title: Dexamethasone produces dose-dependent inhibition of sugammadex reversal in in vitro innervated primary human muscle cells.
abstract: BACKGROUND
  Corticosteroids are frequently used during anesthesia to provide substitution therapy in patients with adrenal insufficiency, as a first-line treatment of several life-threatening conditions, to prevent postoperative nausea and vomiting, and as a component of multimodal analgesia. For these last 2 indications, dexamethasone is most frequently used. Due to the structural resemblance between aminosteroid muscle relaxants and dexamethasone, concerns have been raised about possible corticosteroid inhibition in the reversal of neuromuscular block by sugammadex. We thus investigated the influence of dexamethasone on sugammadex reversal of rocuronium-induced neuromuscular block, which could be relevant in certain clinical situations.
  
  
  METHODS
  The unique co-culture model of human muscle cells innervated in vitro with rat embryonic spinal cord explants to form functional neuromuscular junctions was first used to explore the effects of 4 and 10 μM rocuronium on muscle contractions, as quantitatively evaluated by counting contraction units in contraction-positive explant co-cultures. Next, equimolar and 3-fold equimolar sugammadex was used to investigate the recovery of contractions from 4 and 10 μM rocuronium block. Finally, 1, 100, and 10 μM dexamethasone (normal, elevated, and high clinical levels) were used to evaluate any effects on the reversal of rocuronium-induced neuromuscular block by sugammadex.
  
  
  RESULTS
  Seventy-eight explant co-cultures from 3 time-independent experiments were included, where the number of contractions increased to 10 days of co-culturing. Rocuronium showed a time-dependent effect on depth of neuromuscular block (4 μM rocuronium: baseline, 10, 20 minutes administration; P < 0.0001), while the dose-dependent effect was close to nominal statistical significance (4, 10 μM; P = 0.080). This was reversed by equimolar concentrations of sugammadex, with further and virtually complete recovery of contractions with 3-fold equimolar sugammadex (P < 0.0001). Dexamethasone diminished 10 μM sugammadex-induced recovery of contractions from rocuronium-induced neuromuscular block in a dose-dependent manner (P = 0.026) with a higher sugammadex concentration (30 μM) being close to statistically significantly improving recovery (P = 0.065). The highest concentration of dexamethasone decreased the recovery of contractions by equimolar sugammadex by 26%; this effect was more pronounced when 3-fold equimolar (30 μM) sugammadex was used for reversal (48%).
  
  
  CONCLUSIONS
  This is the first report in which the effects of rocuronium and sugammadex interactions with dexamethasone have been studied in a highly accessible in vitro experimental model of functionally innervated human muscle cells. Sugammadex reverses rocuronium-induced neuromuscular block; however, concomitant addition of high dexamethasone concentrations diminishes the efficiency of sugammadex. Further studies are required to determine the clinical relevance of these interactions.
authors.affiliation: From the *Department of Anesthesiology and Intensive Therapy, University Medical Centre Ljubljana; and †Institute for Biostatistics and Medical Informatics and ‡Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Rezonja
authors.forename: Maja
authors.initials: M
authors.lastname: Sostaric
authors.forename: Gaj
authors.initials: G
authors.lastname: Vidmar
authors.forename: Tomaz
authors.initials: T
authors.lastname: Mars
mesh_terms: D000732:Androstanols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000779:Anesthetics, Local / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008858:Microscopy, Phase-Contrast; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D061251:Primary Cell Culture; D051381:Rats; D000077123:Rocuronium; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D000077122:Sugammadex; D047408:gamma-Cyclodextrins / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000732:Androstanols; D000779:Anesthetics, Local; D000932:Antiemetics; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D003907:Dexamethasone; D000077123:Rocuronium