Effect of Thermal Injury on the Pharmacokinetics and Pharmacodynamics of Atracurium in Humans

Marathe, Punit; Dwersteg, Jochen F.; Pavlin, Edward G.; Haschke, Richard H.; Heimbach, David M.; Slattery, John T.

doi:10.1097/00000542-198905000-00007

Cited by 62 publications

(37 citation statements)

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“…As sepsis (501,502,508,711) and nonseptic critical illness, i.e., thermal injury and burns (180,454,462,463), have been reported to attenuate the action of nondepolarizing blocking agents, such as d-tubocurarine or rocuronium, a series of studies were performed to determine the underlying mechanisms of this rather unexpected facilitation of neuromuscular transmission in animal models of experimental sepsis, with sepsis as the only confounding condition inducing muscle weakness. Direct exposure of frog sartorius muscle to Escherichia coli endotoxin (10 g/ml) resulted in elevations of miniature-endplate potential (MEPP) frequencies without changing MEPP amplitudes.…”

Section: B Neuromuscular Transmission In Sepsis and Systemic Inflammmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Section: B Neuromuscular Transmission In Sepsis and Systemic Inflammmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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“…(Martyn et al 1980) and atracurium (Marathe et al 1989). An Five received a 30 % body surface area scald under halothane anaesthesia, and five were sham-operated and pair-fed with the scalded rats.…”

Section: University Of Newcastle Upon Tyne Newcastle Upon Tynementioning

confidence: 99%

Cellular Neurophysiology

1996

The Journal of Physiology

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LE1 9HNRecent evidence suggests that principal neurones of the MNTB (medial nucleus of the trapezoid body) predominantly express GluRDo subunits (Geiger et al. 1995). Such Ca2+-permeable AMPA receptors exhibit rectification through a voltage-dependent block by internal polyamines (Kamboj et al. 1995). Previous reports of spermine-induced rectification of both native and cloned AMPA receptors have used agonist application. Here we set out to determine if intracellular spermine can induce rectification of a synaptic current in MNTB neurones.Transverse slices (200 ,um) of the brainstem were prepared from Lister Hooded rats (8-12 days), killed by decapitation. Whole-cell patch clamp recordings from MNTB neurones were made at 25°C with pipettes containing (mM): 130 CsCl, 10 Hepes, 5 EGTA and 1 MgCl2. Standard bicarbonatebuffered artificial cerebrospinal fluid with 1 mm Ca2+, 2 mM Mg2, 20-50 UM DL-AP5, 4-8 /M MK801, 5/M (5,7)-dichlorokynurenic acid and 2 /SM strychnine was continuously perfused over the slice. The presynaptic axons were stimulated with a bipolar electrode to evoke excitatory postsynaptic currents (EPSCs) in voltage clamped MNTB neurones.AMPA receptor-mediated EPSCs in MNTB neurones decay with a time course that can be described by the sum of two exponentials and have previously been found to have a linear current-voltage relationship. We have found that inclusion of spermine (100-500 uM) in the patch pipette resulted in rectification of the peak of the EPSC. Examination of the more slowly decaying component of the AMPA receptor-mediated EPSC suggests that it does not rectify. The rectification index at +60/-60 mV for the peak was 0 37 + 0-10 and for the slow component was 1-03 ± 0 33 (mean + S.D., n = 5 for 200 jM spermine). Studies on expressed channels have shown that argiotoxin 636 will block GluRDo subunits (Herlitze et al. 1993 We have identified some glutamate receptor subtypes expressed by magnocellular cholinergic neurones in dissociated culture. Dissociated cultures were prepared from postnatal day 11-14 Sprague-Dawley rats (killed by decapitated) using the method of Allen et al. (1993). After 5-30 days in culture, magnocellular neurones were voltageclamped using the whole-cell variant of the patch-clamp technique.Localized pressure application of 100 /M N-methyl-D-aspartate (NMDA) elicited an inward current that was sensitive to 1 mM Mg2+ and to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5, 30 /M, n = 3). The non-NMDA receptor agonists a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, 30 uM) and kainate (1 mM) elicited inward currents that were antagonized by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10-30 /M, n = 5 for each agonist).When applied by pressure ejection from a micropipette, the response to AMPA, but not to kainate, displayed strong desensitization. Bath application of AMPA and of kainate produced large steady-state currents with EC50 ± S.E.M. of 2 7 + 0A4 (n = 5) and 138 + 25 #M (n = 10), respectively. Cycloth...

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“…Pharmaco dynamic explanations as the principal mechanism for resistance to the effects of nondepolarising muscle relaxants are documented by the need to achieve higher drug concentrations to produce given degrees of twitch suppression in burn injured patients compared to non-burn injured patients. [1] We present research findings of a problem we encountered due to accidental subcutaneous deposition of vecuronium bromide in a burns patient.…”

Section: Introductionmentioning

confidence: 99%