title: Deep sedation and mechanical ventilation without paralysis for 3 weeks in normal beagles: exaggerated resistance to metocurine in gastrocnemius muscle.
abstract: BACKGROUND
  Patients in the intensive care unit may have muscle weakness in the recovery phase, and disuse atrophy may play a role in this weakness. To assess this problem, the authors measured changes in the potency of the nondepolarizing neuromuscular blocking agent metocurine in a canine model that involved 3 weeks of intensive care, nonparalyzing anesthesia with pentobarbital, and positive-pressure ventilation.
  
  
  METHODS
  Six dogs were anesthetized with pentobarbital to a sufficient depth that spontaneous and reflex muscle movements were absent. Their tracheas were intubated, their lungs were mechanically ventilated, and they received round-the-clock intensive medical and nursing care for 3 weeks. Transduced gastrocnemius muscle responses to metocurine were determined weekly. A 4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater concentrations on progressive weeks) yielded more than 80% paralysis. Serial metocurine plasma concentrations during the onset of the block and recovery provided data to determine pharmacokinetics using NONMEM. Metocurine plasma concentrations and the degree of paralysis were used to model the effect compartment equilibration constant, and the Hill equation was used to yield the slope factor and potency within the effect compartment.
  
  
  RESULTS
  The metocurine effect compartment concentration associated with a 50% diminution of twitch height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was significantly different from 257+/-34 ng/ml, the value on day 0. There were no pharmacokinetic differences.
  
  
  CONCLUSIONS
  The absence of muscle tone and reflex responsiveness for 3 weeks was associated with exaggerated resistance to the neuromuscular blocker metocurine.
authors.affiliation: Department of Anesthesiology, School of Medicine, University of California, Davis 95616, USA. gagronert@ucdavis.edu
authors.forename: G A
authors.initials: GA
authors.lastname: Gronert
authors.forename: D L
authors.initials: DL
authors.lastname: Fung
authors.forename: S C
authors.initials: SC
authors.lastname: Haskins
authors.forename: E P
authors.initials: EP
authors.lastname: Steffey
mesh_terms: D000818:Animals; D004285:Dogs; D004351:Drug Resistance; D007362:Intensive Care Units; D018482:Muscle, Skeletal / Q000187:drug effects*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D012121:Respiration, Artificial; D013997:Time Factors; D014403:Tubocurarine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D003473:Neuromuscular Nondepolarizing Agents; C032943:metocurine; D014403:Tubocurarine