would show faster reversal by sugammadex due to up-regulation of immature nAChRs as compared to the control group.

In previous clinical experiments, a shorter duration of neuromuscular blocking was observed in the corticosteroid treated group when recovering spontaneously 10 , This means that the larger the resistance, the faster the recovery smaller recovery profiles. In this regard, it was expected that recovery profiles would be inversely negatively correlated with IC50 representing resistance. However, in our study the correlation of IC50 with recovery profiles was positive, as was the correlation of IC50 and the total molar concentration of administered drugs.

Therefore, it is speculated that the time to sugammadex-mediated recovery from neuromuscular blockade may be correlated with the binding capacity of the NMBAs and sugammadex instead of the resistance property of receptors. This could be explained by the fact that the reversal mechanism of sugammadex is not associated with the neuromuscular junction but with the chemical-encapsulating of the amino steroidal NMBAs with high affinity When the neuromuscular block is reversed by sugammadex unlike with spontaneous recovery or by cholinesterase inhibitors , the time to recovery from the neuromuscular block seems to be determined by the binding of the NMBAs and sugammadex rather than the up-or down-regulated nAChRs.

Nondepolarizing NMBAs are frequently used for anaesthetic management for patients who have used corticosteroids for a long period. More nondepolarizing NMBAs are required for these patients to achieve same degree of neuromuscular blockade, though the reversal of neuromuscular blockade by sugammadex may not be influenced. There were several limitations to this study. First, only an ex vivo setting was employed, which means that only a pharmacodynamic model but not a pharmacokinetic model was evaluated.


Therefore, clinical applications from our result may be limited. Nevertheless, the result from our study will provide a preliminary theoretical basis for the rational application of sugammadex in patients with protracted steroid use. Second, only young rats around 8 weeks were used in this study. Steroid use is more frequent in the elderly; therefore, a similar study involving older rats could be more relevant to clinical steroid use.

Third, only one kind of control group sham to Dexa1 group was assigned. Assigning sham groups equivalent to each experimental group could have provided more information, especially regarding the unexpected difference in the Dexa7 group. In conclusion, protracted exposure to dexamethasone causes resistance of the rat diaphragm to rocuronium as demonstrated by a right shift in dose-response curves, and the pharmacodynamic change resulting from dexamethasone treatment was restored to near normal by 3 days after treatment cessation in 7—8-week-old rats.


The protracted exposure to dexamethasone seemed to have no effect on sugammadex reversal in the rat diaphragm, as the reversal period by sugammadex seemed to be correlated with the binding capacity of the NMBAs and sugammadex but not with the resistance property. Flow diagram of the experiment is shown in Fig.

The control group received the same amount of saline 0. The rats in the dexamethasone group were assigned to three subgroups, Dexa1, Dexa3, and Dexa7, based on the time of day for dexamethasone treatment withdrawal. For each experimental group, 18 rats were assigned. The left hemidiaphragm with attached phrenic nerve, central tendon, and intact rib cage were rapidly removed. The diaphragms with phrenic nerve attached were excised en bloc , and the isolated phrenic nerve-hemidiaphragm was prepared.

The peripheral portion of the phrenic nerve was positioned to bipolar platinum electrodes and the central tendinous portion was suspended with a force displacement transducer Grass FT03, Grass Instrument Co. The potency of rocuronium was tested using the cumulative dose-response method. Dose-response curves were constructed and the IC50 values were measured.

All drugs were applied using an air displacement micropipette. Supplementary Fig. Immunostaining was performed using the streptavidin—peroxidase method. A sodium citrate buffer 0. The sections were routinely counterstained with haematoxylin. The average optical density was analysed in 5 randomly selected microscopic fields in six sections from each group at a fold magnification with an optical microscope BX51TF01; Olympus Corporation, Tokyo, Japan.

Image analysis measurements were performed by a blind observer. The colour threshold tool of ImageJ software ver. The competition analysis data IC50, slope at IC50 were determined from a four-variable logistic sigmoidal dose-response model fitted to the dose-response curves using Prism 6 Graph-Pad Software, Inc. The IC50 ratio was defined as the IC50 of the dose-response curve in the dexamethasone group divided by that in the control group.

Differences in continuous variables among the groups were analysed using analysis of variance followed by the Bonferroni method for multiple pairwise comparisons. All data are available upon request, please contact Seok Kyeong Oh email address:nanprayboy korea. Coutinho, A. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.

Buchman, A. Side effects of corticosteroid therapy. Odedra, B. Time course of the effect of catabolic doses of corticosterone on protein turnover in rat skeletal muscle and liver. Dardevet, D. Glucocorticoid-induced insulin resistance of protein synthesis is independent of the rapamycin-sensitive pathways in rat skeletal muscle. Rieu, I. Glucocorticoid excess induces a prolonged leucine resistance on muscle protein synthesis in old rats. Chen, D. Different magnitude of resistance to non-depolarizing muscle relaxants in dexamethasone-treated rat diaphragm associated with altered acetylcholine receptor expression.

Dexamethasoneinduced hyposensitivity to rocuronium in rat diaphragm associated with musclefiber transformation. Arts, W. Long-term effect of glucocorticosteroids on neuromuscular blocking in mice. Psychiatry 40 , — Leeuwin, R. Effects of corticosteroids on neuromuscular blocking actions of d-tubocurarine. Attenuation of a rocuronium-induced neuromuscular block in patients receiving prednisolone. Acta Anaesthesiol. Influence of a continuous prednisolone medication on the time course of neuromuscular block of atracurium in patients with chronic inflammatory bowel disease.

Parr, S. Betamethasone-induced resistance to vecuronium: a potential problem in neurosurgery?

Neuromuscular block.

Anaesth Intensive Care 19 , — Kaplan, I. Steroids induce acetylcholine receptors on cultured human muscle: implications for myasthenia gravis. USA 87 , — Braun, S. Long-term treatment with glucocorticoids increases synthesis and stability of junctional acetylcholine receptors on innervated cultured human muscle. Maestrone, E. Functional aspects of dexamethasone upregulated nicotinic acetylcholine receptors in C2C12 myotubes. Martyn, J. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms.

Anesthesiology , — Lee, S. Immobilization with atrophy induces de novo expression of neuronal nicotinic alpha7 acetylcholine receptors in muscle contributing to neurotransmission. Albuquerque, E. Mammalian nicotinic acetylcholine receptors: from structure to function. Fischer, U. Expression of functional alpha7 nicotinic acetylcholine receptor during mammalian muscle development and denervation. Tsuneki, H. Mouse muscle denervation increases expression of an alpha7 nicotinic receptor with unusual pharmacology.

Glucocorticoid effects on insulin- and IGF-I-regulated muscle protein metabolism during aging. Sine, S. End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. Liu, L. Pharmacodynamic changes with vecuronium in sepsis are associated with expression of alpha7- and gamma-nicotinic acetylcholine receptor in an experimental rat model of neuromyopathy.

Historic and scientific background

Huang, Y. Differences in pharmacodynamic responses to rocuronium in normal or injured orbicularis oris are associated with expression of acetylcholine receptor subunits. Sengupta, P. Lindeman, K. Corticosteroid withdrawal restores responses to calcium chelators and enhances cholinergic responsiveness. Sekhon, H. Because of their effects on diaphragmatic tone, NMBAs have been suggested as a method for decreasing ventilator asynchrony and pulmonary pressures.

Whether other agents would have an effect on these outcomes has not been addressed in the literature. Therapeutic Hypothermia: NMBAs have been proposed as part of many treatment algorithms for patients undergoing therapeutic hypothermia post cardiac arrest. Although this has not been studied in critical care, these physiologic changes have been demonstrated in surgical patients undergoing hypothermia during cardiopulmonary bypass.

Another retrospective study addressed the selection of NMBAs in patients undergoing therapeutic hypothermia post cardiac arrest. Owing to the retrospective nature and small sample size of this study, it is difficult to assess the overall power to detect any difference offered by vecuronium similar to what was observed with cisatracurium. It is possible that confounding variables may have a stronger influence than the selected neuroblockade agent on overall outcomes. Elevated Intracranial Pressure ICP : ICP is routinely managed by deep sedation and analgesia, reducing oxygen consumption and cerebral metabolism while controlling pain, motion, and ventilator asynchrony.

ICU stay was an average of 3 days longer, more patients developed pneumonia, and there was a trend toward increased risk of sepsis in extended-NMBA patients. Additionally, although there were more deaths in the non-NMBA group, the NMBA group had a greater incidence of vegetative or severely disabled survivors.

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Historically, this has occurred through the use of neostigmine postoperatively. Because nondepolarizing NMBAs are competitive antagonists of the nicotinic receptor, neostigmine increases the competitive pressure of acetylcholine at the site of drug action. Although neostigmine is effective at improving recovery times post NMBA administration, it can be unreliable because of its indirect mechanism of action.

Failure to fully reverse NMBAs postoperatively has been shown to increase the rates of residual weakness and dysphagia and the risk of aspiration. In December , the FDA approved sugammadex Bridion , a novel direct-reversal agent for rocuronium and vecuronium. Classified as a gamma-cyclodextrin, sugammadex creates a drug-drug complex with free NMBA, thereby reducing the available agent concentrations. These pharmacokinetic effects on NMBA concentration are both rapid and complete. However, because of their size, cisatracurium, atracurium, and succinylcholine are unaffected by sugammadex.

There are no trials providing specific guidance on the management of unintentional awareness during neuromuscular blockade. Regardless, it is considered standard practice to establish and maintain appropriate levels of analgesia and deep sedation prior to and during neuromuscular blockade. The monitoring of patients on NMBAs is imperative, but methods are often complicated by clinical course, coadministration of sedatives and analgesics, and additional therapeutic modalities e. PNS is commonly regarded as the monitoring method of choice, but it has limitations.

Additional monitoring parameters include spontaneous breathing and trends in vital signs. PNS is recommended independently for patients on a continuous infusion of NMBAs and as an adjunct in other clinical situations. In a paralyzed patient, the twitch response should be observed with the first stimulus, but this should diminish because of the blockade of motor neurons.

Although there are significant benefits to the use of NMBAs in particular situations, there are also short-term and long-term complications. In the acute setting, the use of NMBAs can lead to increased ICU stay, prolonged mechanical ventilation, venous thromboembolism, skin tearing and ulcerations, infection, corneal damage, and anaphylaxis.

Long-term administration can lead to immobility or increased recovery time because of impaired neuromuscular transmission and muscular weakness. The pharmacist can play a highly important role in the regulation and use of NMBAs across a wide range of clinical-practice sites. By understanding the mechanism of action, therapeutic indications, supporting literature, and clinical side effects of this high-alert class of medications, the pharmacist can have an invaluable effect on patient care and patient safety.

Evaluation of residual neuromuscular block and late recurarization in the post-anesthetic care unit

Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults. Ann Pharmacother. Succinylcholine: a new approach to muscular relaxation in anesthesiology. N Engl J Med. Naguib M, Lien CA. Pharmacology of muscle relaxants and their antagonists. Philadelphia, PA: Churchill Livingstone; Anectine succinylcholine package insert.

Rocuronium package insert. Nimbex cisatracurium package insert. Airway management in the emergency department; a one-year study of tracheal intubations. Ann Emerg Med. Rapid-sequence intubation at an emergency medicine residency: success rate and adverse events during a two-year period. Acad Emerg Med. Complications of emergency intubation with and without paralysis. Am J Emerg Med. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. Greenberg SB, Vender J.

The use of neuromuscular blocking agents in the ICU: where are we now? Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome.

Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome.

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Crit Care. Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: a systematic review. Comparison of meperidine and pancuronium for the treatment of shivering after cardiac surgery. Can J Anaesth. Comparison of vecuronium and meperidine on the clinical and metabolic effects of shivering after hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth.